Sulfinylaminobenzamide and sulfonylaminobenzamide derivatives

Abstract

To provide a novel compound capable of uncoupling mitochondrial oxidative phosphorylation [Solution] Formula (I): The compounds of TIFF2022123114000275.tif2873 are provided, wherein the variables are as defined herein. The present disclosure relates to novel compounds capable of uncoupling mitochondrial oxidative phosphorylation. The present disclosure also relates to methods for preparing these compounds, pharmaceutical compositions containing such compounds, and methods of using these compounds or pharmaceutical compositions in therapeutic treatments.

Description

Technical Field

[0001] Field The present disclosure relates to novel compounds capable of uncoupling mitochondrial oxidative phosphorylation. The present disclosure also relates to methods for preparing these compounds, pharmaceutical compositions containing such compounds, and methods of using these compounds or pharmaceutical compositions in therapeutic treatment.

Background Art

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

[0003] Mitochondrial dysfunction has been linked 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), among other conditions.

[0004] Non-alcoholic fatty liver disease (NAFLD), a major liver disorder, has recently been 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). Untreated, NAFLD often progresses to NASH and can lead to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), or any or all of these three.

[0005] One treatment proposed to treat NAFLD, NASH, and other diseases mediated at least in part by mitochondrial dysfunction is the use of mitochondrial uncoupling agents. Using a protonophore (i.e., a proton translocator) is one method proposed to "uncouple" the energy transport mechanism of mitochondria. This uncoupling results in the processing (breakdown) of energy-rich compounds such as lipids and fatty acids. Additionally, mitochondrial uncoupling is thought to reduce the generation of reactive oxygen species (ROS). ROS are responsible for DNA damage and protein changes in vivo and can thus cause cell dysfunction or programmed cell death (apoptosis). Several mitochondrial uncoupling compounds have been proposed (see, for example, 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 mitochondrially mediated diseases or conditions without significantly increasing body temperature.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Means for Solving the Problems

[0008] Gist of the Invention In one embodiment of the present disclosure, Formula I:

Chemical Formula

[0009] In another embodiment, R 6is selected from the group consisting of a 5- to 10-membered carbocyclic ring, a 6- to 12-membered heterocyclic ring, and an 8- to 10-membered tricyclic ring, wherein the 5- to 10-membered carbocyclic ring, the 8- to 10-membered tricyclic ring, or the 6- to 12-membered heterocyclic ring may be fused, bridged, or spiro, and the 5- to 10-membered carbocyclic ring, the 6- to 12-membered heterocyclic ring, and the 8- to 10-membered tricyclic ring are substituted with one or more R 7 .

[0010] In another embodiment, R 6 is selected from the group consisting of a 5- to 10-membered carbocyclic ring, an 8- to 10-membered tricyclic ring, and a 6- to 12-membered heterocyclic ring, wherein the 5- to 10-membered carbocyclic ring, the 8- to 10-membered tricyclic ring, or the 6- to 12-membered heterocyclic ring is bridged, and the 5- to 10-membered carbocyclic ring, the 8- to 10-membered tricyclic ring, and the 6- to 12-membered heterocyclic ring are substituted with one or more R 7 .

[0011] In another embodiment, R 6 is selected from the group consisting of a 5- to 10-membered carbocyclic ring and a 6- to 12-membered heterocyclic ring, wherein the 5- to 10-membered carbocyclic ring or the 6- to 12-membered heterocyclic ring is bridged, and the 5- to 10-membered carbocyclic ring and the 6- to 12-membered heterocyclic ring are substituted with one R 7 .

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

[0013] In some embodiments, R 1 is selected from the group consisting of C 1~6 alkyl, -NR 13 R 13 , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 cycloalkyl, and 4- to 12-membered heterocyclyl, wherein C 1~6Alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Cycloalkyl, and each of 4- to 12-membered heterocyclyl is further substituted with one or more R 11 groups.

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

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

[0016] In some embodiments, R 4 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 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 , -NO2, where C 1~6 alkyl, C 1~6Alkoxy, C 1~6 Hydroxyalkyl, and C 1~6 Heteroalkyl are further substituted with one or more R 9 groups.

[0017] In some embodiments, R 4 is selected from the group consisting of -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 alkoxy, and wherein this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 14 is selected from the group consisting of C 1~6 alkyl, C 3~6 cycloalkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and wherein this C 1~6 alkyl, C 3~6 cycloalkyl, C 1~6 hydroxyalkyl, and C 1~6 heteroalkyl are optionally substituted with one or more R 16 groups, and R 16 is independently selected from halo, -CN, -OH.

[0018] In some embodiments, R 4 is selected from the group consisting of -H, -F, -Cl, -OH, -CN, -SR 14 , -SF5, C 1~6 alkyl, and C 1~6 alkoxy, and wherein this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 14 is selected from the group consisting of C 1~3 haloalkyl.

[0019] In some embodiments, R 3 is selected from the group consisting of -H, halo, -OH, -CN, C 1~6 alkyl, 6- to 10-membered aryl, 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, -S(O) 0~2 R 14 , -NO2, and -SF5, where this C 1~6 alkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 3~12 cycloalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 heteroalkyl are optionally further substituted with one or more R 9 groups.

[0020] In some embodiments, R 3 is selected from the group consisting of -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 , and -SF5, where this C 1~6 alkyl, C 1~6 alkoxy, C 3~12 cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R 16 groups, and R 14 is C 1~3 haloalkyl.

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

[0022] In another embodiment of the present disclosure, Formula II:

Chemical formula

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

[0024] In some embodiments, R 21 is selected from the group consisting of C 1~6 alkyl, -NR 33 R 33 , 6 - to 10 - membered aryl, 5 - to 10 - membered heteroaryl, C 3~12 cycloalkyl, and 4 - to 12 - membered heterocyclyl, where each of C 1~6 alkyl, 6 - to 10 - membered aryl, 5 - to 10 - membered heteroaryl, C 3~12 cycloalkyl, and 4 - to 12 - membered heterocyclyl is further substituted with one or more R 31 groups.

[0025] In some embodiments, R 22 is -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 24is -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 is selected from the group consisting of alkoxy, and wherein this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 34 is C 1~6 alkyl, C 3~6 cycloalkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, wherein this C 1~6 alkyl, C 3~6 cycloalkyl, C 1~6 hydroxyalkyl, and C 1~6 heteroalkyl is optionally substituted with one or more R 36 groups, and R 36 is independently selected from halo, -CN and -OH.

[0029] In some embodiments, R 24 is -H, -F, -Cl, -OH, -CN, -SR 34 , -SF5, C 1~6 alkyl, and C 1~6 alkoxy, and wherein this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 34 is C 1~3 selected from the group consisting of haloalkyl.

[0030] In some embodiments, R 23 is -H, halo, -OH, -CN, C 1~6 alkyl, C 1~6 alkoxy, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, 3- to 12-membered cycloalkyl, C1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, -S(O) 0~2 R 34 , -NO2 and -SF5, and this C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, and 3- to 12-membered cycloalkyl are optionally further substituted with one or more R 36 groups.

[0031] In some embodiments, R 23 is selected from the group consisting of -H, -F, -Cl, -OH, -CN, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, -SR 34 , and -SF5, and this C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 heteroalkyl are further substituted with one or more R 36 groups, and R 34 is C 1~3 haloalkyl.

[0032] In another embodiment of the present disclosure, Formula III:

Chemical formula

[0033] In some embodiments, R 47 is -H, halo, -CN, -OH, 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, -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 aryl, 5 - to 10 - membered heteroaryl, and 4 - to 12 - membered heterocyclyl; where this 4 - to 12 - membered heterocyclyl, 6 - to 10 - membered aryl, 5 - to 10 - membered heteroaryl, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6Each of heteroalkyl and 3- to 12-membered cycloalkyl is optionally substituted with one or more Rs. 55 and is optionally substituted with one or more Rs as needed.

[0034] In some embodiments, R 47 is selected from the group consisting of -H, halo, -CN, -OH, C 1~6 alkyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3- 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 , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl; wherein this 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 1~6 alkyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and each of 3- to 6-membered cycloalkyl is optionally substituted with one or more Rs. 56 and is optionally substituted with one or more Rs as needed.

[0035] In some embodiments, R 47 is selected from the group consisting of -H, halo, -CN, -OH, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6 heteroalkyl, and 6- to 10-membered aryl; wherein this 6- to 10-membered aryl, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, and C 1~6Each heteroalkyl is optionally substituted with one or more R 56 wherein R 56 is selected from halo, -CN, -NO2, -SF5, C 1~3 alkyl, C 1~3 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl; In some embodiments, Q is selected from the group consisting of -S(O)2-, -S(O)-, and -S(O)(NR 48 ).

[0036] In some embodiments, R 41 is selected from C 1~6 alkyl, -NR 53 R 53 , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 cycloalkyl, and 4- to 12-membered heterocyclyl, wherein each of C 1~6 alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 cycloalkyl, and 4- to 12-membered heterocyclyl is further optionally substituted with one or more R 51 groups.

[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 selected from the group consisting of, where 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, and 5 - to 10 - membered heteroaryl, each is optionally substituted with one or more R 49 groups.

[0038] In some embodiments, each R 49 is independently, -H, oxo, -OH, -CN, halo, C 1~3 alkyl, C 1~3 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3 - 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 、 -SF5, and -NO2 selected from the group consisting of, where C 1~3 alkyl, C 1~3Each of alkoxy and 3- to 6-membered cycloalkyl is optionally substituted with -CN, one or more halos, or C 1~6 heteroalkyl.

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

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

[0041] In some embodiments, R 44 is selected from the group consisting of -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 , -NO2, where C 1~6 alkyl, C 1~6Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl is further substituted with one or more R 49 groups.

[0042] In some embodiments, R 44 is selected from the group consisting of -H, -F, -Cl, -OH, -CN, -S(O) 0~2 R 54 , -NO2, -SF5, C 1~6 alkyl, and C 1~6 alkoxy, and wherein this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 54 is selected from the group consisting of C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, wherein this C 1~6 alkyl, C 1~6 hydroxyalkyl, and C 1~6 heteroalkyl is optionally substituted with one or more R 55 groups, and R 55 is independently selected from halo, -CN, -OH, oxo.

[0043] In some embodiments, R 44 is selected from the group consisting of -H, -F, -Cl, -OH, -CN, -SR 54 , -SF5, C 1~6 alkyl, and C 1~6 alkoxy, and wherein this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 54 is C 1~3 haloalkyl.

[0044] In some embodiments, R 43 is selected from the group consisting of -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 , and -NO2, and wherein 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, and 5- to 10-membered heteroaryl are further substituted with one or more R 49 groups.

[0045] In some embodiments, R 49 is -H, oxo, -OH, -CN, halo, C 1~3 alkyl, C 1~3 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3- 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 selected from the group consisting of, wherein C 1~3 alkyl, C 1~3 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and each of 3- to 6-membered cycloalkyl is optionally substituted with -CN or one or more halos.

[0046] In some embodiments, R 43 is -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 and selected from the group consisting of -NO2, wherein 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, and 5- to 10-membered heteroaryl are further substituted with one or more R 49 groups.

[0047] In some embodiments, R 49 is -H, oxo, -OH, -CN, halo, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6 heteroalkyl, 3- 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 selected from the group consisting of, wherein C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6 heteroalkyl, and each of 3 - to 6 - membered cycloalkyl is optionally substituted with -CN or one or more halos.

[0048] In another embodiment of the present disclosure, formula IV: [Chemical formula] A compound of or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof is provided, wherein in formula IV: Q is selected from the group consisting of -S(O)2-, -S(O)-, -S(O)(NH)-, -S(O)(NR 68 )-; R 61 is selected from the group consisting of C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, -NR 73 R 73 、 6 - to 10 - membered aryl, 5 - to 10 - membered heteroaryl, C 3~12 cycloalkyl, and 4 - to 12 - membered heterocyclyl, wherein each of 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 is optionally further substituted with one or more R 71 groups; R 71 is hydroxyl, oxo, halo, -CN, C 1~6 alkyl, C 2~6 alkenyl, C2~6 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 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 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-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl each is optionally substituted with one or more R 69 groups; Each R 69is 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-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 、-SF5, -NO2, and is selected from the group consisting of; where 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 are each optionally substituted with one or more R 76 groups; each R 73 is independently -H, C 1~6 alkyl, C 1~6 hydroxyalkyl, C1~6 heteroalkyl, C 3~6 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 are optionally substituted with one or more R 75 groups; each R 74 is independently, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, C 3~6 cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R 1~6 groups; 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 are optionally substituted with one or more R 75 groups; each R 75 is 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, wherein 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more R 76 groups; Each R 76 is 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 hydroxyalkyl, thioalkyl, thiohaloalkyl, thiocycloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3- to 6-membered cycloalkyl, -C(O)NH2 and -S(O)2NH2; R 62 is selected from the group consisting of -H, -CN, -F, -Cl, C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 heteroalkyl, C 1~3 alkoxy and C 1~3 haloalkoxy; R 63 and each of R 64 is independently -H, halo, -OH, -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, -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 and selected from the group consisting of -NO2, 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-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl may be further optionally substituted with one or more R 69 groups; where R 62 and R 63 or R 63 and R 64 may optionally combine together with the atoms to which they are attached 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 fused to the phenyl to which they are attached and each being optionally substituted with one or more R 69 groups; R 67 is -H, halo, -CN, -OH, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, 3- 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 aryl, 5- to 10-membered heteroaryl and 4- to 12-membered heterocyclyl; wherein each of this 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, tri-C 1~4 Alkylsilyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl, and each of 3- to 12-membered cycloalkyl is optionally substituted with one or more R 75 ; R 68 is, C 1~6 Alkyl, -C(O)R 74 , 3- 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 wherein C 1~6 alkyl, C 1~6 alkylcarbonyl, 3 - to 12 - membered cycloalkyl, C 1~6 heteroalkyl, 6 - to 10 - membered aryl, 5 - to 10 - membered heteroaryl, and 4 - to 12 - membered heterocyclyl each is optionally substituted with 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 optionally substituted 3 - to 6 - membered cycloalkyl, one or more R 76 optionally substituted 4 - to 12 - membered heterocyclyl, one or more R 76 optionally substituted 6 - to 10 - membered aryl, and one or more R 76 optionally substituted 5 - to 10 - membered heteroaryl;

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

[0050] In some embodiments, R 61 is selected from the group consisting of C 1~6 alkyl, -NR 73 R 73 、 6 - to 10 - membered aryl, 5 - to 10 - membered heteroaryl, C 3~12 cycloalkyl, and 4 - to 12 - membered heterocyclyl, wherein C 1~6Alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 Cycloalkyl, and each of 4- to 12-membered heterocyclyl is further substituted with one or more R 71 groups.

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

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

[0053] In some embodiments, R 64 is selected from the group consisting of -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 , -NO2, where C1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Heteroalkyl is further substituted with one or more R 69 groups.

[0054] In some embodiments, R 64 is selected from the group consisting of -H, -F, -Cl, -OH, -CN, -S(O) 0~2 R 74 , -SF5, -NO2, C 1~6 alkyl, and C 1~6 alkoxy, and wherein this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F. And R 74 is C 1~6 alkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and wherein this C 1~6 alkyl, C 1~6 hydroxyalkyl, and C 1~6 heteroalkyl are optionally substituted with one or more R 75 groups, and R 75 is independently selected from halo, -CN, -OH, oxo.

[0055] In some embodiments, R 64 is selected from the group consisting of -H, -F, -Cl, -OH, -CN, SR 74 , -SF5, C 1~6 alkyl, and C 1~6 alkoxy, and wherein this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 74 is C 1~3 haloalkyl.

[0056] In some embodiments, R 63is -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 , and -NO2, wherein 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, and 5- to 10-membered heteroaryl are further substituted with one or more R 69 groups.

[0057] In some embodiments, R 69 is -H, oxo, -OH, -CN, halo, C 1~3 alkyl, C 1~3 alkoxy, C 1~6 hydroxyalkyl, C1~6 heteroalkyl, 3- 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 selected from the group consisting of, wherein C 1~3 alkyl, C 1~3 alkoxy, C1 ~6 hydroxyalkyl, C 1~6 heteroalkyl, and each of 3- to 6-membered cycloalkyl is optionally substituted with -CN or one or more halos.

[0058] In some embodiments, R 63 is -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 , and -NO2, wherein 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, and 5- to 10-membered heteroaryl are further substituted with one or more R 69 groups.

[0059] In some embodiments, R 69 is -H, oxo, -OH, -CN, halo, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6heteroalkyl, 3- 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 selected from the group consisting of, wherein C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6 heteroalkyl, and each of 3- to 6-membered cycloalkyl is optionally substituted with -CN or one or more halos.

[0060] Also provided is a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, Formula IV, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, together with a pharmaceutically acceptable excipient.

[0061] Also provided is a method of treating NAFLD, NASH, ASH or lipodystrophy, the method comprising administering to a patient in need thereof a composition comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof.

[0062] In another embodiment, R 7 is -H, halo, -CN, -OH, 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, -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 aryl, 5 - to 10 - membered heteroaryl, and 4 - to 12 - membered heterocyclyl; wherein each of this 4 - to 12 - membered heterocyclyl, 6 - to 10 - membered aryl, 5 - to 10 - membered heteroaryl, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and each of 3 - to 12 - membered cycloalkyl is optionally substituted with one or more R 15 to provide a compound of formula I.

[0063] In another embodiment, R 7 is -H, halo, -CN, -OH, C 1~6 alkyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3 - 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 aryl, 5 - to 10 - membered heteroaryl, 4 - to 12 - membered heterocyclyl; wherein each of this 4 - to 12 - membered heterocyclyl, 6 - to 10 - membered aryl, 5 - to 10 - membered heteroaryl, C 1~6 alkyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6Hydroxyalkyl, C 1~6 Heteroalkyl, and each of the 3- to 6-membered cycloalkyls is optionally substituted with one or more R 16 to provide a compound of formula I.

[0064] In another embodiment, R 7 is selected from the group consisting of -H, halo, -CN, -OH, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6 heteroalkyl, and 6- to 10-membered aryl, where each of this 6- to 10-membered aryl, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, and C 1~6 heteroalkyl is optionally substituted with one or more R 16 where R 16 is selected from halo, -CN, -NO2, -SF5, C 1~3 alkyl, C 1~3 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl to provide a compound of formula I;

[0065] In another embodiment, R 8 is selected from the group consisting of C 1~6 alkyl, -C(O)R 14 3- 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 where C 1~6 alkyl, 3- to 12-membered cycloalkyl, C 1~6 ​Each of heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl is optionally substituted with one or more Rs 16 to provide a compound of formula I.

[0066] In another embodiment, R 27 is selected from -H, halo, -CN, -OH, 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, -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 , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl; where each of this 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and 3- to 12-membered cycloalkyl is optionally substituted with one or more Rs 35 to provide a compound of formula II;

[0067] In another embodiment, R 27 is selected from the group consisting of -H, halo, -CN, -OH, C 1~6 alkyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, 3- 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 , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl; wherein each of the 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 1~6 alkyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and 3- to 6-membered cycloalkyl is optionally substituted with one or more R 36 . Compounds of formula II are provided.

[0068] In another embodiment, R 27 is selected from the group consisting of -H, halo, -CN, -OH, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6 heteroalkyl, and 6- to 10-membered aryl; wherein each of the 6- to 10-membered aryl, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, and C 1~6 heteroalkyl is optionally substituted with one or more R 36 , where R 36 is halo, -CN, -NO2, -SF5, C 1~3 alkyl, C 1~3 haloalkyl Ru, C 1~6 alkoxy, C 1~6 There is provided a compound of formula II selected from haloalkoxy, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl;

[0069] In another embodiment, R 28 is C 1~6 alkyl, -C(O)R 34 a 3- to 12-membered cycloalkyl, C 1~6 heteroalkyl, a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, a 4- to 12-membered heterocyclyl, -C(O)OR 34 -C(O)NR 33 R 33 and -SO2R 34 selected from the group consisting of, wherein C 1~6 alkyl, a 3- to 12-membered cycloalkyl, C 1~6 heteroalkyl, a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, and a 4- to 12-membered heterocyclyl are each optionally substituted with one or more R 36 There is provided a compound of formula II;

[0070] In another embodiment of the present invention, there is provided a method of treating a disease or condition in a patient in need of treating a disease or condition mediated at least in part by mitochondrial dysfunction, the method comprising administering to the patient an effective amount of a compound of a pharmaceutical composition of the present disclosure comprising each individual compound exemplified below.

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

DETAILED DESCRIPTION OF THE INVENTION

[0072] Detailed Description of the Invention Definition The following description sets forth methods and parameters, etc. However, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure and is provided as an illustration of exemplary embodiments.

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

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

[0075] References to "about" values or parameters herein include (and describe) embodiments directed to the 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 the description of "X". Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes multiple species of such compounds, and a reference to "an assay" includes references to one or more assays known to those of skill in the art and their equivalents.

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

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

[0078] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon chain. As used herein, alkyl has 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). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specified number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), iso-butyl (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] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 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 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

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

[0081] "Alkoxy" means 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 through an acyclic oxygen. Examples include cyclopropoxy and cyclobutoxy.

[0082] It should be understood that when an alkyl group, alkenyl group, or alkynyl group is optionally substituted, the resulting divalent (or higher-valent) group can be named alkylene, alkenylene, or alkynylene. For simplicity herein, whether the moiety is monovalent, divalent, or polyvalent, the names "alkyl, alkenyl, and alkynyl" are presented. The same is true for all substituents herein that can have different names based on valence.

[0083] "Haloalkoxy" means an alkoxy group as defined above in which one or more hydrogen atoms are replaced by halogen.

[0084] "Thioalkyl" means the group "alkyl-S-".

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

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

[0087] "Sulfonylalkyl" means the group "C 1~6 alkyl-S(O)2-".

[0088] "Sulfonylhaloalkyl" means halogenated C 1~6 alkyl-S(O)2.

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

[0090] "Amino" means the group -NR y R y where each R y is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl or heteroaryl, each of which is optionally substituted as defined herein.

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

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

[0093] "Keto" or "oxo" refers to the group =O.

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

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

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

[0097] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring, or a plurality of rings including fused ring systems, bridged 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 "carbocyclic" ring system. The term "cycloalkyl" encompasses cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl , has 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 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0098] Examples of bicyclic hydrocarbon ring system (or bicyclic ring system) 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 (bicycl[2.2.1]heptanyl); spiro[5.2]octanyl, spiro[4.3]octanyl, and spiro[5.4]decanyl, etc., but are not limited thereto.

[0099] Tricyclic groups include a ring system in which three rings are fused, bridged, or spiro, and include, for example, but not limited to, adamantanyl (IUPAC name: tricyclo[3.3.1.13,7]decanyl).

[0100] Polycyclic hydrocarbon ring system substituents include ring systems of more than three rings, and include, for example, but not limited to, cubanyl (IUPAC name: pentacyclo[4.2.0.0 2,5 .0 3,8 .0 4,7 octanyl).

[0101] The expression -S(O)(NH)- is represented by the formula:

Chemical formula

Chemical formula

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

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

[0104] "Heteroalkyl" refers to an alkyl group in which one or more (and any associated hydrogen atoms) of the carbon atoms are each independently replaced by the same or different heteroatom groups. 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 heteroatom groups. Examples of heteroatom 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 optionally substituted. 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 optionally substituted. As used herein, heteroalkyl includes from 1 to 10 carbon atoms, from 1 to 8 carbon atoms, or from 1 to 4 carbon atoms, and from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom.

[0105] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, independently having one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl has from 1 to 20 ring carbon atoms (i.e., C 1~20 heteroaryl), from 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or from 3 to 8 carbocyclic atoms (i.e., C 3~8 heteroaryl); and independently contains from 1 to 5 heteroatoms, from 1 to 4 heteroatoms, from 1 to 3 ring heteroatoms, from 1 to 2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused 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 this heteroaryl may be attached through any ring of this fused system. Any aromatic ring having a single ring or multiple fused rings and containing at least one heteroatom is considered heteroaryl, regardless of its attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not include aryl as defined above and does not overlap with aryl.

[0106] "Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from N, NO, O, S, S(O), S(O)(NH), S(O)(NR) and S(O)2. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bicyclic heterocyclyl groups, bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyl may be a single ring or multiple rings, where the multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl, regardless of its bond (i.e., it may be bonded through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, regardless of its bond to the remainder of the molecule, and this ring may be fused to an aryl ring or a heteroaryl ring. As used herein, heterocyclyl is

[0107] having from 4 to 20 ring atoms (i.e., 4- to 20-membered heterocyclyl), from 4 to 12 ring atoms (i.e., 4- to 12-membered heterocyclyl), from 4 to 10 ring atoms (i.e., 4- to 10-membered heterocyclyl), from 4 to 8 ring atoms (i.e., 4- to 8-membered heterocyclyl), or from 4 to 6 ring carbon atoms (i.e., 4- to 6-membered heterocyclyl); and alone standing and 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 point to another substituent may be via carbon or, if appropriate, via a heteroatom. The heterocyclyl may contain one or more oxo groups and / or thioxo groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, 4- to 7-membered sultam, 4- to 7-membered cyclic carbamate, 4- to 7-membered cyclic carbonate, 4- to 7-membered cyclic sulfide,

Chemical formula

[0108] As used herein, the term "nitrogen- or sulfur-containing heterocyclyl" means a heterocyclyl moiety containing 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, such as oxygen, may be present in addition to this nitrogen, sulfur, or combinations thereof. Examples of nitrogen- or sulfur-containing heterocyclyls 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 unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by hydroxyl.

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

[0115] "Polycyclic" 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 alternative chemical names commonly used may be employed. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups or "arylenyl" groups, respectively. Also, unless explicitly indicated otherwise, when a combination of groups is referred to as one moiety in this specification (e.g., arylalkyl), the last-mentioned group contains the atom by which this moiety is attached to the remainder of the molecule.

[0120] The terms "as required" or "as necessary" mean that the event or situation described subsequently may or may not occur, and that this description includes the case where the event or situation occurs and the case where it does not occur. Also, the term "optionally substituted" refers to the fact that any one or more hydrogen atoms on the specified atom or group may or may not be replaced by a moiety other than hydrogen. "Optionally substituted" can range from zero to the maximum number of possible substitutions, and each occurrence is independent. When the term "substituted" is used, the substitution must be made at the position of the hydrogen atom that can be substituted by the indicated substituent. The substitution as required may be the same as or different from the (required) substitution.

[0121] When a moiety is "optionally substituted" and this reference is made with respect to any general term such as "alkyl", "alkenyl", "alkynyl", "haloalkyl", "cycloalkyl", "aryl" or "heteroaryl", this general term is (C 1~3 alkyl), (C 4~6 alkyl), -O(C 1~4 alkyl), (C 3~10 cycloalkyl), and O-(C 3~10It may refer to any antecedent that specifically describes these, such as (cycloalkyl). For example, "any aryl" includes both "aryl" and "-O(aryl)", and examples of aryl such as phenyl or naphthyl. Also, the term "any heterocyclyl" includes both the term "heterocyclyl" and "O-(heterocyclyl)", as well as examples of heterocyclyl such as oxetanyl, tetrahydropyranyl, morpholino, and piperidinyl. In the same manner, the term "any heteroaryl" includes the term "heteroaryl" and "O-(heteroaryl)" and specific heteroaryls such as pyridine.

[0122] Some of the compounds exist as tautomers. The tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with its imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that these compounds include both the amide tautomer and the imidic acid tautomer. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0123] Any formula or structure given herein is also intended to represent both the unlabeled and isotopically labeled forms of the compound. An isotopically labeled compound has the structure shown 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 the present disclosure include, 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 125It includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as I. Various isotopically labeled compounds of the present disclosure, for example, radioisotopes, such as 3 H, 13 C and 14 C incorporated ones. Such isotopically labeled compounds can be useful in metabolic studies, reaction kinetics 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 the radiotherapy of patients.

[0124] The present disclosure also includes "deuterated analogs" of the 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 thus 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(12):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 the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism and excretion (ADME). Substitution with a heavier isotope, such as deuterium, can provide certain therapeutic advantages resulting from greater metabolic stability, such as an increase in in vivo half-life, a reduction in the required dose of administration and / or an improvement in the therapeutic index. 18The F-labeled compounds may be useful for PET or SPECT studies. The isotopically labeled compounds and their prodrugs of the present disclosure can generally be prepared by substituting unlabeled isotopes with readily available isotopically labeled reagents in the schemes or by performing the procedures disclosed in the following examples and preparations. In this context, it is understood that deuterium is considered a substituent of the compounds of formula I.

[0126] The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope means 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. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) means deuterium.

[0127] In many cases, the compounds of the present disclosure can form acid salts and / or base salts due to the presence of amino groups and / or carboxyl groups or groups similar thereto. can form acid salts and / or base salts due to the presence of amino groups and / or carboxyl groups or groups similar thereto.

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

[0129] The "pharmaceutically acceptable salts" of a given compound refer to salts that maintain the biological effectiveness and properties of the given compound and are not undesirable biologically or otherwise. Examples of "pharmaceutically acceptable salts" or "physiologically acceptable salts" include salts with inorganic acids and salts with organic acids. Further, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying the solution of the acid salt. Conversely, when the product is the free base, addition salts, particularly pharmaceutically acceptable addition salts, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art recognize 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 acids and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. 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-toluene-sulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include, by way of example only, salts of sodium, potassium, lithium, ammonium, calcium, and magnesium.Examples of salts derived from organic bases include salts of primary, secondary, and tertiary amines such as 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), tri(substituted alkenyl)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, etc., but are not limited thereto. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine, etc.

[0130] The term "substituted" means that one or more hydrogen atoms of the designated atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. 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, nitroExamples include, but are not limited to, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar infinite structures (e.g., a substituted aryl having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, and the substituted aryl group is further substituted with a substituted heteroalkyl group, etc.) achieved by defining substituents with further substituents added without limitation are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitutions of a substituted aryl group having two other substituted aryl groups are limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl substituted with 5 fluorines 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 describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as being optionally substituted, any substituent of that group itself is unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including, but not limited to, hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 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, each of which is unsubstituted.One of ordinary skill in the art will recognize that the substituents and other moieties of the compounds of the general formula in this specification should be selected for the purpose of providing compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into pharmaceutically acceptable stable pharmaceutical compositions. Compounds having such stability are envisioned to fall within the scope of the present invention. It should be understood by one of ordinary skill in the art that any combination of the definitions and substituents described above should not result in impossible species or compounds.

[0131] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where any conventional media and agents are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Additional active ingredients can also be incorporated into these compositions.

[0132] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where any conventional media and agents are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Additional active ingredients can also be incorporated into these compositions.

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

[0134] Although the active ingredient can be administered alone, these active ingredients can be formulated into pharmaceutical preparations (formulations It may preferably be provided as a finished product). The formulations of the present invention contain, 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 of being compatible with the other ingredients of the formulation and must be physiologically harmless to its recipient.

[0135] Examples of these formulations include those suitable for the above-mentioned administration routes. For simplicity, these formulations may be provided in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Techniques and formulations are generally found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing the active ingredient into association with an inert ingredient (such as a carrier, a pharmaceutical excipient, etc.) which constitutes one or more secondary ingredients. Generally, these formulations are prepared by uniformly and intimately bringing into association a liquid carrier or 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 discrete 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 of the compounds of the present invention, together with one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. The pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents, such as sweetening agents, flavoring agents, coloring agents, and preservatives, for the purpose of providing a palatable preparation. Tablets containing the active ingredient as a mixture with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets are acceptable. These excipients can be, 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; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia gum; and lubricants, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or coated by known techniques, and known techniques include microencapsulation for providing a sustained action over a longer period by delaying disintegration and adsorption in the gastrointestinal tract. For example, time-delay materials, such as glyceryl monostearate or glyceryl distearate, can be used alone or together with waxes.

[0138] The amount of active ingredient combined with the inert ingredients to produce the dosage form will vary 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 from about 1 to 1000 mg of active material, formulated with a suitable and convenient amount of carrier material (e.g., inert ingredient or excipient material). In certain embodiments, this carrier material varies from about 5 to about 95% (weight:weight) of the total composition. In some embodiments, the pharmaceutical compositions described herein contain from 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 a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein contain less than about 400 mg of a compound of formula I. In some embodiments, the pharmaceutical compositions described herein contain about 100 mg of a 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, for example, suitable for oral administration, flavoring and odor-masking agents may be mentioned.

[0140] There is further provided a veterinary composition containing at least one active ingredient as defined above together with a veterinary carrier.

[0141] A veterinary carrier is a substance useful for the purpose of administering the composition, which can be a solid, liquid or gaseous substance, which are 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 dosage of the active ingredient depends at least on the nature of the condition being treated, its toxicity, whether the compound is used prophylactically (lower dosages), the method of delivery, and the pharmaceutical formulation, and is determined by the clinician using conventional dosage escalation studies. Route of administration

[0143] One or more compounds of formula I (referred to herein as the active ingredient), or a pharmaceutically acceptable salt thereof, is 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, intrathecal, and epidural). The preferred route may vary, for example, depending on the condition of the recipient. One advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally. Thus, in one embodiment, the pharmaceutical compositions described herein are in oral dosage form. In certain embodiments, the pharmaceutical compositions described herein are in oral solid dosage form. Ultimately, determining the appropriate dosage and route of administration suitable for a particular patient having 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 Ingredient (mg / capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 Mix the above ingredients and fill into hard gelatin capsules.

[0145] Formulation Example 2 Prepare a tablet formulation using the following ingredients: Amount Ingredient (mg / tablet) Active ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 These components are blended and then compressed to form tablets.

[0146] Formulation Example 3 A dry powder inhalation formulation containing the following components is prepared: Component Weight % Active ingredient 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 Tablets each containing 50 mg of the active ingredient are prepared as follows: Amount Component (mg / tablet) Active ingredient 50.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 140 mg

[0148] The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and thoroughly mixed. The solution of polyvinylpyrrolidone is mixed with the resulting powder and then passed through a 16 mesh U.S. sieve. The granules thus produced are dried at 50 °C to 60 °C and passed through a 16 mesh U.S. sieve. Then, sodium carboxymethyl starch, magnesium stearate and talc previously passed through a No. 30 mesh U.S. sieve are added to these granules and, after mixing, compressed in a tableting machine to obtain tablets each weighing 120 mg.

[0149] Formulation Example 5 Suppositories each containing 25 mg of the active ingredient are prepared as follows: Component Amount Active ingredient 25 mg Saturated fatty acid glyceride Up to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glyceride melted in advance using the minimum heat required. Then, this mixture is poured into a suppository mold with a nominal volume of 2.0 g and allowed to cool.

[0150] Formulation Example 6 Suppositories each containing 50 mg of the active ingredient per 5.0 mL dose are prepared as follows: Component Amount Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and coloring agent q.v. Purified water Up to 5.0 mL The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethyl cellulose prepared in advance. Sodium benzoate, flavor and coloring agent are diluted with some water and added with stirring. Then, sufficient water is added to yield the required volume.

[0151] Formulation Example 7 A subcutaneous preparation can be prepared as follows: Component Amount Active ingredient 5.0 mg Corn oil 1.0 mL

[0152] Formulation Example 8 An injectable preparation having the following composition is prepared: Component Amount Active ingredient 2.0 mg / mL Mannitol, USP 50 mg / mL Gluconic acid, USP q.s. (pH 5 - 6) Water (distilled, sterilized) q.s. to 1.0 mL Nitrogen gas, NF q.s.

[0153] Formulation Example 9 Prepare a topical preparation having the following composition: Component 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 q.s. to 100

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

[0155] Formulation Example 10 Sustained - release composition Component Range of weight % Active ingredient 50 - 95 Microcrystalline cellulose (filler) 1 - 35 Methacrylic acid copolymer 1 - 35 Sodium hydroxide 0.1 - 1.0 Hydroxypropylmethylcellulose 0.5 - 5.0 Magnesium stearate 0.5 - 5.0

[0156] The sustained-release agent of the present disclosure can be prepared as follows: A compound, a pH-dependent binder, and any necessary excipients are intimately mixed (dry blended). Then, this dry-blended mixture is granulated in the presence of an aqueous solution of a strong base (which is sprayed onto the blended powder). The granules are dried, sieved, mixed with a lubricant (such as talc or magnesium stearate) as necessary, 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 a water-miscible solvent up to 25%, such as a lower alcohol).

[0157] The obtained tablets can be coated with a film-forming agent as necessary for the purposes of identification, taste masking, and improving ease of swallowing. This film-forming agent is typically present in an amount in the range of 2% to 4% of the weight of the tablets. Suitable film-forming agents are well known in the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate / methyl-butyl methacrylate copolymer - Eudragit® E - Roehm.Pharma), and the like. These film-forming agents can optionally contain colorants, plasticizers, and other auxiliary components.

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

[0159] For the purpose of affecting the dissolution rate, the time for wet mixing the powder containing the compound is controlled. Preferably, the total time of powder mixing, i.e., the time during which this powder is exposed to the sodium hydroxide solution, ranges from 1 minute to 10 minutes, preferably from 2 minutes to 5 minutes. After granulation, the particles are taken out of the granulator and placed in a fluidized bed dryer at about 60 °C for drying.

[0160] Formulation Example 11 Tablet formulations are prepared using the following ingredients: Amount Ingredient (mg / tablet) Active ingredient 300.0 Cellulose, microcrystalline 100.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 These ingredients are blended and compressed to form tablets.

[0161] Method As used herein, a method for treating and / or preventing hyperlipidemia in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I). For example, the compounds herein can be used to treat primary (genetic) lipid disorders (e.g., familial hypercholesterolemia, Wolman disease, and cholesteryl ester storage disease), as well as secondary (acquired) lipid disorders (e.g., true diabetes, elevated cholesterol (especially elevated LDL cholesterol), combined hyperlipidemia / type IIb, elevated triglycerides alcohol abuse, chronic kidney disease, hypothyroidism, and hyperlipidemia associated with primary biliary ry cholangitis).

[0162] In a subject in need of treating and / or preventing a metabolic disorder including, but not limited to, diabetes (including type I and type II diabetes), metabolic syndrome, dyslipidemia, obesity, insulin resistance, hypertension, high serum cholesterol, and hypertriglyceridemia, a method for treating and / or preventing this metabolic disorder is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[0163] In a patient in need of treating and / or preventing a liver disease, a method for treating and / or preventing a liver disease is also disclosed, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I). The presence of an active liver disease can be detected by the presence of elevated enzyme levels in the blood. Specifically, blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) that are higher than the clinically acceptable normal range are known to be indicators of ongoing liver damage. Daily monitoring of the 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 within the acceptable normal range is adopted as clinical evidence reflecting a decrease in the severity of the patient's ongoing liver damage.

[0164] In certain embodiments, this liver disease is a chronic liver disease. Chronic liver diseases involve progressive destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis. Generally, chronic liver diseases can be caused by viruses (e.g., hepatitis B, hepatitis C, cytomegalovirus (CMV), or Epstein - Barr virus (EBV)), toxic agents or drugs (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 Cholangitis (formerly known as Primary Biliary Cirrhosis), or primary sclerosing cholangitis), or other causes (e.g., right - sided heart failure).

[0165] In one embodiment, provided herein is a method for reducing the level of cirrhosis. In one embodiment, cirrhosis is pathologically characterized by loss of the normal microscopic lobular architecture, with 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 syndrome (obesity, combined hyperlipidemia, type II diabetes mellitus, and hypertension). NAFLD is thought to encompass a range of disease activity and begins with fat accumulation in the liver (hepatic steatosis).

[0167] Both obesity and insulin resistance have been shown to likely play strong roles 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 pharmaceuticals, 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 associated with the consumption of soft drinks in the presence of high-fructose corn syrup, which can cause an increase in abdominal fat accumulation, although sucrose consumption shows a similar effect (presumably due to its breakdown to fructose). Genetic characteristics are also known to play a role, and two genetic mutations for this susceptibility have been identified.

[0168] If untreated, NAFLD can progress to non-alcoholic steatohepatitis (NASH), which is the most extreme form of NAFLD, a condition in which steatosis is combined with inflammation and fibrosis. NASH is considered to be a major cause of liver cirrhosis. Accordingly, provided herein is a method of treating and / or preventing non-alcoholic steatohepatitis (NASH) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I).

[0169] In the present specification, there is also provided a method for treating and / or preventing hepatic fibrosis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I). Hepatic fibrosis is an excessive accumulation of extracellular matrix proteins including collagen, which occurs in most types of chronic liver diseases. In certain embodiments, advanced hepatic fibrosis results in cirrhosis and liver failure. Methods for measuring liver histology, 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 can improve the 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, fibroid or fibrotic degeneration) is reduced by more than about 90%. In one embodiment, the level of hepatic fibrosis (which is the formation of fibrous tissue, fibroid or fibrotic 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 fibrogenesis in the liver. Hepatic fibrogenesis is a process that results in the deposition of excessive hepatic extracellular matrix components, known as fibrosis. This can be caused by, for example, chronic viral hepatitis B and C, alcoholic liver disease, drug-induced liver disease, hemochromatosis, autoimmune hepatitis, Wilson's disease, primary biliary cirrhosis (Primary Biliary Cholangitis (formerly known as Primary Biliary Cirrhosis), sclerosing cholangitis, and many conditions such as schistosomiasis of the liver are observed. In one embodiment, the level of fibrosis is reduced by more than about 90%. In one embodiment, the level of fibrosis 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 2%.

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

[0173] Also disclosed herein is a method of treating or preventing a cardiovascular disorder in a patient in need of treating or preventing a cardiovascular disorder, the method comprising administering a therapeutically effective amount of a compound of formula (I). Cardiovascular diseases include, for example, any one or more of heart failure (including congestive heart failure, dilated heart failure, systolic heart failure, heart failure with preserved ejection fraction), acute heart failure, ischemia, recurrent ischemia, myocardial infarction, arrhythmia, angina (including exercise-induced angina, variant angina, stable angina, unstable angina), acute coronary syndrome, diabetes, intermittent claudication, and idiopathic pulmonary fibrosis.

[0174] Also provided herein is a method of improving a pathological consequence or outcome associated with oxidative stress in a patient in need of improving a pathological consequence or outcome associated with oxidative stress, the method comprising administering to the patient a therapeutically effective amount of a mitochondrial uncoupling compound.

[0175] Combination therapy The compounds of the present disclosure are contemplated to be useful in desired combination products. Such products may be in the form of the compound alone, although it is sometimes preferred to co-formulate two or more compounds in a single dosage form.

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

[0177] In some embodiments, the compounds of the present disclosure are formulated together with one or more additional 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 are administered sequentially and can be administered at a different time point than the compounds of the present disclosure.

[0178] Combinations for liver diseases and conditions In some embodiments, the therapeutic agent or combination of therapeutic agents is an ACE inhibitor, an acetyl-CoA carboxylase inhibitor, an adenosine A3 receptor agonist, an adiponectin receptor agonist, an AKT protein kinase inhibitor, an AMP-activated protein kinase (AMPK), an amylin receptor agonist, an angiotensin II AT-1 receptor antagonist, an autotaxin inhibitor, a bioactive lipid, a calcitonin agonist, a caspase inhibitor, a caspase-3 stimulator, a cathepsin inhibitor, a caveolin-1 inhibitor, a CCR2 chemokine antagonist, a CCR3 chemokine antagonist, a CCR5 chemokine antagonist, a chloride channel stimulator, a CNR1 inhibitor, a cyclin D1 inhibitor, a cytochrome P450 7A1 inhibitor, a DGAT1 / 2 inhibitor, a dipeptidyl peptidase IV inhibitor, an endothelin modulator, an eotaxin ligand inhibitor, an extracellular m Trick 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 inhibitor, IL-10 agonist, IL-17 antagonist, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, integrin modulator, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, Jak2 tyrosine kinase inhibitor, Klotho beta stimulator, 5-lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor, LPL gene stimulator, lysophosphatidic acid-1 receptor antagonist, lysyl oxidase homolog 2 inhibitor, matrix metalloprotease (MMP) inhibitor, MEKK-5 protein kinase inhibitor, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG binding protein 2 modulator, microRNA-21 (miR-21) inhibitor, myelin basic protein stimulator, NACHT LRRInhibitor of PYD domain-containing protein 3 (NLRP3), NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), nicotinic acid receptor 1 agonist, P2Y13 purinergic receptor stimulator, PDE3 inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDGF receptor beta modulator, phospholipase C inhibitor, PPAR alpha agonist, PPAR delta agonist, PPAR gamma agonist, PPAR gamma modulator, protease-activated receptor-2 antagonist, protein kinase modulator, Rho-associated protein kinase inhibitor, sodium glucose transporter-2 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, stearoyl-CoA desaturase-1 inhibitor, suppressor of cytokine signaling-1 stimulator, suppressor of cytokine signaling-3 stimulator, transforming growth factor beta (TGF-β), transforming growth factor beta-activated kinase 1 (TAK1), thyroid hormone receptor beta agonist, TLR-4 antagonist, transglutaminase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulator, or YAP / TAZ modulator.

[0179] Non-limiting examples of therapeutic agents and targets include the following: ACE inhibitors, such as enalapril; Acetyl-CoA carboxylase (ACC) inhibitors, such as DRM-01, NDI-010976 (firsocostat), gemcabene, PF-05175157, QLT-091382, PF-05221304; Adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502, CGS21680; Adiponectin receptor agonists, such as ADP-355; Amylin / calcitonin receptor agonists, such as KBP-042; AMP-activated protein kinase stimulators, such as, O-304; Angiotensin II AT-1 receptor antagonists, such as, irbesartan; Autotaxin inhibitors, such as, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063; Bioactive lipids, such as, DS-102; Cannabinoid receptor type 1 (CNR1) inhibitors, such as, namacizumab, GWP-42004; Caspase inhibitors, such as, emricasan; Pan cathepsin B inhibitors, such as, VBY-376; Pan cathepsin inhibitors, such as, VBY-825; CCR2 / CCR5 chemokine antagonists, such as, cenicriviroc; CCR2 chemokine antagonists, such as, propagermanium; CCR3 chemokine antagonists, such as, bertilimumab; Chloride channel stimulators, such as, cobiprostone; Diacylglycerol acyltransferase 2 (DGAT2) inhibitors, such as, IONIS-DGAT2Rx, PF-06865571; Diacylglycerol acyltransferase 1 (DGAT1) inhibitors, such as, GSK-3008356; Dipeptidyl peptidase IV inhibitors, such as, linagliptin, evogliptin; Eotaxin ligand inhibitors, such as, bertilimumab; Extracellular matrix protein modulators, such as, CNX-024; Farnesoid X receptor (FXR) agonists, such as 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, such as INT-767; Fatty acid synthase inhibitors, such as TVB-2640; Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282; Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BMS-986036; Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723; Galectin-3 inhibitors, such as GR-MD-02; Glucagon-like peptide 1 (GLP1R) agonists, such as AC-3174, liraglutide, semaglutide; G-protein coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777; Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s020; HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; IL-10 agonists, such as peg-ilodecakin; Ileal sodium bile acid cotransporter inhibitors, such as A-4250, volixibat potassium ethanolate hydrate (SHP-262), GSK2330672; Insulin sensitizers, such as KBP-042, MSDC-0602K, Px-102, RG-125 (AZD4076), VVP-100X; Beta Klotho (KLB)-FGF1c agonists, such as NGM-313; 5-Lipoxygenase inhibitors, such as tipelukast (MN-001); Lipoprotein lipase inhibitors, such as CAT-2003; LPL gene stimulants, such as alipogene tiparvovec; Liver X receptor (LXR) inhibitors, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238; Lysophosphatidic acid-1 receptor antagonists, such as 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, such as PXS-4728A; Methionine aminopeptidase-2 inhibitors, such as ZGN-839; Methyl CpG binding protein 2 modulators, such as mercaptamine; Mineralocorticoid receptor antagonists (MCRA), such as MT-3995; Myelin basic protein stimulants, such as olesoxime; Myeloperoxidase inhibitors, such as PF-06667272; NADPH oxidase 1 / 4 inhibitors, such as GKT-831; Nicotinic acid receptor 1 agonists, such as ARI-3037MO; NACHT LRR PYD domain-containing protein 3 (NLRP3) inhibitors, e.g., KDDF-201406-03, NBC-6; Nuclear receptor modulators, e.g., DUR-928; P2Y13 purinergic receptor agonists, e.g., CER-209; PDE3 / 4 inhibitors, e.g., tipepidine (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-associated protein kinase (ROCK) inhibitors, e.g., KD-025; Sodium-glucose cotransporter-2 (SGLT2) inhibitors, e.g., ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, sotagliflozin; SREBP transcription factor inhibitors, e.g., CAT-2003, MDV-4463; Stearoyl-CoA desaturase-1 inhibitors, e.g., aramchol; Thyroid hormone receptor beta agonists, e.g., MGL-3196, MGL-3745, VK-2809; TLR-4 antagonists, 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 therapeutic agents, is A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogen tiparvovec, alamethicol, ARI-3037MO, ASP-8232, belimumab, betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriviroc, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colecalciferol, dapagliflozin, deuterated pioglitazone R-enantiomer, 2,4-Dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, Elafibranor (GFT-505), Emricasan, Enalapril, Ertugliflozin, Evogliptin, F-351, GKT-831, GNF-5120, GRI-0621, GR-MD-02, Celonsertib, GS-9674, Hydrochlorothiazide, Icosapent ethyl ester, IMM-124-E, INT-767, IONIS-DGAT2Rx, Ipragliflozin, Irbesartan, 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, Namatizumab, NC-101, NDI-010976, ND-L02-s0201, NGM-282, NGM-313, NGM-386, NGM-395, Norursodeoxycholic acid, O-304, Obeticholic acid, 25HC3S, Olesoxime, PAT-505, PAT-048, Pegilodecakin, Pioglitazone, Pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, Remogliflozin etabonate, RG-125 (AZD4076), Saroglitazar, Semaglutide, Simtuzumab, Solithromycin, Sotagliflozin, Statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV-45478, Tipelcast (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, Ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, Bismodegib, Boryxabat potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, or ZGN-839.,

[0180] Combinations for Metabolic Diseases or Conditions Examples of metabolic disorders include, but are not limited to, diabetes (including type I and type II diabetes), metabolic syndrome, 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, sulfonylureas, biguanides, α-glucosidase inhibitors, and incretin mimetics. Accordingly, one aspect of the present disclosure is a method of treating a metabolic disease, the method comprising administering a compound of the present disclosure in combination with one or more compounds useful for treating a metabolic disease to a subject in need thereof, particularly a human subject.

Examples

[0182] The following examples are included to demonstrate specific embodiments of the present disclosure. Those skilled in the art should recognize that the techniques disclosed in the following examples represent techniques that function well in the practice of the present disclosure and, accordingly, can be considered to constitute specific modes for its practice. However, those skilled in the art should recognize that, in light of the present disclosure, many changes can be made to the specific embodiments disclosed and still obtain similar or analogous results without departing from the spirit and scope of the present disclosure. List of Abbreviations and Acronyms Abbreviation Meaning °C Degrees Celsius Ac Acetyl aq. Aqueous br Broad BSA Bovine Serum Albumin d Doublet DCM Dichloromethane dd Doublet of Doublets ddd Doublet of Doublets of Doublets DMA Dimethylacetamide DMF Dimethylformamide DMSO Dimethyl sulfoxide dt Doublet - triplet 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 EtOAc Ethyl acetate EtOH Ethanol (Ethyl alcohol) FBS Fetal bovine serum g Gram HATU 1 - [Bis(dimethylamino)methylene]-1H - 1,2,3 - triazolo[4,5 - b]pyridinium 3 - oxide hexafluorophosphate HEPES 2 - [4-(2 - Hydroxyethyl)piperazin - 1 - yl]ethanesulfonic acid HCl Hydrochloric acid HOBT 1 - Hydroxybenzotriazole HPLC High - performance liquid chromatography Hrs Hours 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 M - H Mass peak - hydrogen Me Methyl MeCN Acetonitrile MeOH Methanol (Methyl alcohol) Mg Milligram MgSO4 Magnesium sulfate MHz Megahertz Min Minute ml / mL Milliliter mM Millimolar concentration mmol Millimole MS Mass spectrometry μwave Microwave n- Normal nBu / Bu n-Butyl (normal butyl) nL Nanoliter nm Nanometer NMP 1-Methylpyrrolidin-2-one NMR Nuclear magnetic resonance NP-40 Nonylphenoxypolyethoxyethanol Ph Phenyl q Quartet q.s. Quantity sufficient to achieve the stated function RP Reverse phase Rt Room temperature s Singlet t Triplet T3P 1-Propane phosphonic anhydride TBTU O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate THF Tetrahydrofuran

[0183] Source of chemical substances 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. include.

[0184] General Synthesis 1

Chemical Formula

[0185] Step 1: 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) was added pyridine (7.86 mL, 97.1 mmol). The solution was stirred at room temperature for 18 hours. The reaction was quenched with 1N HCl and stirred for 5 minutes. The mixture was extracted with DCM (3 times). The combined organic layers were washed with brine dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography to give methyl 4-fluoro-2-(methylsulfonamido)benzoate.

[0186] Step 2: To a solution of methyl 4-fluoro-2-(methylsulfonamido)benzoate (1.65 g, 6.67 mmol) in THF / MeOH / water (1:1:1, 66.0 mL) was added lithium hydroxide monohydrate (1.40 g, 33.4 mmol). The mixture was stirred at room temperature for 18 hours. The reaction was quenched with 1N HCl and concentrated. The crude product was diluted with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give 4-fluoro-2-(methylsulfonamido)benzoic acid, which was used without further purification.

[0187] Procedure 3: A mixture of 4-fluoro-2-(methylsulfonamido)benzoic acid (650 mg, 2.79 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentan-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. The solution was concentrated, diluted with ethyl acetate and its pH was adjusted to 3 by the addition of 1N HCl. The mixture was extracted with EtOAc (3 times) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography followed by crystallization to give 4-fluoro-2-(methylsulfonamido)-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]

Chem.

[0189] Procedure 2: A 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) was stirred at room temperature for 18 h. The reaction mixture was concentrated and the crude product was purified by reverse phase chromatography to afford 2-(cyclopropanesulfonamido)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H 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] + ​Calculated 393.09; found 393.75。

[0190]

Chem.

[0191]

Chem.

[0192]

Chemical Structure

[0193]

Chem.

[0194]

Chem.

[0195]

Chemical Structure

[0196]

Chemical Structure

[0197]

Chem.

[0198]

Chem.

[0199]

Chem.

[0200]

Chemical Structure

[0201]

Chem.

[0202]

Chem.

[0203]

Chem.

[0204]

Chemical Structure

[0205]

Chemical Structure

[0206]

Chemical Structure

[0207]

Chem.

[0208] [Chemistry] Example 21: Preparation of 4-Fluoro-N-(3-fluorobicyclo[1.1.1]pentan- 1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamido)benzamide According to General Synthesis 1, 4-(methylsulfonyl)benzenesulfonyl chloride (1.2 eq) 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)sulfonamido)benzamide, which was 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] [Chemistry] Example 22: Preparation of 4-Fluoro-2-((3-(methylsulfonyl)phenyl)sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 4-(methylsulfonyl)benzenesulfonyl chloride (1.2 eq) 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)sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, and it was 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]

Chemical Structure

[0211]

Chem.

[0212] [Chemistry] Example 25: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((4-(ethylsulfonyl)phenyl)sulfonamido)-4-(trifluoromethyl)benzamide According to General Synthesis 1, methyl 2-amino-4-(trifluoromethyl)benzoate and 4-(ethylsulfonyl)benzenesulfonyl chloride (1.3 equivalents) were used at room temperature for 48 hours 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-((4-(ethylsulfonyl)phenyl)sulfonamido)-4-(trifluoromethyl)benzamide, which was 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] [Chemistry] Example 26: Preparation of 2-((4-(ethylsulfonyl)phenyl)sulfonamido)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, methyl 2-amino-4-(trifluoromethyl)benzoate and 4-(ethylsulfonyl)benzenesulfonyl chloride (1.3 equiv) were used at room temperature for 48 h in Step 1, then 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride was used in Step 3 to synthesize 2-((4-(ethylsulfonyl)phenyl)sulfonamido)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, and it was 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]

Chemical Structure

[0215] Example 28: Preparation of 2-((4-(Cyclopropylsulfonyl)phenyl)sulfonamido)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide

Chemical formula

[0216] Procedure 2: A 10 mL vessel was charged with methyl 4-fluoro-2-((4-iodophenyl)sulfonamido)benzoate (100 mg, 0.230 mmol), sodium cyclopropanesulfinate (58.9 mg, 0.460 mmol), copper(I) trifluoromethanesulfonate toluene complex (119 mg, 0.230 mmol), and DMSO (2.3 mL). The mixture was degassed with nitrogen for 10 minutes. trans-1,2-Diaminocyclohexane (55.2 μL, 0.460 mmol) was added and the solution was heated at 120 °C for 10 hours and then stirred at room temperature for 48 hours. The mixture was diluted with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude mixture was purified by silica gel chromatography to afford methyl 2-((4-(cyclopropylsulfonyl)phenyl)sulfonamido)-4-fluorobenzoate. 1 H 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] Procedures 3-4: Following General Synthesis 1, 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in Procedure 3 to synthesize 2-((4-(cyclopropylsulfonyl)phenyl)sulfonamido)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was purified by reverse-phase chromatography. 11H 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]

Chem.

[0219]

Chem.

[0220]

Chem.

[0221]

Chemical Structure

[0222]

Chemical Structure

[0223]

Chem.

[0224]

Chem.

[0225] Example 36: Preparation of 2-((4-(1H-imidazol-1-yl)phenyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide

Chem.

[0226] Step 4: In a 10 mL microwave vial, 2-((4-iodophenyl)sulfonamido)-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 degassed 15:1 DMA / water (2.0 mL) were added. Then, the mixture was degassed with nitrogen for 10 min and then heated at 110 °C for 18 h with stirring. The mixture was cooled to room temperature, filtered, and the solid was rinsed with EtOAc. The solution was concentrated and purified by reverse phase chromatography to obtain 2-((4-(1H-imidazol-1-yl)phenyl)sulfonamido)-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]

Chem.

[0228]

Chem.

[0229]

Chemical Structure

[0230]

Chem.

[0231]

Chem.

[0232]

Chemical Structure

[0233]

Chem.

[0234] [Chem.] Example 44: Preparation of 2-((4-((Difluoromethyl)sulfonyl)phenyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide According to General Synthesis 1, methyl 2-amino-4-(trifluoromethyl)benzoate and 4-((difluoromethyl)sulfonyl)benzenesulfonyl chloride (2.0 equiv) were used at room temperature for 36 h in Step 1, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in Step 3 to synthesize 2-((4-((difluoromethyl)sulfonyl)phenyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide, which was 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] [Chem.] Example 45: Preparation of N-(bicyclo[2.2.1]heptan-1-yl)-2-((4-(methylsulfonyl)phenyl)sulfonamido)-4-(trifluoromethyl)benzamide According to General Synthesis 1, methyl 2-amino-4-(trifluoromethyl)benzoate and 4-(methylsulfonyl)benzenesulfonyl chloride (2.5 equiv) were used at room temperature for 48 h in Step 1, 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)sulfonamido)-4-(trifluoromethyl)benzamide, which was 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]

Chemical Structure

[0237]

Chem.

[0238]

Chem.

[0239]

Chemical Structure

[0240]

Chem.

[0241]

Chem.

[0242]

Chemical Structure

[0243]

Chem.

[0244] General synthesis 2

Chem.

[0245] Step 2: To a solution of methyl 2-((1-methylethyl)sulfonamido)-4-(trifluoromethyl)benzoate (304 mg, 0.935 mmol) in THF / MeOH / water (1:1:1, 30.0 mL) was added lithium hydroxide monohydrate (196 mg, 4.67 mmol). The mixture was stirred at room temperature for 18 h. The reaction was quenched with 1 N HCl and concentrated. The crude product was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give 2-((1-methylethyl)sulfonamido)-4-(trifluoromethyl)benzoic acid as a solid, which was used without further purification.

[0246] Step 3: A mixture of 2-((1-methylethyl)sulfonamido)-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 min. N,N-Diisopropylethylamine (126 μL, 0.723 mmol) was added and the solution was stirred at room temperature for 1 h. The solution was concentrated and the crude product was purified by crystallization to give 2-((1-methylethyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)benzamide. 1 H 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]

Chem.

[0248]

Chem.

[0249]

Chemical Structure

[0250]

Chem.

[0251]

Chem.

[0252]

Chemical Structure

[0253]

Chem.

[0254]

Chem.

[0255]

Chemical Structure

[0256]

Chem.

[0257]

Chem.

[0258]

Chemical Structure

[0259]

Chem.

[0260] [Chemistry] Example 68: Preparation of N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1-methylethyl)sulfonamido)-5-(trifluoromethyl)benzamide According to General Synthesis 2, methyl 2-bromo-5-(trifluoromethyl)benzoate 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-methylethyl)sulfonamido)-5-(trifluoromethyl)benzamide, which was 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] [Chemistry] Example 69: Preparation of 2-((1-methylethyl)sulfonamido)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 2, methyl 2-bromo-5-(trifluoromethyl)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)sulfonamido)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide, which was purified by crystallization. 1 H 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]

Chemical Structure

[0263]

Chem.

[0264]

Chem.

[0265]

Chemical Structure

[0266]

Chem.

[0267] [Chem.] Example 75: Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(oxetane-3-sulfonamido)-5-(trifluoromethyl)benzamide According to General Synthesis 2, methyl 2-bromo-5-(trifluoromethyl)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]octan-1-yl)-2-(oxetane-3-sulfonamido)-5-(trifluoromethyl)benzamide, which was purified by crystallization. 1 1H 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] [Chem.] Example 76: Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((2-methylthiazol)-5-sulfonamido)-4-(trifluoromethyl)ben zamide 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]octan-1-yl)-2-((2-methylthiazol)-5-sulfonamide)-4-(trifluoromethyl)benzamide, which was 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]

Chemical Structure

[0270]

Chem.

[0271]

Chem.

[0272]

Chemical Structure

[0273]

Chem.

[0274]

Chem.

[0275] General Synthesis 3

Chemical Structure

[0276] Step 2: N-(4-chloro-2-cyanophenyl)-2-methylpropane-2-sulfinamide (0.609 g, 2.37 mmol) was treated with a 32 wt% solution of peracetic acid in acetic acid (20.6 g, 271 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with saturated aqueous sodium bicarbonate solution. The mixture was then extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to a residue to give N-(4-chloro-2-cyanophenyl)-2-methylpropane-2-sulfonamide as a solid. LCMS-ESI - (m / z): [M-H] - 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 pellets (1.257 g, 31.43 mmol) were added to this solution and it was stirred at 100 °C for 18 h. The reaction mixture was then acidified with 1 M aqueous hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to a residue to afford 5-chloro-2-((1,1-dimethylethyl)sulfonamido)benzoic acid as a solid. LCMS-ESI - (m / z): [M-H] - calcd 290.03;found 290.06。

[0278] Step 4: A solution of 5-chloro-2-((1,1-dimethylethyl)sulfonamido)benzoic acid (0.041 g, 0.14 mmol), 3-phenylbicyclo[1.1.1]pentan-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 h. The crude product was purified by reverse phase HPLC to afford 5-chloro-2-((1,1-dimethylethyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide as a solid. 1 H 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): [M-H] - calcd 431.12;found 431.36。

[0279] [Chemistry] Example 84: Preparation of 5-chloro-2-((1,1-dimethylethyl)sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 3, 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (2.5 equivalents) was used in Step 4 to synthesize 5-chloro-2-((1,1-dimethylethyl)sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, chloroform-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): [M-H] - (m / z): [M-H] - calcd 423.08; found 423.24.

[0280] [Chemistry] Example 85: Preparation of 5-chloro-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-((1,1-dimethylethyl)sulfonamido)benzamide According to General Synthesis 3, 3-aminobicyclo[1.1.1]pentane-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)sulfonamido)benzamide. 1 H 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): [M-H] - calcd 380.08; found 380.23。

[0281] General synthesis 4

Chem.

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

[0283] Step 3: A solution of 2-((4-(methylsulfonyl)phenyl)sulfonamido)-5-(trifluoromethyl)benzoic acid (0.040 g, 0.095 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentan-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 h. The crude product was purified by reverse phase HPLC to afford 2-((4-(methylsulfonyl)phenyl)sulfonamido)-5-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benz amide 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]

Chem.

[0285]

Chem.

[0286]

Chemical Structure

[0287]

Chemistry

[0288] [Chem.] Example 91: Preparation of 5-chloro-2-((4-(methylsulfonyl)phenyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 4, methyl 2-amino-5-chlorobenzoate (1.0 equivalent) was used in Step 1, and 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride (2.0 equivalents) was used in Step 3 to synthesize 5-chloro-2-((4-(methylsulfonyl)phenyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide. 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): [M-H] - calcd 529.07; found 529.33.

[0289] [Chem.] Example 92: Preparation of 4,5-dichloro-2-((4-(methylsulfonyl)phenyl)sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 4, methyl 2-amino-4,5-dichlorobenzoate (1.0 equivalent) was used in Step 1 to synthesize 4,5-dichloro-2-((4-(methylsulfonyl)phenyl)sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 11H 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): [M-H] - calcd 554.98; found 555.28。

[0290]

Chem.

[0291]

Chem.

[0292]

Chemical Structure

[0293]

Chem.

[0294]

Chem.

[0295]

Chem.

[0296]

Chemical Structure

[0297]

Chem.

[0298]

Chem.

[0299]

Chem.

[0300]

Chem.

[0301] General Synthesis 5

Chem.

[0302] Procedure 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(diphenylphosphino)xanthene (16 mg, 0.028 mmol), and tricalcium phosphate (59 mg, 0.28 mmol). The solution was heated to 110 °C and stirred for 4 h. The volatile materials 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 combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to a residue. The residue was purified by silica flash chromatography to give 5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(propylsulfonamido)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): [M-H] - calcd 399.15;found 399.24。

[0303]

Chemical Structure

[0304] A mixture containing both methyl 2-(N-(methylsulfonyl)methylsulfonamido)-5-(trifluoromethyl)benzoate and methyl 2-(methylsulfonamido)-5-(trifluoromethyl)benzoate (unknown ratio, combined estimated 6.9 mmol) was taken as a suspension in tetrahydrofuran (30 mL) and treated with water and methanol (10 mL each), then sodium hydroxide (1.7 g, 42 mmol) was added. The mixture was allowed to stand at room temperature overnight and then, the next day, heated at 65 °C with stirring. When the hydrolysis was complete, the mixture was acidified with 10% hydrochloric acid and extracted three times with ethyl acetate (3 × 30 mL). The combined organic layers were washed once with saturated aqueous sodium chloride 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 give the desired intermediate. LCMS-ESI - (m / z): [M-H]- Calculated 282.01; found 282.02. Step 3: Preparation of tert-Butyl (4-carbamoyl-bicyclo[2.2.2]octan-1-yl)carbamate

[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) cooled in an ice-water 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 and then at room temperature for 3 hours. The mixture was sonicated for about 2 minutes and then stirred vigorously, during which time the mixture was cooled again in an ice-water bath. A solution of ammonium hydroxide (28.0 - 30.0% based on NH3, 17 mL, 125 mmol) was added, the cooling bath was removed, and the mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was partitioned between water (approx. 30 mL) and ethyl acetate (approx. 200 mL). The aqueous phase was extracted twice with ethyl acetate. The combined organics were washed successively with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium bicarbonate, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the desired intermediate. LCMS-ESI + (m / z): [M+H] + Calculated 269.18; found 269.06. Step 4: Preparation of tert-Butyl (4-cyanobicyclo[2.2.2]octan-1-yl)carbamate

[0306] Phosphorus oxychloride (9.0 mL, 96 mmol) was added via syringe with magnetic stirring to a solution of tert-Butyl (4-carbamoyl-bicyclo[2.2.2]octan-1-yl)carbamate (5.2 g, 19 mmol) in pyridine (80 mL) cooled (ice-water bath) It was added slowly via [a certain medium]. This mixture was stirred in an ice bath for 30 minutes and then for 30 minutes after removing this bath. This mixture was added via a pipette to ice water (approximately 400 mL). 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)carbamic acid tert-butyl (0.60 g, 2.4 mmol) was taken in water in a sealed container as a suspension, heated at 160 °C for 22 hours, and then allowed to cool. This mixture was treated with concentrated hydrochloric acid (0.5 mL) and concentrated to obtain a mixture of 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] + calcd 169.13;found 169.01), which was carried over without further separation. Step 6 (General Synthesis 6): Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(methylsulfonamido)-5-(trifluoromethyl)benzamide

[0308] A mixture of 2-(methylsulfonamido)-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 about 1 minute. Then a solution of 1-propanephosphonic anhydride (T3P, 50 wt% in DMF, 0.74 ml, 1.27 mmol) was added and the mixture was stirred at 85 °C overnight. 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 aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was first purified by flash chromatography (silica gel) and then by reverse phase HPLC (acetonitrile / water / 0.1% trifluoroacetic acid) to give 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]

Chemical Structure

[0310] [Chem.] Example 107: Synthesis of 2-((4-(Methylsulfonamido)phenyl)sulfonamido)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide 2-((4-Iodophenyl)sulfonamido)-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)sulfonamido)-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 taken in water and reacted at 150 °C for 5 hours with stirring. The mixture was acidified with acetic acid and purified by RP-HPLC to obtain 2-((4-(methylsulfonamido)phenyl)sulfonamido)-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): [M-H] - calcd 570.06;found 570.13.

[0311] General Syntheses 7 and 8 [Chem.] 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). The mixture was stirred overnight at room temperature. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The latter was extracted three times with ethyl acetate. The combined organic extracts were washed successively with 10% aqueous hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to afford the desired intermediate. LCMS-ESI - (m / z): [M-H] - 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 while trifluoroacetic acid (0.93 mL, 12 mmol) was added dropwise. The bath was removed and the mixture was gradually warmed to room temperature. When LC / MS analysis indicated that the conversion was complete, the mixture was concentrated under reduced pressure. The residue was co-evaporated once with diethyl ether and then carried on to the next step without further purification. LCMS-ESI - (m / z): [M-H] - calcd 145.01; found 144.92。

[0313] Step 3 (General Synthesis 8): Preparation of 2-((1-cyanocyclopropane)-1-sulfonamido)-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 (approx. 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 block at 100 °C for approximately 3 days. After cooling, the mixture was partitioned between ethyl acetate and 10% hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with water and once with saturated aqueous sodium chloride, 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 give the desired product. 11H 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): [M-H] - calcd 466.07; found 466.22。

[0314]

Chem.

[0315]

Chem.

[0316]

Chem.

[0317]

Chem.

[0318]

Chem.

[0319]

Chem.

[0320]

Chem.

[0321]

Chem.

[0322] General Synthesis 9

Chemical formula

[0323] Step 2: Preparation of 2-((1,1-dimethylethyl)sulfonamido)-N-(8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)benzamide The title compound was prepared as a mixture of diastereomers from 2-((1,1-dimethylethyl) sulfonamido)-5-(trifluoromethyl)benzoic acid (115 mg, 0.35 mmol) and 8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (79 mg, 0.39 mmol) according to General Synthesis 10. 1 H 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): [M-H] - calcd 510.14; found 510.31。

[0324] General Synthesis 10

Chemical Structure

[0325]

Chemical formula

[0326]

Chemical formula

[0327]

Chemical Structure

[0328]

Chem.

[0329]

Chem.

[0330]

Chemical Structure

[0331]

Chem.

[0332]

Chem.

[0333]

Chemical Structure

[0334]

Chem.

[0335]

Chem.

[0336]

Chemical formula

[0337]

Chem.

[0338] [Chemistry] 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 General Synthesis 5 using pyrrolidine-1-sulfonamide (1.5 eq) 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): [M-H] - calcd 426.16; found 426.30.

[0339] [Chemistry] 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 eq) in Step 2. 11H 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): [M-H] - calcd 412.14; found 412.30。

[0340]

Chem.

[0341]

Chem.

[0342]

Chem.

[0343]

Chemical formula

[0344] Procedure 2: Preparation of 3-Fluoro-2-(methylsulfonamido)-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-(methylsulfonamido)benzoic acid (0.13 g, 0.54 mmol) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (0.11 g, 0.57 mmol). 1 1H 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]

Chem.

[0346]

Chemical Structure

[0347]

Chemical formula

[0348]

Chem.

[0349]

Chem.

[0350] Step 2: Preparation of 2-((2,4-dichlorophenyl)sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to Step 3 of General Synthesis 4, 2-((2,4-dichlorophenyl)sulfonamido)benzoic acid (0.13 g, 0.36 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-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]

Chemical Structure

[0352] Step 2: Preparation of 2-fluoro-6-(methylsulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide As in Step 3 of General Synthesis 4, 2-fluoro-6-(methylsulfonamido)benzoic acid (88 mg, 0.38 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.05 equivalents) to give the desired product. 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 1 + ​(m / z): [M+H] + Calculated 367.1; found 367.0。

[0353]

Chemistry

[0354] Step 2: 2-((2,2,2-trifluoroethyl)sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide In the same manner as in Step 3 of General Synthesis 4, 2-((2,2,2-trifluoroethyl)sulfonamido)benzoic acid (0.10 g, 0.35 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-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]

Chemical Structure

[0356]

Chemical Structure

[0357]

Chemical formula

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

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

[0360] Step 4: Preparation of 2-(Methylsulfonamido)-4-(pentafluoro-λ 6 -sulfanyl)benzoic Acid The title intermediate was prepared from 2-amino-4-(pentafluoro-λ 6-sulfanyl) benzoic acid methyl ester, 4-fluoro-2-(methylsulfonamido) benzoic acid was prepared in a manner similar to the method obtained from 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: Preparation of 2-(methylsulfonamido)-4-(pentafluoro-λ 6 -sulfanyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Similar to Step 3 of General Synthesis 4, 2-(methylsulfonamido)-4-(pentafluoro-λ 6 -sulfanyl)benzoic acid (98 mg, 0.29 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.2 equiv) to obtain the desired product. 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): [M-H] - calcd 473.0; found 473.3。

[0362]

Chemical formula

[0363]

Chemical Structure

[0364] Step 2: Preparation of 4-cyano-2-(methylsulfonamido)benzoic acid A mixture of 4-iodo-2-(methylsulfonamido)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 at 140 °C overnight. The mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was taken up in water (approx. 25 mL), treated with N,N-ethylenediamine (approx. 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 aqueous sodium chloride. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the desired intermediate. LCMS-ESI - (m / z): [M-H] - calcd 239.02;found 239.03。

[0365] Step 3: Preparation of 4-cyano-2-(methylsulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide In a similar manner to Step 3 of General Synthesis 4, 4-cyano-2-(methylsulfonamido)benzoic acid (0.12 g, 0.50 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.05 equiv) to afford 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): [M-H] - calcd 372.1;found 372.3。

[0366]

Chem.

[0367] Step 2: Preparation of 4-Fluoro-2-(pyrimidine-2-sulfonamido)benzoic Acid A solution of methyl 4-fluoro-2-(N-(pyrimidin-2-ylsulfonyl)pyrimidine-2-sulfonamido)benzoate (0.92 g, 2.0 mmol) in tetrahydrofuran (15 mL) was treated with an aqueous sodium hydroxide solution (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. When the reaction was complete, the mixture was acidified to approximately pH 1 by the addition of 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, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was triturated 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): [M-H] - calcd 296.02;found 296.17。

[0368] Step 3: Preparation of 4-Fluoro-2-(pyrimidine-2-sulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 4, 4-fluoro-2-(pyrimidine-2-sulfonamido)benzoic acid (86 mg, 0.29 mmol) was coupled with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (0.32 mmol, 1.1 equiv) in Step 3 to afford 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]

Chemical formula

[0370]

Chem.

[0371] Procedure 2: Preparation of 2-((4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)sulfonamido)-5-(methylsulfonyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 4, 4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)benzenesulfonyl chloride (2.1 mmol) and methyl 2-amino-5-(methylsulfonyl)benzoate (1.7 mmol) were used in Step 1, and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (0.32 mmol, 1.2 equiv) was used in Step 3 to synthesize the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.85 (s, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 3.18 (s, 3H), 2.37 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 554.2;found 554.1.

[0372]

Chemical Structure

[0373]

Chem.

[0374] Step 2: Preparation of tributyl(tert-butylthio)stannane To a solution of 2-methyl-2-propanethiol (1.3 g, 15 mmol) and triethylamine (2.5 mL, 18 mmol) in dry carbon tetrachloride (100 mL) under argon was added tributyltin chloride (4.1 mL, 15 mmol) dropwise over 20 minutes with vigorous magnetic stirring. The suspension was stirred at room temperature for 2 days and then left standing for an additional day and overnight. The suspension was filtered through a pad of Celite diatomaceous earth. The filtrate was 5 It was washed successively with aqueous acetic acid (100 mL) and water (100 mL) of %. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the putative desired intermediate, which was carried over without further purification.

[0375] Step 3: Preparation of methyl 2-((4-(tert-butylthio)phenyl)sulfonamido)-4-fluorobenzoate A mixture of methyl 4-fluoro-2-((4-iodophenyl)sulfonamido)benzoate (0.90 g, 2.1 mmol), tributyl(tert-butylthio)stannane (1.6 g, 4.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol, 7.5 mol%) in N,N-dimethylformamide (DMF, 10 mL) was heated in a microwave reactor at 130 °C for 30 minutes. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether and washed three times with a 10% aqueous potassium fluoride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude desired intermediate, which was carried over without further purification. LCMS-ESI + (m / z): ...

Claims

1. Formula I: 【Chemical 256】 a compound of or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, wherein: Q is -S(O) ２ -, -S(O)-, -S(O)(NH)-, -S(O)(NR ８ )- and is selected from the group consisting of R １ is selected from the group consisting of C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, -NR １３ R １３ , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３～１２ cycloalkyl, and 4- to 12-membered heterocyclyl, where each of 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 is optionally further substituted with one or more R １１ groups; 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 , -SF ５ , -NO ２ , -NR １３ R １３ , -NR １３ SO ２ R １４ , -OS(O) ２ R １４ , -C(O)OR １４ , -C(O)R １４ , -NR １３ C(O)OR １４ , -NR １３ C(O)NR １３ R １３ , -NR １３ S(O) ２ NR 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 Each of heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more R ９ groups; Each R ９ is independently selected from the group consisting of -H, oxo, -OH, -CN, halo, 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 １３ R １３ -, -NR １３ C(O)OR １４ -, -OS(O) ２ R 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 SO ２ R １４ , -C(O)R １４ , -NR １３ C(O)NR １３ R １３ , -NR １３ S(O) ２ NR １３ R １３ , SF ５ and -NO ２ and is selected from the group consisting thereof, where each of 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, and 5- to 10-membered heteroaryl is optionally substituted with one or more R １６ groups; Each R １３ is independently selected from the group consisting of -H, C １～６ alkyl, C １～６ hydroxyalkyl, C １～６ heteroalkyl, C ３～６ cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein the 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 are optionally substituted with one or more R １５ groups; Each R １４ is independently selected from the group consisting of C １～６ alkyl, C １～６ hydroxyalkyl, C １～６ heteroalkyl, C ３～６ cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where the 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 are optionally substituted with one or more R １５ groups; Each R １５ is independently, -H, halo, -CN, -OH, oxo, -NO ２ , -SF ５ , 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 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) ２ NH ２ , -NH ２ , -S(O) ２ NR １６ R １６ , C(O)R １６ , -C(O)NR １６ R １６ and C(O)OR １６ is selected from the group consisting of, wherein the 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R １６ groups; Each R １６ is independently selected from the group consisting of halo, -CN, -OH, -NH ２ , oxo, -NO ２ , -SF ５ , C １～３ alkyl, C １～３ haloalkyl, C １～６ alkoxy, C １～６ haloalkoxy, C １～６ hydroxyalkyl, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3- to 6-membered cycloalkyl, -C(O)NH ２ and -S(O) ２ NH ２ and is selected from the group consisting of; R ２ is selected from the group consisting of -H, -CN, -F, -Cl, C １～３ alkyl, C １～３ haloalkyl, C １～３ heteroalkyl, C １～３ alkoxy and C １～３ haloalkoxy; R ３ and R ４ each independently is selected from the group consisting of -H, halo, -OH, -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, -SF ５ -, -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 SO ２ R １４ -, -NR １３ S(O) ２ NR 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 -, and -NO ２ wherein the 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, and 5- to 10-membered heteroaryl may be substituted with one or more R ９ The base may be further substituted as necessary; R ５ is selected from the group consisting of -H, -CN, -F, -Cl, C １～３ alkyl, C １～３ haloalkyl, C １～３ heteroalkyl, C １～３ alkoxy and C １～３ haloalkoxy; Here, R ２ and R ３ , or R ３ and R ４ , or R ４ and R ５ may optionally combine together with the atoms to which they are attached 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 fused to the phenyl to which they are attached and each being optionally substituted with one or more R ９ groups; R ６ is azabicyclo[3.2.1]octan-3-yl or oxabicyclo[3.2.1]octan-3-yl, and where R6 is substituted with one or more R ７ ; R ７ is selected from the group consisting of -H, halo, -CN, oxo, -OH, -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 , -P(O)RR １４ R １４ , -C(O)OH, -C(O)OR １４ , -C(O)NR １３ R １３ , -S(O) ２ NR １３ R １３ , and -C(O)R １４ and n is 1, 2, or 3; R ８ is selected from the group consisting of C １～６ alkyl, -C(O)R １４ cycloalkyl having 3 to 12 members, C １～６ heteroalkyl, aryl having 6 to 10 members, heteroaryl having 5 to 10 members, heterocyclyl having 4 to 12 members, -C(O)OR １４ , -C(O)NR １３ R １３ , and -SO ２ R １４ , where each of C １～６ alkyl, -C(O)R １４ cycloalkyl having 3 to 12 members, C １～６ heteroalkyl, aryl having 6 to 10 members, heteroaryl having 5 to 10 members, and heterocyclyl having 4 to 12 members is halo, -CN, oxo, hydroxyl, C １～６ alkyl, C １～６ alkoxy, -S(O) １～２ R １４ , -S(O) ２ NR １３ R １３ , -NO ２ , -SF ５ , C １～６ haloalkyl, C １～６ haloalkoxy, C １～６ hydroxyalkyl, -NR １３ R １３ , -C(O)OR １４ , C １～６ heteroalkyl, cycloalkyl having 3 to 6 members optionally substituted with one or more R １６ , heterocyclyl having 4 to 12 members optionally substituted with one or more R １６ , aryl having 6 to 10 members optionally substituted with one or more R １６ , and heteroaryl having 5 to 10 members optionally substituted with one or more R １６ is optionally substituted; wherein, C1-6 heteroalkyl contains 1 to 6 carbon atoms and 1 to 3 heteroatom groups and wherein, C1-3 heteroalkyl contains 1 to 3 carbon atoms and 1 to 3 heteroatom groups, wherein said heteroatom groups are selected from -NR-, -O-, -S-, -S(O)-, and -S(O)2-, wherein, R is H, alkyl, aryl, cycloalkyl, heteroalkyl containing 1 to 10 carbon atoms and 1 to 3 heteroatom groups, heteroaryl or heterocyclyl; provided that: (i) R ６ is azabicyclo[3.2.1]octan-3-yl or oxabicyclo[3.2.1]octan-3-yl, R ３ is H, and R ７ is, when being -H, halo, cyano, oxo, or -OH, R ４ is C ７～１２ cycloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ hydroxyalkyl, C １～６ heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, 7- to 12-membered monocyclic heterocyclyl, -SF ５ , -NR １３ R １３ , -NR １３ C(O)OR １４ , -NR １３ SO ２ R １４ , -NR １３ S(O) ２ NR 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 , -SH, and -NO ２ selected from the group consisting of, wherein the C ７～１２ cycloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ hydroxyalkyl, C １～６ heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl and 7- to 12-membered monocyclic heterocyclyl are optionally substituted with one or more R ９ ; 5- to 6-membered heterocyclyl is optionally substituted with R １７ , and 8- to 10-membered bicyclic heterocyclyl is optionally substituted with one or more R １８ which is replaced as necessary; Here, R １７ is selected from the group consisting of -OH, oxo, -CN, C ２～６ alkenyl, C ２～６ alkynyl, 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 SO ２ R １４ , -NR １３ S(O) ２ NR 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 ; And here, R １８ is C ２～６ alkenyl, C ２～６ alkynyl, 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 SO ２ R １４ , -NR １３ S(O) ２ NR 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 is selected from the group consisting of, and wherein, the compound of formula I is 【Chemical 1】 not a compound or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof.

2. Q is -S(O) ２ -, -S(O)-, and -S(O)(NR ８ )-selected from the group consisting of the compound according to claim 1

3. R １ is selected from the group consisting of C １～６ alkyl, -NR １３ R １３ , 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３～１２ cycloalkyl, and 4- to 12-membered heterocyclyl, wherein each of C １～６ alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３～１２ cycloalkyl, and 4- to 12-membered heterocyclyl is further substituted with one or more R １１ groups, the compound according to claim 1 or 2.

4. R ２ is a compound according to any one of claims 1 to 3, selected from the group consisting of -H, -CN, -F, methyl, methoxy, and C １ haloalkoxy.

5. R ２ is the compound according to claim 4 selected from the group consisting of -H and -F.

6. R ４ is selected from the group consisting of -H, halo, -OH, -CN, C １～６ alkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, C １～６ heteroalkyl, -SF ５ , -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 SO ２ R １４ , -NR １３ S(O) ２ NR 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 , and -NO ２ and is further substituted with one or more R １～６ groups, wherein the C １～６ alkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, and C ９ heteroalkyl of any one of claims 1 to 5.

7. R ４ is selected from the group consisting of -H, -F, -Cl, -OH, -CN, -S(O) ０～２ R １４ , -C(O)R １４ , -SF ５ , -NO ２ , C １～６ alkyl, and C １～６ alkoxy, and wherein the C １～６ alkyl or C １～６ alkoxy is optionally substituted with one or more -F, and R １４ is C １～６ alkyl, C ３～６ cycloalkyl, C １～６ hydroxyalkyl, and C １～６ heteroalkyl, and wherein the C １～６ alkyl, C ３～６ cycloalkyl, C １～６ hydroxyalkyl, and C １～６ heteroalkyl is optionally substituted with one or more R １６ groups, and R １６ is independently selected from the group consisting of halo, -CN, and -OH, the compound according to claim 6

8. R ４ is selected from the group consisting of -H, -F, -Cl, -OH, -CN, -SR １４ , -SF ５ , C １～６ alkyl, and C １～６ alkoxy, and wherein said C １～６ alkyl or C １～６ alkoxy is optionally substituted with one or more -F, and R １４ is selected from the group consisting of C １～３ haloalkyl, the compound according to claim 7.

9. R ３ is selected from the group consisting of -H, halo, -OH, -CN, C １～６ alkyl, 6- to 10-membered aryl, 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, -S(O) ０～２ R １４ , -NO ２ , and -SF ５ , wherein the C １～６ alkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C ３～１２ cycloalkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, and C １～６ heteroalkyl are optionally further substituted with one or more R ９ groups, a compound according to any one of claims 1 to 8.

10. R ３ is selected from the group consisting of -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 and -SF ５ wherein the C １～６ alkyl, C １～６ alkoxy, C ３～１２ cycloalkyl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R ９ and R １４ is C １～３ haloalkyl, the compound according to claim 9.

11. R ５ is a compound according to any of claims 1 to 10, selected from the group consisting of -H, -F, and methyl.

12. 【Fig. 260】 a compound selected from the group consisting of.

13. 【Fig. 262】 a compound which is.

14. Formula I: 【Chemical 256】 a compound of or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof [wherein: Q is selected from the group consisting of -S(O)2-, -S(O)-, -S(O)(NH)-, -S(O)(NR8)-; R1 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NR13R13, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl is optionally further substituted with one or more R11 groups; R11 is selected from the group consisting of hydroxyl, oxo, halo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -P(O)R14R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, -S(O)0-2R14, -S(O)1-2NR13R13, -SF5, -NO2, -NR13R13, -NR13SO2R14, -OS(O)2R14, -C(O)OR14, -C(O)R14, -NR13C(O)OR14, -NR13C(O)NR13R13, -NR13S(O)2NR13R13, and -C(O)NR13R13, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more R9 groups; Each R9 is independently selected from the group consisting of -H, oxo, -OH, -CN, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NR13R13, -NR13C(O)OR14, -OS(O)2R14, -C(O)OR14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -S(O)0-2R14, -S(O)1-2NR13R13, -C(O)NR13R13, -NR13SO2R14, -C(O)R14, -NR13C(O)NR13R13, -NR13S(O)2NR13R13, SF5 and -NO2, wherein each of C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more R16 groups; Each R13 is independently selected from the group consisting of -H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more R15 groups; Each R14 is independently selected from the group consisting of C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R15 groups; Each R15 is independently selected from the group consisting of -H, halo, -CN, -OH, oxo, -NO2, -SF5, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)(NH)R16, -S(O)(NR8)R16, -S(O)(NH)NR16R16, -S(O)(NR8)NR16R16, -S(O)0-2R16, -S(O)2NH2, -NH2, -S(O)2NR16R16, C(O)R16, -C(O)NR16R16, and C(O)OR16, wherein the 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R16 groups; Each R16 is independently selected from the group consisting of halo, -CN, -OH, -NH2, oxo, -NO2, -SF5, C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3- to 6-membered cycloalkyl, -C(O)NH2, and -S(O)2NH2; R² is selected from the group consisting of -H, -CN, -F, -Cl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ heteroalkyl, C₁₋₃ alkoxy and C₁₋₃ haloalkoxy; Each of R³ and R⁴ is independently selected from the group consisting of -H, halo, -OH, -CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF₅, -S(O)₀₋₂R₁₄, -S(O)(NH)R₁₄, -S(O)(NR₈)R₁₄, -S(O)(NH)NR₁₃R₁₃, -S(O)(NR₈)NR₁₃R₁₃, -SH, -NR₁₃R₁₃, -NR₁₃SO₂R₁₄, -NR₁₃S(O)₂NR₁₃R₁₃, -NR₁₃C(O)NR₁₃R₁₃, -NR₁₃C(O)OR₁₄, tri-C₁₋₄ alkylsilyl, -C(O)R₁₄, -C(O)OR₁₄, -C(O)NR₁₃R₁₃, and -NO₂, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally further substituted with one or more R⁹ groups; R⁵ is selected from the group consisting of -H, -CN, -F, -Cl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ heteroalkyl, C₁₋₃ alkoxy and C₁₋₃ haloalkoxy; Here, R2 and R3, or R3 and R4, or R4 and R5, together with the atoms to which they are attached, may optionally combine 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 fused to the phenyl to which they are attached and each being optionally substituted with one or more R9 groups; R6 is azabicyclo[3.2.1]octan-3-yl or oxabicyclo[3.2.1]octan-3-yl, and here R6 is substituted with one or more R7; R7 is selected from the group consisting of -H, halo, -CN, oxo, -OH, -S(O)0-2R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, -NR13R13, -P(O)R14R14, -C(O)OH, -C(O)OR14, -C(O)NR13R13, -S(O)2NR13R13, and -C(O)R14, and n is 1, 2, or 3; R8 is selected from the group consisting of C1-6 alkyl, -C(O)R14, 3- to 12-membered cycloalkyl, C1-6 heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, -C(O)OR14, -C(O)NR13R13, and -SO2R14, wherein each of C1-6 alkyl, -C(O)R14, 3- to 12-membered cycloalkyl, C1-6 heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl is optionally substituted with halo, -CN, oxo, hydroxyl, C1-6 alkyl, C1-6 alkoxy, -S(O)1-2R14, -S(O)2NR13R13, -NO2, -SF5, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxyalkyl, -NR13R13, -C(O)OR14, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl optionally substituted with one or more R16, 4- to 12-membered heterocyclyl optionally substituted with one or more R16, 6- to 10-membered aryl optionally substituted with one or more R16, and 5- to 10-membered heteroaryl optionally substituted with one or more R16; wherein C1-6 heteroalkyl contains 1 to 6 carbon atoms and 1 to 3 heteroatom groups, and wherein C1-3 heteroalkyl contains 1 to 3 carbon atoms and 1 to 3 heteroatom groups, and wherein said heteroatom groups are selected from -NR-, -O-, -S-, -S(O)-, and -S(O)2-, and wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl containing 1 to 10 carbon atoms and 1 to 3 heteroatom groups, heteroaryl or heterocyclyl; provided that: (i) when R6 is azabicyclo[3.2.1]octan-3-yl or oxabicyclo[3.2.1]octan-3-yl, R3 is H, and R7 is -H, halo, cyano, oxo, or -OH, R4 is selected from the group consisting of C7-12 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, 7-membered to 12-membered monocyclic heterocyclyl, -SF5, -NR13R13, -NR13C(O)OR14, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, tri-C1-4 alkylsilyl, -C(O)R14, -C(O)OR14, -C(O)NR13R13, -S(O)0-2R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, and -NO2, wherein the C7-12 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl and 7-membered to 12-membered monocyclic heterocyclyl are optionally substituted with one or more R9s; the 5-membered to 6-membered heterocyclyl is optionally substituted with R17, and the 8-membered to 10-membered bicyclic heterocyclyl is optionally substituted with one or more R18s; wherein R17 is selected from the group consisting of -OH, oxo, -CN, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3-membered to 12-membered cycloalkyl, 4-membered to 12-membered heterocyclyl, 6-membered to 10-membered aryl, 5-membered to 10-membered heteroaryl, -S(O)0-2R14, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, -NR13C(O)OR14, -C(O)R14, -C(O)OR14 and -C(O)NR13R13; And here, R18 is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)0-2R14, -NR13R13, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, -NR13C(O)OR14, -C(O)R14, -C(O)OR14 and -C(O)NR13R13] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog of the compound according to claim 12 or 13, or the compound according to claim 12 or 13, containing together with a pharmaceutically acceptable excipient.

15. Formula I: 【Chemical 256】 The compound or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog [where: Q is selected from the group consisting of -S(O)2-, -S(O)-, -S(O)(NH)-, -S(O)(NR8)-, R1 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NR13R13, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl, where each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl is optionally further substituted with one or more R11 groups; R11 is selected from the group consisting of hydroxyl, oxo, halo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -P(O)R14R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, -S(O)0-2R14, -S(O)1-2NR13R13, -SF5, -NO2, -NR13R13, -NR13SO2R14, -OS(O)2R14, -C(O)OR14, -C(O)R14, -NR13C(O)OR14, -NR13C(O)NR13R13, -NR13S(O)2NR13R13, and -C(O)NR13R13, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more R9 groups; Each R9 is independently selected from the group consisting of -H, oxo, -OH, -CN, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NR13R13, -NR13C(O)OR14, -OS(O)2R14, -C(O)OR14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -S(O)0-2R14, -S(O)1-2NR13R13, -C(O)NR13R13, -NR13SO2R14, -C(O)R14, -NR13C(O)NR13R13, -NR13S(O)2NR13R13, SF5 and -NO2, wherein each of C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more R16 groups; Each R13 is independently selected from the group consisting of -H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more R15 groups; Each R14 is independently selected from the group consisting of C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where the C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R15 groups; Each R15 is independently selected from the group consisting of -H, halo, -CN, -OH, oxo, -NO2, -SF5, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)(NH)R16, -S(O)(NR8)R16, -S(O)(NH)NR16R16, -S(O)(NR8)NR16R16, -S(O)0-2R16, -S(O)2NH2, -NH2, -S(O)2NR16R16, C(O)R16, -C(O)NR16R16, and C(O)OR16, where the 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R16 groups; Each R16 is independently selected from the group consisting of halo, -CN, -OH, -NH2, oxo, -NO2, -SF5, C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3- to 6-membered cycloalkyl, -C(O)NH2, and -S(O)2NH2; R2 is selected from the group consisting of -H, -CN, -F, -Cl, C1-3 alkyl, C1-3 haloalkyl, C1-3 heteroalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; Each of R3 and R4 is independently selected from the group consisting of -H, halo, -OH, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O)0-2R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, -NR13R13, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, -NR13C(O)OR14, tri-C1-4 alkylsilyl, -C(O)R14, -C(O)OR14, -C(O)NR13R13, and -NO2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally further substituted with one or more R9 groups; R5 is selected from the group consisting of -H, -CN, -F, -Cl, C1-3 alkyl, C1-3 haloalkyl, C1-3 heteroalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; Here, R2 and R3, or R3 and R4, or R4 and R5, together with the atoms to which they are attached, may optionally combine 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 fused to the phenyl to which they are attached and each being optionally substituted with one or more R9 groups; R6 is azabicyclo[3.2.1]octan-3-yl or oxabicyclo[3.2.1]octan-3-yl, and here R6 is substituted with one or more R7; R7 is selected from the group consisting of -H, halo, -CN, oxo, -OH, -S(O)0-2R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, -NR13R13, -P(O)R14R14, -C(O)OH, -C(O)OR14, -C(O)NR13R13, -S(O)2NR13R13, and -C(O)R14, and n is 1, 2, or 3; R8 is selected from the group consisting of C1-6 alkyl, -C(O)R14, 3- to 12-membered cycloalkyl, C1-6 heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, -C(O)OR14, -C(O)NR13R13, and -SO2R14, wherein each of C1-6 alkyl, -C(O)R14, 3- to 12-membered cycloalkyl, C1-6 heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl is optionally substituted with halo, -CN, oxo, hydroxyl, C1-6 alkyl, C1-6 alkoxy, -S(O)1-2R14, -S(O)2NR13R13, -NO2, -SF5, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxyalkyl, -NR13R13, -C(O)OR14, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl optionally substituted with one or more R16, 4- to 12-membered heterocyclyl optionally substituted with one or more R16, 6- to 10-membered aryl optionally substituted with one or more R16, and 5- to 10-membered heteroaryl optionally substituted with one or more R16; wherein C1-6 heteroalkyl contains 1 to 6 carbon atoms and 1 to 3 heteroatom groups, and wherein C1-3 heteroalkyl contains 1 to 3 carbon atoms and 1 to 3 heteroatom groups, and wherein said heteroatom groups are selected from -NR-, -O-, -S-, -S(O)-, and -S(O)2-, and wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl containing 1 to 10 carbon atoms and 1 to 3 heteroatom groups, heteroaryl or heterocyclyl; provided that: (i) when R6 is azabicyclo[3.2.1]octan-3-yl or oxabicyclo[3.2.1]octan-3-yl, R3 is H, and R7 is -H, halo, cyano, oxo, or -OH, R4 is selected from the group consisting of C7-12 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, 7-membered to 12-membered monocyclic heterocyclyl, -SF5, -NR13R13, -NR13C(O)OR14, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, tri-C1-4 alkylsilyl, -C(O)R14, -C(O)OR14, -C(O)NR13R13, -S(O)0-2R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, and -NO2, wherein the C7-12 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl and 7-membered to 12-membered monocyclic heterocyclyl are optionally substituted with one or more R9; the 5-membered to 6-membered heterocyclyl is optionally substituted with R17, and the 8-membered to 10-membered bicyclic heterocyclyl is optionally substituted with one or more R18; wherein R17 is selected from the group consisting of -OH, oxo, -CN, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3-membered to 12-membered cycloalkyl, 4-membered to 12-membered heterocyclyl, 6-membered to 10-membered aryl, 5-membered to 10-membered heteroaryl, -S(O)0-2R14, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, -NR13C(O)OR14, -C(O)R14, -C(O)OR14 and -C(O)NR13R13; And here, R18 is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)0-2R14, -NR13R13, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, -NR13C(O)OR14, -C(O)R14, -C(O)OR14 and -C(O)NR13R13] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog of the compound according to claim 12 or 13, a composition for treating metabolic disorders.

16. The composition according to claim 15, wherein the metabolic disorder is selected from the group consisting of diabetes (including type I and type II diabetes), metabolic syndrome, dyslipidemia, obesity, insulin resistance, hypertension, high serum cholesterol, and high triglycerides.

17. Formula I: 【Chemical 256】 a compound or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof [where: Q is selected from the group consisting of -S(O)2-, -S(O)-, -S(O)(NH)-, -S(O)(NR8)-; R1 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NR13R13, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl is optionally further substituted with one or more R11 groups; R11 is selected from the group consisting of hydroxyl, oxo, halo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -P(O)R14R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, -S(O)0-2R14, -S(O)1-2NR13R13, -SF5, -NO2, -NR13R13, -NR13SO2R14, -OS(O)2R14, -C(O)OR14, -C(O)R14, -NR13C(O)OR14, -NR13C(O)NR13R13, -NR13S(O)2NR13R13, and -C(O)NR13R13, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more R9 groups; Each R9 is independently selected from the group consisting of -H, oxo, -OH, -CN, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -NR13R13, -NR13C(O)OR14, -OS(O)2R14, -C(O)OR14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -S(O)0-2R14, -S(O)1-2NR13R13, -C(O)NR13R13, -NR13SO2R14, -C(O)R14, -NR13C(O)NR13R13, -NR13S(O)2NR13R13, SF5 and -NO2, wherein each of C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more R16 groups; Each R13 is independently selected from the group consisting of -H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more R15 groups; Each R14 is independently selected from the group consisting of C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, where the C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R15 groups; Each R15 is independently selected from the group consisting of -H, halo, -CN, -OH, oxo, -NO2, -SF5, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)(NH)R16, -S(O)(NR8)R16, -S(O)(NH)NR16R16, -S(O)(NR8)NR16R16, -S(O)0-2R16, -S(O)2NH2, -NH2, -S(O)2NR16R16, C(O)R16, -C(O)NR16R16, and C(O)OR16, where the 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R16 groups; Each R16 is independently selected from the group consisting of halo, -CN, -OH, -NH2, oxo, -NO2, -SF5, C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, 3- to 6-membered cycloalkyl, -C(O)NH2, and -S(O)2NH2; R2 is selected from the group consisting of -H, -CN, -F, -Cl, C1-3 alkyl, C1-3 haloalkyl, C1-3 heteroalkyl, C1-3 alkoxy and C1-3 haloalkoxy; Each of R3 and R4 is independently selected from the group consisting of -H, halo, -OH, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -SF5, -S(O)0-2R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, -NR13R13, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, -NR13C(O)OR14, tri-C1-4 alkylsilyl, -C(O)R14, -C(O)OR14, -C(O)NR13R13, and -NO2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally further substituted with one or more R9 groups; R5 is selected from the group consisting of -H, -CN, -F, -Cl, C1-3 alkyl, C1-3 haloalkyl, C1-3 heteroalkyl, C1-3 alkoxy and C1-3 haloalkoxy; Here, R2 and R3, or R3 and R4, or R4 and R5, together with the atoms to which they are attached, may optionally combine 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 fused to the phenyl to which they are attached and each being optionally substituted with one or more R9 groups; R6 is azabicyclo[3.2.1]octan-3-yl or oxabicyclo[3.2.1]octan-3-yl, and here R6 is substituted with one or more R7; R7 is selected from the group consisting of -H, halo, -CN, oxo, -OH, -S(O)0-2R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, -NR13R13, -P(O)R14R14, -C(O)OH, -C(O)OR14, -C(O)NR13R13, -S(O)2NR13R13, and -C(O)R14, and n is 1, 2, or 3; R8 is selected from the group consisting of C1-6 alkyl, -C(O)R14, 3- to 12-membered cycloalkyl, C1-6 heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 12-membered heterocyclyl, -C(O)OR14, -C(O)NR13R13, and -SO2R14, wherein each of C1-6 alkyl, -C(O)R14, 3- to 12-membered cycloalkyl, C1-6 heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl is optionally substituted with halo, -CN, oxo, hydroxyl, C1-6 alkyl, C1-6 alkoxy, -S(O)1-2R14, -S(O)2NR13R13, -NO2, -SF5, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxyalkyl, -NR13R13, -C(O)OR14, C1-6 heteroalkyl, 3- to 6-membered cycloalkyl optionally substituted with one or more R16, 4- to 12-membered heterocyclyl optionally substituted with one or more R16, 6- to 10-membered aryl optionally substituted with one or more R16, and 5- to 10-membered heteroaryl optionally substituted with one or more R16; wherein C1-6 heteroalkyl contains 1 to 6 carbon atoms and 1 to 3 heteroatom groups, and wherein C1-3 heteroalkyl contains 1 to 3 carbon atoms and 1 to 3 heteroatom groups, and wherein said heteroatom groups are selected from -NR-, -O-, -S-, -S(O)-, and -S(O)2-, and wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl containing 1 to 10 carbon atoms and 1 to 3 heteroatom groups, heteroaryl or heterocyclyl; provided that: (i) when R6 is azabicyclo[3.2.1]octan-3-yl or oxabicyclo[3.2.1]octan-3-yl, R3 is H, and R7 is -H, halo, cyano, oxo, or -OH; R4 is selected from the group consisting of C7-12 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl, 7- to 12-membered monocyclic heterocyclyl, -SF5, -NR13R13, -NR13C(O)OR14, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, tri-C1-4 alkylsilyl, -C(O)R14, -C(O)OR14, -C(O)NR13R13, -S(O)0-2R14, -S(O)(NH)R14, -S(O)(NR8)R14, -S(O)(NH)NR13R13, -S(O)(NR8)NR13R13, -SH, and -NO2, wherein the C7-12 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 4-membered heterocyclyl, 7-membered heterocyclyl and 7- to 12-membered monocyclic heterocyclyl are optionally substituted with one or more R9; the 5- to 6-membered heterocyclyl is optionally substituted with R17, and the 8- to 10-membered bicyclic heterocyclyl is optionally substituted with one or more R18; wherein R17 is selected from the group consisting of -OH, oxo, -CN, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)0-2R14, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, -NR13C(O)OR14, -C(O)R14, -C(O)OR14 and -C(O)NR13R13; And here, R18 is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -S(O)0-2R14, -NR13R13, -NR13SO2R14, -NR13S(O)2NR13R13, -NR13C(O)NR13R13, -NR13C(O)OR14, -C(O)R14, -C(O)OR14 and -C(O)NR13R13] or a composition for treating NAFLD, NASH, ASH or lipodystrophy containing the compound according to claim 12 or 13 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer or deuterated analog of the compound according to claim 12 or 13.

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