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 across the inner mitochondrial membrane from its matrix 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 is associated with 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). If 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 for treating 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. Furthermore, 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 mitochondrial-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 6 is 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, where 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 6is 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 heterobicyclic ring, wherein the 5- to 10-membered carbocyclic ring, the 8- to 10-membered tricyclic ring, or the 6- to 12-membered heterobicyclic ring is bridged, and the 5- to 10-membered carbocyclic ring, the 8- to 10-membered tricyclic ring, and the 6- to 12-membered heterobicyclic ring are each substituted with one or more R 7 groups.

[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 heterobicyclic ring, wherein the 5- to 10-membered carbocyclic ring or the 6- to 12-membered heterobicyclic ring is bridged, and the 5- to 10-membered carbocyclic ring and the 6- to 12-membered heterobicyclic ring are each substituted with one R 7 group.

[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 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.

[0014] In some embodiments, R 2 is selected from the group consisting of -H, -CN, -F, methyl, methoxy, and C 1 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, -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 -, -NO 2 and is selected from the group consisting of, where 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 9 groups.

[0017] In some embodiments, R 4 is -H, -F, -Cl, -OH, -CN, -S(O) 0~2 R14 , -C(O)R 14 , -SF 5 , -NO 2 , C 1~6 alkyl, and C 1~6 alkoxy selected from the group consisting of, and where this 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, C 1~6 heteroalkyl selected from the group consisting of, where 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 16 groups, and R 16 is independently selected from halo, -CN, -OH.

[0018] In some embodiments, R 4 is -H, -F, -Cl, -OH, -CN, -SR 14 , -SF 5 , C 1~6 alkyl, and C 1~6 alkoxy selected from the group consisting of, and where this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 14 is C 1~3 haloalkyl selected from the group consisting of.

[0019] In some embodiments, R 3 is -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 1~6Hydroxyalkyl, C 1~6 Heteroalkyl, -S(O) 0~2 R 14 , -NO 2 , and -SF 5 is selected from the group consisting of, 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 -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 is selected from the group consisting of, 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 , 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 -S(O) 2 -, -S(O)-, and -S(O)(NR 28 )-, and is selected from the group consisting of

[0024] In some embodiments, R 21 is 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, C 1 haloalkyl, C 1~3 heteroalkyl, methoxy, and C 1 haloalkoxy, and is selected from the group consisting of

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

[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, -SF 5 , -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)(NR28 ) NR 33 R 33 、 -NR 33 R 33 、 -NR 33 SO 2 R 34 、 -NR 33 S(O) 2 NR 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 、 -NO 2 selected from the group consisting of, where C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl is further substituted with one or more R 29 groups.

[0028] In some embodiments, R 24 is selected from the group consisting of -H, -F, -Cl, -OH, -CN, S(O) 0~2 R 34 、 -C(O)R 34 、 -NO 2 、 -SF 5 、 C 1~6 alkyl, and C 1~6 alkoxy, and where this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 34 is selected from the group consisting of C 1~6 alkyl, C 3~6 cycloalkyl, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, where this C 1~6 alkyl, C 3~6 cycloalkyl, C 1~6Hydroxyalkyl, and C 1~6 heteroalkyl are 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 selected from the group consisting of -H, -F, -Cl, -OH, -CN, -SR 34 , -SF 5 , C 1~6 alkyl, and C 1~6 alkoxy, and where this C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with one or more -F, and R 34 is selected from the group consisting of C 1~3 haloalkyl.

[0030] In some embodiments, R 23 is selected from the group consisting of -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, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, -S(O) 0~2 R 34 , -NO 2 and -SF 5 , and where 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 23is 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 -SF 5 and is selected from the group consisting of, wherein this C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 heteroalkyl is 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) 2 NR 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; 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 55 .

[0034] In some embodiments, R 47 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 54 , -C(O)OH, -C(O)OR 54 , -C(O)NR 53 R 53 , -S(O) 2 NR 53 R 53 , -C(O)R 54 , 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 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and each of 3- to 6-membered cycloalkyl is optionally substituted with one or more R 56 .

[0035] In some embodiments, R 47is -H, halo, -CN, -OH, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6 heteroalkyl, and selected from the group consisting of 6- to 10-membered aryl, where this 6- to 10-membered aryl, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, and C 1~6 heteroalkyl each may be substituted with one or more R 56 as needed, where R 56 is halo, -CN, -NO 2 , -SF 5 , 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 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, where C 1~6 alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 cycloalkyl, and 4- to 12-membered heterocyclyl each may be further substituted with one or more R 51 groups as needed.

[0037] In some embodiments, R 51 is hydroxyl, oxo, halo, -CN, C 1~6 alkyl, C1~6 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 R 53 , -S(O) 0~2 R 54 , -S(O) 1~2 NR 53 R 53 , -SF 5 , -NO 2 , -NR 53 R 53 , -NR 53 SO 2 R 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, wherein 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 are each 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 SO 2 R 54 , -C(O)R 54 , -SF 5 , and -NO 2 selected from the group consisting of, where C 1~3 alkyl, C 1~3 alkoxy, each of 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, C 1 haloalkyl, C 1~3 heteroalkyl, methoxy and C 1 haloalkoxy.

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

[0041] In some embodiments, R 44 is -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 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 , -NR53 R 53 、 -NR 53 SO 2 R 54 、 -NR 53 S(O) 2 NR 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 、 -NO 2 selected from the group consisting of, 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 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 、 -NO 2 、 -SF 5 、 C 1~6 alkyl, and C 1~6 alkoxy, and where 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, where 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 , -SF 5 , 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 -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, -SF 5 , -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 SO 2 R 54 , -NR 53 S(O) 2 NR 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)NR53 R 53 、 and -NO 2 selected from the group consisting of, where 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, -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 , -C(O)R 54 selected from the group consisting of, where C 1~3 alkyl, C 1~3 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and 3 - to 6 - membered cycloalkyl are each 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 -NO 2 is selected from the group consisting of, 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)OR 54 , -S(O) 0~2 R 54 , -S(O) 1~2 NR 53 R 53 , -C(O)R 54 is 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

[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 1~6 alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3~12 cycloalkyl, and 4- to 12-membered heterocyclyl each is optionally substituted with one or more R71 It is further substituted by a group.

[0051] In some embodiments, R 62 is selected from the group consisting of -H, -CN, -F, methyl, C 1 haloalkyl, C 1~3 heteroalkyl, methoxy and C 1 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, -SF 5 , -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 SO 2 R 74 , -NR 73 S(O) 2 NR 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 , -NO 2 and is selected from the group consisting of, where C 1~6Alkyl, 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 , -SF 5 , -NO 2 , 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 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 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 , -SF 5 , 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, R63 is -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, -SF 5 , -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 SO 2 R 74 , -NR 73 S(O) 2 NR 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 -NO 2 selected from the group consisting of, 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 1~3Alkyl, C 1~3 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 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, C 1 ~6 hydroxyalkyl, C 1~6 heteroalkyl, and 3- to 6-membered cycloalkyl are each 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, -SF 5 , -S(O) 0~2 R 74 , and -NO 2 selected from the group consisting of, 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 69is -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)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 3- to 6-membered cycloalkyl are each 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 )NR 13 R 13 , -NR 13 R 13 , -C(O)OH, -C(O)OR 14 , -C(O)NR 13 R 13 , -S(O) 2 NR 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 3 - to 12 - membered cycloalkyl is optionally substituted with one or more R 15 . Compounds of formula I are provided.

[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) 2 NR 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 alkynyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and 3- to 6-membered cycloalkyl are each optionally substituted with one or more R 16 and provided is 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; wherein 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 are each optionally substituted with one or more R 16 ; where R 16 is selected from halo, -CN, -NO 2 , -SF 5 , C 1~3 alkyl, C 1~3 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl; provided is a compound of formula I;

[0065] In another embodiment, R 8 is 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 -SO 2 R 14 selected from the group consisting of, where C 1~6 alkyl, 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 are each optionally substituted with one or more R 16 groups, compounds of formula I are provided.

[0066] In another embodiment, R 27 is selected from the group consisting of -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) 2 NR 33 R 33 , -C(O)R 34 , 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 2~6Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Each of heteroalkyl and 3- to 12-membered cycloalkyl is optionally substituted with one or more R 35 to provide a compound of formula II;

[0067] In another embodiment, R 27 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 34 , -C(O)OH, -C(O)OR 34 , -C(O)NR 33 R 33 , -S(O) 2 NR 33 R 33 , -C(O)R 34 , 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 1~6 hydroxyalkyl, C 1~6 heteroalkyl, and 3- to 6-membered cycloalkyl is optionally substituted with one or more R 36 to provide a compound of formula II.

[0068] In another embodiment, R 27 is -H, halo, -CN, -OH, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 1~6Selected from the group consisting of heteroalkyl and 6- to 10-membered aryl, where the 6- to 10-membered aryl, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, and C 1~6 each of the heteroalkyls is optionally substituted with one or more R 36 where R 36 is halo, -CN, -NO 2 , -SF 5 , C 1~3 alkyl, C 1~3 haloalkyl , C 1~6 alkoxy, C 1~6 haloalkoxy, thiohaloalkyl, sulfonylalkyl, sulfonylhaloalkyl, sulfonylcycloalkyl, and a compound of formula II is provided;

[0069] In another embodiment, R 28 is C 1~6 alkyl, -C(O)R 34 , 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 34 , -C(O)NR 33 R 33 , and -SO 2 R 34 selected from the group consisting of, where C 1~6 alkyl, 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 are each optionally substituted with one or more R 36 , and a compound of formula II is provided;

[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.

BEST MODE FOR CARRYING OUT THE INVENTION

[0072] DETAILED DESCRIPTION OF THE INVENTION Definitions The following description sets forth methods and parameters, among other things. However, such description is not intended as a limitation on the scope of the present disclosure and should be recognized as being 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 a substituent. For example, -C(O)NH 2 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 otherwise 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 values or parameters herein as "about" include (and describe) embodiments that recite the value or parameter itself. In certain embodiments, the term "about" includes the recited amount ±10%. In other embodiments, the term "about" includes the recited amount ±5%. In certain other embodiments, the term "about" includes the recited 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 a plurality of such compounds, and a reference to "an assay" includes reference 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 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 can be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3) sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ) isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 ) and "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 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, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

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

[0081] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. As used herein, alkoxy includes cyclic hydrocarbons bonded 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. In this specification, for simplicity, whether that moiety is monovalent, divalent, or polyvalent, the names "alkyl, alkenyl, and alkynyl" are presented. The same can be said for all substituents in this specification that can have different names based on valence.

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

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

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

[0086] "Thiocycloalkyl" refers to the group "C 3 - 6 cycloalkyl-S-".

[0087] "Sulfonylalkyl" refers to 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 "C 3 - 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 multiple 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 with heteroaryl, the resulting ring system is heteroaryl. When one or more aryl groups are fused with heterocyclyl, the resulting ring system is heterocyclyl.

[0092] "Cyano" means the group -CN.

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

[0094] "Carbamoyl" means the "O-carbamoyl" group of the group -O-C(O)NR y R z and the group -NRy C(O)OR z refers to both the "N-carbamoyl" group, where R y and R z are 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 ring systems 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), etc.

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

[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, it means that one or two oxygen atoms may be present. For example, S(O) 0 R 14 is synonymous with SR 14 .

[0103] "Halo" or "halogen" 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 may be referred to by using a prefix corresponding to the number of attached halogen moieties. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may be the same or different halogens. Examples of haloalkyls include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ).

[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 may be independently replaced by the same or different heteroatom groups. Examples of heteroatom groups include -NR-, -O-, -S-, -S(O)-, and -S(O) 2 - etc., but are not limited thereto, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -CH 2 OCH 3 , -CH 2 SCH 3 , -CH 2 S(O)CH 3 , and -CH 2 S(O) 2 CH 3include, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl contains 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 having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 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 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 independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, but are not limited thereto, where this heteroaryl may be attached via 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., via any one of the fused rings). Heteroaryl does not include aryl as defined above and does not overlap with aryl.

[0106] "Heterocyclyl" independently refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms 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 rest of the molecule, and this ring may be fused to an aryl ring or a heteroaryl ring. As used herein, heterocyclyl has

[0107] 4 to 20 ring atoms (i.e., 4- to 20-membered heterocyclyl), 4 to 12 ring atoms (i.e., 4- to 12-membered heterocyclyl), 4 to 10 ring atoms (i.e., 4- to 10-membered heterocyclyl), 4 to 8 ring atoms (i.e., 4- to 8-membered heterocyclyl), or 4 to 6 ring carbon atoms (i.e., 4- to 6-membered heterocyclyl); and independently 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. 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 Structure

[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 nitrogen and sulfur atoms 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, wherein one or more hydrogen atoms are replaced by hydroxyl.

[0110] "Nitro" refers to the group -NO 2 .

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

[0112] "Alkylsulfonyl" refers to the group -S(O) 2 R, 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] Specific alternative chemical names that are commonly used may be used. 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 part in this specification (e.g., arylalkyl), the last-mentioned group contains the atom to which this part is attached to the rest 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 this description includes both the case where the event or situation occurs and the case where it does not occur. Also, the term "substituted as required" 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. "Substituted as required" can be from zero to the maximum number of possible substitutions, and each occurrence is independent. When the term "substituted (with)" is used, the substitution must be made at the position of the replaceable hydrogen atom of the indicated substituent. Substitutions as required may be the same as (required) substitutions or different.

[0121] When a moiety is "substituted as required" and this reference is made to a general term such as any "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)", and 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. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with their imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between 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 form and the isotopically labeled form of the compound. Isotopically labeled compounds have 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 isotope-labeled compounds of the present disclosure, for example, radioactive isotopes, such as 3 H, 13 C and 14 C incorporated ones. Such isotope-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 the 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 isotope-labeled compounds and their prodrugs of the present disclosure can generally be prepared by substituting unlabeled isotopes with readily available isotope-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 isotope 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 isotope 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. Thereby, acid salts and / or base salts can be formed.

[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 salt" of a given compound refers to a salt that maintains the biological effectiveness and properties of the given compound and is 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 formed 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 basic compounds. Those skilled in the art recognize the various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic 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. Salts derived from organic bases include, for example, alkylamines (i.e., NH 2 (alkyl)), dialkylamines (i.e., HN(alkyl) 2 ), trialkylamines (i.e., N(alkyl) 3 ), substituted alkylamines (i.e., NH 2 (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., NH 2(alkenyl)), dialkenylamine (i.e., HN(alkenyl) 2 ), trialkenylamine (i.e., N(alkenyl) 3 ), substituted alkenylamine (i.e., NH 2 (substituted alkenyl)), di(substituted alkenyl)amine (i.e., HN(substituted alkenyl) 2 ), tri(substituted alkenyl)amine (i.e., N(substituted alkenyl) 3 , mono-, di- or tri-cycloalkylamine (i.e., NH 2 (cycloalkyl), HN(cycloalkyl) 2 , N(cycloalkyl) 3 ), mono-, di- or tri-arylamine (i.e., NH 2 (aryl), HN(aryl) 2 , N(aryl) 3 ), or salts of primary amines, secondary amines and tertiary amines such as mixed amines, 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 and the like.

[0130] The term "substituted" means that one or more hydrogen atoms of the designated atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. 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, nit Examples include, but are not limited to, oxo, 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 five 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 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 herein are to 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 compositions. Compounds having such stability are contemplated 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 above-described definitions and substituents should not result in species or compounds that are impossible to implement.

[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. The use thereof in therapeutic compositions is contemplated except where any conventional media and agent is incompatible with the active ingredient. 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. The use thereof in therapeutic compositions is contemplated except where any conventional media and agent is incompatible with the active ingredient. 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] While the active ingredients can be administered alone, these active ingredients are 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 formulations suitable for the above 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 (e.g., carrier, pharmaceutical excipient, etc.) that 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 wax.

[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 amount of a convenient carrier material (e.g., an 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. Suitable 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. Accordingly, 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. Finally, it is within the discretion of the trained physician to determine the appropriate dosage and route of administration suitable for a particular patient having a particular disease or disorder to be treated.

[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 Tablet formulations are prepared 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 inhaler.

[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 obtained powder, and then this is 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, this is compressed by 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 pre-melted using the minimum heat required. Then, this mixture is poured into a suppository mold of nominal 2.0 g capacity 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 pre-prepared microcrystalline cellulose and sodium carboxymethyl cellulose. 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 while stirring. Then, add a sufficient amount of 60°C water while stirring vigorously 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 Hydroxypropyl methylcellulose 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 (e.g., 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 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 may contain coloring agents, plasticizers, and other auxiliary components as necessary.

[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 the 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 the 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 disease involves progressive destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis. Generally, chronic liver disease can be caused by viruses (e.g., hepatitis B, hepatitis C, cytomegalovirus (CMV), or Epstein-Barr virus (EBV)), toxic 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 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, the liver disease is a metabolic liver disease. In one embodiment, the 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 medications, such as amiodarone, antiviral drugs (e.g., nucleoside analogs), aspirin (rarely as part of Reye's syndrome in children), corticosteroids, methotrexate, tamoxifen, or tetracycline. NAFLD has also been 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 traits 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 where steatosis is accompanied by inflammation and fibrosis. NASH is considered 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 liver fibrosis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I). Liver fibrosis is an excessive accumulation of extracellular matrix proteins including collagen, which occurs in most types of chronic liver diseases. In certain embodiments, advanced liver 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 liver fibrosis, which is the formation of fibrous tissue, fibroids or fibrotic degeneration, is reduced by more than about 90%. In one embodiment, the level of liver fibrosis, which is the formation of fibrous tissue, fibroids 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. Liver fibrogenesis is a process that results in the accumulation of excessive extracellular matrix components of the liver, known as fibrosis. This is, 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 mansoni of the liver. In one embodiment, the level of fibrosis is reduced by more than about 90%. In one embodiment, the level of fibrosis is at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5% or at least 2%.

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

[0173] Also disclosed herein is a method for treating or preventing a cardiovascular disorder in a patient in need thereof, 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 pectoris (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 for improving a pathological consequence or outcome associated with oxidative stress in a patient in need thereof, 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, but 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 a disease or condition 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 related to 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 ma 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 LRRInhibitors of PYD domain-containing protein 3 (NLRP3), NAD-dependent deacetylase sirtuin stimulators, NADPH oxidase inhibitors (NOX), nicotinic acid receptor 1 agonists, P2Y13 purinergic receptor stimulators, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor beta modulators, phospholipase C inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gamma agonists, PPAR gamma modulators, protease-activated receptor-2 antagonists, protein kinase modulators, Rho-associated protein kinase inhibitors, sodium glucose transporter-2 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, suppressors of cytokine signaling-1 stimulators, suppressors of cytokine signaling-3 stimulators, transforming growth factor beta (TGF-β), transforming growth factor beta-activated kinase 1 (TAK1), thyroid hormone receptor beta agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, or YAP / TAZ modulators.

[0179] Non-limiting examples of therapeutic agents and targets include the following: ACE inhibitors, 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, e.g., O-304; Angiotensin II AT-1 receptor antagonists, e.g., irbesartan; Autotaxin inhibitors, e.g., PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063; Bioactive lipids, e.g., DS-102; Cannabinoid receptor type 1 (CNR1) inhibitors, e.g., namacizumab, GWP-42004; Caspase inhibitors, e.g., emricasan; Pan cathepsin B inhibitors, e.g., VBY-376; Pan cathepsin inhibitors, e.g., VBY-825; CCR2 / CCR5 chemokine antagonists, e.g., cenicriviroc; CCR2 chemokine antagonists, e.g., propagermanium; CCR3 chemokine antagonists, e.g., bertilimumab; Chloride channel stimulators, e.g., cobiprostone; Diacylglycerol acyltransferase 2 (DGAT2) inhibitors, e.g., IONIS-DGAT2Rx, PF-06865571; Diacylglycerol acyltransferase 1 (DGAT1) inhibitors, e.g., GSK-3008356; Dipeptidyl peptidase IV inhibitors, e.g., linagliptin, evogliptin; Eotaxin ligand inhibitors, e.g., bertilimumab; Extracellular matrix protein modulators, e.g., 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, for example, KBP-042, MSDC-0602K, Px-102, RG-125 (AZD4076), VVP-100X; Beta Klotho (KLB)-FGF1c agonists, for example, NGM-313; 5-lipoxygenase inhibitors, for example, tipelukast (MN-001); Lipoprotein lipase inhibitors, for example, CAT-2003; LPL gene stimulants, for example, alipogene tiparvovec; Liver X receptor (LXR) inhibitors, for example, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238; Lysophosphatidic acid-1 receptor antagonists, for example, BMT-053011, UD-009, AR-479, ITMN-10534, BMS-986020, KI-16198; Lysyl oxidase homolog 2 inhibitors, for example, simtuzumab; MEKK-5 protein kinase (ASK-1) inhibitors, for example, selonsertib; Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, for example, PXS-4728A; Methionine aminopeptidase-2 inhibitors, for example, ZGN-839; Methyl CpG binding protein 2 modulators, for example, mercaptamine; Mineralocorticoid receptor antagonist (MCRA), for example, MT-3995; Myelin basic protein stimulants, for example, olesoxime; Myeloperoxidase inhibitors, for example, PF-06667272; NADPH oxidase 1 / 4 inhibitors, for example, GKT-831; Nicotinic acid receptor 1 agonists, for example, ARI-3037MO; NACHT LRR PYD domain-containing protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6; Nuclear receptor modulators, such as DUR-928; P2Y13 purinergic receptor agonists, such as CER-209; PDE3 / 4 inhibitors, such as cilomilast (MN-001); PDE5 inhibitors, such as sildenafil; PDGF receptor beta modulators, such as BOT-191, BOT-509; PPAR agonists, such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, IVA-337; Protease-activated receptor-2 antagonists, such as PZ-235; Protein kinase modulators, such as CNX-014; Rho-associated protein kinase (ROCK) inhibitors, such as KD-025; Sodium glucose cotransporter-2 (SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, sotagliflozin; SREBP transcription factor inhibitors, such as CAT-2003, MDV-4463; Stearoyl-CoA desaturase-1 inhibitors, such as aramchol; Thyroid hormone receptor beta agonists, such as MGL-3196, MGL-3745, VK-2809; TLR-4 antagonists, such as JKB-121; Tyrosine kinase receptor modulators, such as CNX-025; GPCR modulators, such as CNX-023; Nuclear hormone receptor modulators, such as 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, ceronsertib, GS-9674, hydrochlorothiazide,icosapent ethyl ester, IMM-124-E, INT-767, IONIS-DGAT2Rx, ipragliflozin, Irbesarta, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452, LMB-763, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MSDC-0602K, namasizumab, 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, pegidacakin, 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, statin (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV-45478, tipepidast (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, besimodegib, bolicivabat 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 ℃ 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 MgSO 4 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 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 in this specification 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] Example 1: Preparation of 4-Fluoro-2-(methylsulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide

[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 h. The reaction was quenched with 1 N HCl and stirred for 5 min. The mixture was extracted with DCM (3 times). The combined organic layers were washed with brine and dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography to afford 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 h. The reaction was quenched with 1 N HCl and concentrated. The crude product was diluted with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine and dried over MgSO 4 and filtered and concentrated to afford 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 addition of 1N HCl. The mixture was extracted with EtOAc (3 times) and the combined organic layers were washed with brine, dried over anhydrous MgSO 4 and filtered and concentrated. The crude product was purified by silica gel chromatography followed by crystallization to afford 4-fluoro-2-(methylsulfonamido)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, DMSO-d 6 ) 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] Step 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 was concentrated and the crude product was purified by reverse phase chromatography to give 2-(cyclopropanesulfonamido)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. H NMR 1 (400 MHz, DMSO-d 6 ) 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.] Example 3: Preparation of 2-((4-(tert-butyl)phenyl)sulfonamido)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 1, 4-tert-butylbenzenesulfonyl chloride (1.5 equivalents) was used in Step 1, and the reaction mixture was stirred at room temperature for 48 hours. 3-(Trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride was used in Step 3 to obtain 2-((4-(tert-butyl)phenyl)sulfonamido)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide after purification by reverse-phase chromatography. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.81 (s, 1H), 9.49 (s, 1H), 7.81 (dd, J = 8.9, 6.2 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.63 - 7.57 (m, 2H), 7.25 (dd, J = 10.9, 2.6 Hz, 1H), 7.04 (td, J = 8.6, 2.6 Hz, 1H), 2.32 (s, 6H), 1.26 (s, 9H). LCMS-ESI + (m / z): [M+H] + Calculated 485.15; found 485.09.

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

[0192]

Chemical Structure

[0193]

Chem.

[0194]

Chem.

[0195]

Chemical Structure

[0196]

Chemical Structure

[0197]

Chem.

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

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

[0200]

Chemical Structure

[0201]

Chem.

[0202]

Chem.

[0203]

Chem.

[0204]

Chemical Structure

[0205]

Chemical Structure

[0206]

Chemical Structure

[0207]

Chem.

[0208]

Chem.

[0209]

Chem.

[0210]

Chemical Structure

[0211]

Chem.

[0212]

Chem.

[0213]

Chem.

[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 Structure] Step 1: According to Step 1 of General Synthesis 1, 4-Iodobenzenesulfonyl chloride (1.3 equivalents) was used at room temperature for 48 hours to synthesize methyl 4-fluoro-2-((4-iodophenyl)sulfonamido)benzoate, and it was purified by silica gel chromatography. LCMS-ESI + (m / z): [(M - CH 3 OH)+H] + calcd 403.93; found 404.04。

[0216] Procedure 2: A 10 mL vial 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 h and then stirred at room temperature for 48 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO 4 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. 1 H NMR (400 MHz, DMSO-d 6) 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 formula

[0222]

Chemical Structure

[0223]

Chem.

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

[0225] Example 36: Preparation of 2-((4-(1H-imidazol-1-yl)phenyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide [Chemistry] Steps 1-3: According to General Synthesis 1, ethyl 2-aminobenzoate and 4-iodobenzenesulfonyl chloride (1.2 equiv) were used in Step 1 at room temperature for 48 h, and then 3-phenylbicyclo[1.1.1]pentan-1-amine hydrochloride was used in Step 3 to synthesize 2-((4-iodophenyl)sulfonamido)-N-(3-phenylbicyclo[1.1.1]pentan-1-yl)benzamide, which was purified by silica gel chromatography. LCMS-ESI + (m / z): [M+H] + calcd 545.04; found 545.07。

[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-d 6 ) 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.

[0235]

Chem.

[0236]

Chemical Structure

[0237]

Chem.

[0238]

Chem.

[0239]

Chemical Structure

[0240]

Chem.

[0241]

Chem.

[0242]

Chemical Structure

[0243]

Chemical Structure

[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 times). The combined organic layers were washed with brine, dried over MgSO 4 and 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-d 6 ) 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] + Calculated 453.15; found 453.00

[0247]

Chem.

[0248]

Chem.

[0249]

Chemical Structure

[0250]

Chem.

[0251]

Chem.

[0252]

Chemical Structure

[0253]

Chem.

[0254]

Chem.

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

[0256]

Chem.

[0257]

Chem.

[0258]

Chem.

[0259]

Chemical Structure

[0260]

Chem.

[0261]

Chem.

[0262]

Chemical Structure

[0263]

Chem.

[0264] [Chemistry] Example 72: Preparation of N-(4-cyanobicyclo[2.2.2]octan-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 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-((1-methylethyl)sulfonamido)-5-(trifluoromethyl)benzamide, which was purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.92 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 8.7 Hz,1H), 3.50 - 3.39 (m, 1H), 2.01 (s, 12H), 1.24 (d, J = 6.8 Hz, 6H). LCMS-ESI + (m / z): [M+H] + calcd 444.16;found 444.09.

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

[0266]

Chemical Structure

[0267]

Chem.

[0268] [Chemistry] Example 76: Preparation of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((2-methylthiazol)-5-sulfonamido)-4-(trifluoromethyl)benz enzamide 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-sulfonamido)-4-(trifluoromethyl)benzamide, which was purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d 6 ) 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] [Chemistry] Example 77: Preparation of 4-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1,1-dimethylethyl)sulfonamido)benzamide According to step 3 of general synthesis 1, 2-bromo-4-cyanobenzoic acid and 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride were used, and then 2-methylpropane-2-sulfonamide (2.0 equivalents) was used in general synthesis 8 to synthesize 4-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1,1-dimethylethyl)sulfonamide)benzamide, which was purified by reverse-phase chromatography. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.48 (s, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 1.99 (s, 12H), 1.28 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 415.18;found 414.93.

[0270]

Chemical Structure

[0271]

Chem.

[0272]

Chem.

[0273]

Chemical formula

[0274]

Chem.

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

[0276] Step 2: N-(4-chloro-2-cyanophenyl)-2-methylpropane-2-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. The mixture was then 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 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 give 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 give 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] - Calculated 431.12; found 431.36

[0279]

Chem.

[0280]

Chem.

[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 give 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 give 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-d 6 ) 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]

Chem.

[0288] [Chemical formula] 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] [Chemical formula] 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. 1 H NMR (400 MHz, DMSO-d 6) 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]

Chemical Structure

[0296]

Chemical Structure

[0297]

Chem.

[0298]

Chem.

[0299]

Chemical Structure

[0300]

Chem.

[0301] General Synthesis 5

Chem.

[0302] Step 2: A solution of 2-bromo-5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)benzamide (50 mg, 0.14 mmol) and propane-1-sulfonamide (26 mg, 0.21 mmol) in 1 mL of toluene was treated with tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol), 9,9-dimethyl-4,5-bis(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 afford 5-cyano-N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-(propylsulfonamido)benzamide. 1 H NMR (400 MHz, DMSO-d 6 ) 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]

Chem.

[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, then the next day it was 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 were added 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) 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% base, 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 3 (m / z): [M+H] + Calculated 269.18; found 269.06. + 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 [the specific means]. 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), and this was carried over without further separation. Step 6 (General Synthesis 6): Preparation of N - (4 - cyanobicyclo[2.2.2]octan - 1 - yl)-2 - (methylsulfonamide)-5 - (trifluoromethyl)benzamide

[0308] A mixture of 2-(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-propane phosphonic 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-d 6 ) 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 give 2-((4-(methylsulfonamido)phenyl)sulfonamido)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide. 1 H NMR (400 MHz, DMSO-d 6 ) 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 Synthesis 7 and 8 [Chemical formula] 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 obtain 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-water 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 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 each with water and 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. 1 H NMR (400 MHz, DMSO-d 6) 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] [Chemical formula] Example 114: Synthesis of N-(4-cyanobicyclo[2.2.2]octan-1-yl)-2-((1,1-dimethylethyl)sulfonamido)-4-(trifluoromethyl)benzamide N-(4-Cyanobicyclo[2.2.2]octan-1-yl)-2-((1,1-dimethylethyl)sulfonamido)-4-(trifluoromethyl)benzamide was synthesized by following General Synthesis 3, using 2-bromo-4-(trifluoromethyl)benzonitrile (1 equivalent) in Step 1 and 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride (1.8 equivalents) in Step 4. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.49 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 2.00 (s, 12H), 1.27 (s, 9H). LCMS-ESI - (m / z): [M-H] - calcd 456.16; found 456.32.

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

[0321]

Chemical Structure

[0322] General Synthesis 9

Chemical Structure

[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-d 6 ) 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 Structure

[0326]

Chemical Structure

[0327]

Chemical Structure

[0328]

Chem.

[0329]

Chem.

[0330]

Chemical Structure

[0331]

Chem.

[0332]

Chem.

[0333]

Chemical Structure

[0334]

Chem.

[0335]

Chem.

[0336]

Chemical Structure

[0337]

Chem.

[0338] [Chemical formula] 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-d 6 ) 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] [Chemical formula] 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. 1 H NMR (400 MHz, DMSO-d 6) 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] Step 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-d 6 ) δ 9.57 (singlet, 1H), 9.29 (singlet, 1H), 7.45 (doublet of doublet of doublets, J = 10.1, 7.2, 2.6 Hz, 1H), 7.38 (multiplet, 2H), 3.09 (singlet, 3H), 2.32 (singlet, 6H). LCMS-ESI + (m / z): [M+H] + calcd 367.1;found 367.0).

[0345]

Chemical Structure

[0346]

Chemical Structure

[0347] [Chemical Structure] Example 139: Preparation of N-(cubane-1-yl)-4-fluoro-2-(methylsulfonamido)benzamide Following the same procedure as in Step 3 of General Synthesis 4, 4-fluoro-2-(methylsulfonamido)benzoic acid (80 mg, 0.34 mmol) was coupled with cubane-1-amine hydrochloride (PharmaBlock, 1.05 equiv) to afford the desired product. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.76 (s, 1H), 9.51 (s, 1H), 8.02 (dd, J = 9.0, 6.3 Hz, 1H), 7.31 (dd, J = 11.2, 2.6 Hz, 1H), 7.05 (ddd, J = 8.9, 8.1, 2.6 Hz, 1H), 4.20 (m, 3H), 3.94 (m, 4H), 3.22 (s, 3H). LCMS-ESI + (m / z): [M+H] + calcd 335.1; found: 335.0。

[0348]

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-d 6 ) 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 In the same manner 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 equiv) to give the desired product. 1 H NMR (400 MHz, DMSO-d 6 ​) δ 9.51 (s, 1H), 9.33 (s, 1H), 7.48 (td, J = 8.3, 6.4 Hz, 1H), 7.33 - 7.23 (m, 1H), 7.13 (ddd, J = 9.5, 8.4, 1.0 Hz, 1H), 3.08 (s, 3H), 2.33 (s, 6H). LCMS-ESI + (m / z): [M+H] + calcd 367.1; found 367.0。

[0353]

Chem.

[0354] Project 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-d 6 ) 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 under a hydrogen atmosphere for 3 hours and then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain the desired substance. LCMS-ESI + (m / z): [M+H] + calcd 264.00; found 263.96。

[0359] Step 3: Preparation of Methyl 2-Amino-4-(pentafluoro-λ 6 -sulfanyl)benzoate To a cold (ice 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 2.0 M trimethylsilyldiazomethane in hexane (1.8 mL, 3.7 mmol) was added via syringe over 5 minutes. After stirring overnight at room temperature, the mixture was cooled in an ice 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 obtain 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, prepared in a method similar to the method for obtaining 4-fluoro-2-(methylsulfonamido)benzoic acid 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 equivalents) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d 6 ) 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 Structure

[0363]

Chemical formula

[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 obtain 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 the same manner as in 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 equivalents) to obtain the desired product. 1 H NMR (400 MHz, DMSO-d 6 ) 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]

Chemical Structure

[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 eq) in Step 3 to afford the desired product. 1 H NMR (400 MHz, DMSO-d 6 ) 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 Structure

[0370]

Chemical formula

[0371] Step 2: 2-((4-(2-(methyl-d 3)Propan-2-yl-1,1,1,3,3,3-d 6 ) (phenyl)sulfonamido)-5-(methylsulfonyl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide Preparation According to General Synthesis 4, 4-(2-(methyl-d 3 )Propan-2-yl-1,1,1,3,3,3-d 6 )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 eq) was used in Step 3 to synthesize the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) 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 formula] Example 152: Preparation of 2-((4-(tert-butylsulfonyl)phenyl)sulfonamido)-4-fluoro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)benzamide According to General Synthesis 4, 2-((4-(tert-butylsulfonyl)phenyl)sulfonamido)-4-fluorobenzoic acid (0.15 g, 0.31 mmol) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (1.1 eq) were coupled in Step 3 to obtain the desired product.1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.76 (s, 1H), 9.46 (s, 1H), 7.99 (s, 4H), 7.77 (dd, J = 8.9, 6.2 Hz, 1H), 7.25 (dd, J = 10.5, 2.6 Hz, 1H), 7.12 (m, 1H), 2.29 (s, 6H), 1.21 (s, 9H). LCMS-ESI + (m / z): [M+H] + calcd 549.11; found 548.95。

[0373]

Chem.

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, 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 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, 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 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, 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 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 each be substituted with one or more R ９ The base is further optionally substituted; 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 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 -SO ２ R １４ selected from the group consisting of, where 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, and 4- to 12-membered heterocyclyl each 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, 3- to 6-membered cycloalkyl optionally substituted with one or more R １６ 4- to 12-membered heterocyclyl optionally substituted with one or more R １６ 6- to 10-membered aryl optionally substituted with one or more R １６ 5- to 10-membered heteroaryl optionally substituted with one or more R １６ and 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 it is -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, where 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 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 is selected from the group consisting of 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 compounds according to any one of claims 1-5.

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 said 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 said 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 the 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 selected from the group consisting of, 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 one 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 that 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, 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 may optionally combine 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 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, 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 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, in combination with a pharmaceutically acceptable excipient.

15. Formula I: 【Chemical 256】 A compound of 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, 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- 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 R9s; 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 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- 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 compound according to claim 12 or 13 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer or deuterated analog of a 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 Formula 256】 a compound of 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 R9s; 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 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- 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.

Images