Novel HDAC inhibitors and their therapeutic uses

Abstract

Described herein are novel compounds, compositions, and methods for treating diseases, including cancer, using such compounds, compositions, and methods. The compounds include those having the formula (I): An example is TIFF2024543207000561.tif42165.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 285,558, filed December 3, 2021, the entire disclosure of which is incorporated herein by reference in its entirety and for all purposes. Provided herein are compounds and compositions and methods thereof. In some embodiments, compounds are provided for inhibiting histone deacetylase (HDAC). In some embodiments, methods are provided for treating diseases or disorders such as cancer. [Background technology]

[0002] Histone deacetylases (HDACs) are a class of epigenetic proteins implicated in various diseases, including cancer, and inhibiting specific HDACs in certain patients may treat or otherwise ameliorate such diseases. There are four families of HDACs, encompassing 18 HDAC isoforms. Jenke, R., et al. Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives. Cancers 13:634 (2021). While several HDAC inhibitors have been approved by the U.S. Food and Drug Administration (FDA), it is not known that currently approved HDAC therapies are specific to only a few HDAC isoforms, increasing the potential for adverse effects due to broad inhibitory properties. Therefore, there is a need for selective HDAC inhibitors for treating diseases or disorders such as cancer. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Jenke, R., et al.Anticancer Therapy with HDAC Inhibitors:Mechanism-Based Combination Strategies and Future Perspectives.Cancers 13:634(2021) Summary of the Invention

[0004] In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is an optionally substituted aryl or heteroaryl; L 1 is -CR'2-, -CR'2CR'2-, or a bond; each R' is independently H or C1-C6 alkyl, or two R's together with the carbon or carbons to which they are attached form a 3- to 6-membered cycloalkyl ring; Each R 1 , R 3 , and R 4 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen; R 2 each is optionally substituted aryl or heteroaryl; R 5 is NH2 or OH, R 6 is H or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2-heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted; R 8 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is optionally substituted, or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, a composition is provided comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0006] In some embodiments, methods are provided for treating a disease or disorder that can be treated by inhibition of HDAC, comprising administering to a patient in need thereof a compound described herein or a composition described herein.

[0007] In some embodiments, there is provided the use of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder that can be treated by the inhibition of histone deacetylase (HDAC). In some embodiments, there is provided the use of a compound disclosed herein in the manufacture of a medicament for treating cancer.

[0008] In one embodiment, there is provided the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a composition as described herein, in the treatment of a disease or disorder that can be treated by the inhibition of histone deacetylase (HDAC).

[0009] In one embodiment, there is provided a compound described herein or a pharmaceutically acceptable salt thereof, or a composition as described herein, for use in a method for treating a disease or disorder that can be treated by inhibition of histone deacetylase (HDAC), the method comprising administering to a patient in need thereof a compound described herein or a pharmaceutically acceptable salt thereof, or a composition as described herein.

[0010] Further objects and advantages of the present invention will be apparent to those skilled in the art from the disclosure herein, which is intended to be illustrative only and not limiting. Accordingly, other embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0011] In some embodiments, provided herein are compounds useful for treating diseases or disorders associated with the inhibition of HDAC (e.g., cancer) (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), or compounds in Table 1, or pharmaceutically acceptable salts thereof).

[0012] compound Provided herein is a compound of Formula (I). Unless the context requires otherwise, throughout this specification, reference to a "compound of Formula (I)" or "compounds of Formula (I)" refers to all embodiments of Formula (I), including, for example, compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), and (If), as well as the compounds in Table 1. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided. In some embodiments, a compound of Formula (I) is provided as a pharmaceutically acceptable salt. In some embodiments, a compound of Formula (I) is provided as the corresponding free base (i.e., not a salt).

[0013] In some embodiments, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is an optionally substituted aryl or heteroaryl; L 1 is -CR'2-, -CR'2CR'2-, or a bond; each R' is independently H or C1-C6 alkyl, or two R's together with the carbon or carbons to which they are attached form a 3- to 6-membered cycloalkyl ring; Each R 1 , R 3 , and R 4 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen; R 2 each is optionally substituted aryl or heteroaryl; R 5 is NH2 or OH, R 6 is H or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted; R 8 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted or R 7 and R 8are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is optionally substituted, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is an aryl or heteroaryl having 5 to 10 ring atoms and 1 to 4 ring atoms selected from N, O, and S; ... 9 is substituted with a group, L 1 is -CR'2-, -CR'2CR'2-, or a bond; each R' is independently H or C1-C6 alkyl, or two R's together with the carbon or carbons to which they are attached form a 3- to 6-membered cycloalkyl ring; Each R 1 , R 3 , and R 4 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, heteroaryl having 5 to 10 ring atoms and having 1 to 4 ring atoms selected from N, O, and S; R 2 is 0 to 4 R 10 is substituted with a group, R 5 is NH2 or OH, R 6 is H or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2)0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, wherein the heteroaryl has 5 to 10 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl has 0 to 4 R 11 is substituted with a group, R 8 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', where the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl or heteroalkyl is substituted with 0 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is substituted with 0 to 4 R 10 or substituted with a group R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is joined to 0-4 R 10 is substituted with a group, Each R 9 are independently C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 4 groups independently selected from halogen and OH; Each R 10 or R 11 are independently C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D2, or halogen; heterocyclyl has 4 to 11 ring atoms, with 1 to 4 ring atoms selected from N, O, and S; each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E is optionally replaced by Each R C are independently H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 4 substituents independently selected from halogen and OH; or Two Rs attached to the same nitrogen D are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, which heterocycle is optionally substituted with 1-4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; Provided herein is the compound, or a pharmaceutically acceptable salt thereof, wherein W is 0, 1, or 2.

[0015] In some embodiments, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is an aryl or heteroaryl having 5 to 10 ring atoms and 1 to 4 ring atoms selected from N, O, and S; ... 9 is substituted with a group, L 1 is -CR'2-, -CR'2CR'2-, or a bond; each R' is independently H or C1-C6 alkyl, or two R's together with the carbon or carbons to which they are attached form a 3- to 6-membered cycloalkyl ring; Each R 1 , R 3 , and R 4 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, heteroaryl having 5 to 10 ring atoms and having 1 to 4 ring atoms selected from N, O, and S; R 2 is 0 to 4 R 10 is substituted with a group, R 5 is NH2 or OH, R 6 is H or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, wherein the heteroaryl has 5 to 10 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl has 0 to 4 R 11 is substituted with a group, R 8is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', where the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl or heteroalkyl is substituted with 0 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is substituted with 0 to 4 R 10 or substituted with a group R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is joined to 0-4 R 10 is substituted with a group, Each R 9 are independently C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 4 groups independently selected from halogen and OH; Each R 10 and R 11 are independently C1-C6 alkyl, C1-C6 alkenyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen; heterocyclyl has 4 to 11 ring atoms, with 1 to 4 ring atoms selected from N, O, and S; each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E is optionally replaced by Each R C are independently H, OH, and NR 122. C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 4 substituents independently selected from halogen and OH; or Two Rs attached to the same nitrogen D are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, which heterocycle is optionally substituted with 1-4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; Each R E are independently H, halo, OH, O-C1-C6 alkyl, C1-C6 alkyl, -C1-C6 haloalkyl; Each R 12 are independently H or C1-C6 alkyl, W is 0, 1, or 2. The compound or a pharmaceutically acceptable salt thereof is provided.

[0016] As generally defined herein, A is an optionally substituted aryl or heteroaryl. In some embodiments, A is an aryl or heteroaryl, where heteroaryl has 5-10 ring atoms and 1-4 ring atoms selected from N, O, and S, and A is 0-4 R 9 is substituted with an R 9 is as defined herein. In some embodiments of the compounds of Formula (I), A is phenyl or heteroaryl, where heteroaryl has 5, 6, or 9 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and A is selected from 0 to 4 R9 is substituted with a group.

[0017] In some embodiments, A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, benzothiophene, thienopyridine (e.g., thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3-b]pyridine), or furopyridine (e.g., furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-b]pyridine), each of which is selected from 0-9 R 9 is substituted with a group.

[0018] In some embodiments, A is phenyl, benzofuran, or benzothiophene, each of which contains 0-9 R 9 is substituted with a group.

[0019] In some embodiments, A is 0 to 9 R 9 It is a phenyl substituted with a group.

[0020] In some embodiments, A is 0 to 9 R 9 It is a benzofuran substituted with a group.

[0021] In some embodiments, A is 0 to 9 R 9 It is a benzothiophene substituted with a group.

[0022] In some embodiments, A is 0 to 9 R 9 In some embodiments, A is a thiazole substituted with 0 to 9 R groups. 9 In some embodiments, A is a thiophene substituted with 0-9 R groups. 9 In some embodiments, A is a pyridine substituted with 0-9 R groups. 9 In some embodiments, A is a pyridazine substituted with 0 to 9 R groups. 9In some embodiments, A is a thienopyridine substituted with 0 to 9 R groups (e.g., thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3-b]pyridine). 9 and furopyridines substituted with a group (for example, furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-b]pyridine).

[0023] In some embodiments, A is [ka] Each is selected from 0 to 9 R 9 group, wherein the left attachment point is: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0024] In some embodiments, A is [ka] Each is selected from 0 to 9 R 9 group, wherein the left attachment point is: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0025] In some embodiments of the compounds of Formula (I), A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, or benzothiophene; Here, for example, A is [ka] A is 0 to 4 R 9 is substituted with a group.

[0026] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0027] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0028] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0029] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0030] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0031] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0032] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0033] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0034] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0035] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0036] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0037] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0038] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0039] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0040] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0041] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0042] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0043] In some embodiments, A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl.

[0044] In some embodiments of compounds of Formula (I), A is any R 9 It is not substituted with any group.

[0045] As generally defined herein, L 1 is -CR'2-, -CR'2CR'2-, or a bond, where R' is as defined herein.

[0046] In some embodiments of the compounds of Formula (I), L 1 is a bond.

[0047] In some embodiments, L 1 is -CR'2-. In some embodiments, L 1 is -CR'2CR'2-. In some embodiments, L 1 is a bond, -CH2-, and [ka] In some embodiments, L 1 is selected from a bond and —CH—. In some embodiments, L 1 is a bond and [ka] In some embodiments, L 1 is -CH-. In some embodiments, L 1teeth, [ka] is.

[0048] As generally defined herein, each R 1 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen. In some embodiments of the compound of Formula (I), R 1 is H. In some embodiments, R 1 is selected from H, -Me, -CF3, -Cl, and -F.

[0049] As generally defined herein, each R 3 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen. In some embodiments of the compound of Formula (I), R 3 is H. In some embodiments, R 3 is selected from H, -Me, -CF3, -Cl, and -F.

[0050] As generally defined herein, each R 4 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen. In some embodiments of the compound of Formula (I), R 4 is H. In some embodiments, R 4 is selected from H, -Me, -CF3, -Cl, and -F.

[0051] In some embodiments of the compounds of Formula (I), R 1 is H or R 3 is H or R 4 is H or R 1 , R 3 , and R 4 Each of is H.

[0052] As generally defined herein, R 5 is —NH or —OH. In some embodiments of the compounds of Formula (I), R5 is —NH. In some embodiments, R 5 is -OH.

[0053] As generally defined herein, R 6 is H or C1-C6 alkyl. In some embodiments of the compound of Formula (I), R 6 is H. In some embodiments, R 6 is selected from H and -Me. In some embodiments, R 6 is Me.

[0054] As generally defined herein, each R 2 is independently aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted. In some embodiments, R 2 is aryl or heteroaryl, where heteroaryl has 5 to 10 ring atoms and has 1 to 4 ring atoms selected from N, O, and S; R 2 is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), and R 10 is as defined herein.

[0055] In some embodiments of the compounds of Formula (I), R 2 is phenyl or monocyclic heteroaryl, where heteroaryl has 5 or 6 ring atoms and has 1 to 2 ring atoms selected from N, O, and S; R 2 is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), and R 10 is as defined herein. In some embodiments, R 2 is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), where R 10is as defined herein. In some embodiments, R 2 is a monocyclic heteroaryl, where the heteroaryl has 5 or 6 ring atoms and has 1 to 2 ring atoms selected from N, O, and S; R 2 is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), and R 10 is as defined herein. In some embodiments of the compounds of Formula (I), R 2 is a monocyclic heteroaryl, where heteroaryl is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, or thiophene (where, for example, R 2 is 2-thiophenyl), each R 2 is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), and R 10 is as defined herein. In some embodiments, R 2 are selected from phenyl, pyridine, pyrimidine, pyridazine, pyrazine, thiazole, and thiophene, each of which is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 is substituted with a group).

[0056] In some embodiments, R 2 is selected from phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, 4-pyridine, 3-pyridazine, pyrazine, 2-thiazole, 5-thiazole, 2-thiophene, and 3-thiophene, each of which is selected from 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), where R 10 is as defined herein.

[0057] In some embodiments, R 2are selected from phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, 4-pyridine, 3-pyridazine, 5-thiazole, 2-thiophene, and 3-thiophene, each of which is selected from 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), where R 10 is as defined herein.

[0058] In some embodiments, R 2 are selected from phenyl and thiophene, each of which has 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), where R 10 is as defined herein.

[0059] In some embodiments, R 2 are selected from phenyl and 2-thiophene, each of which is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), where R 10 is as defined herein.

[0060] In some embodiments, R 2 is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), where R 10 is as defined herein.

[0061] In some embodiments, R 2 is 0 to 4 R 10 groups (e.g., 0, 1, 2, 3, or 4 R 10 group), where R 10 is as defined herein.

[0062] In some embodiments, R 2is unsubstituted. In some embodiments, R 2 is one R 10 where R 10 is as defined herein. In some embodiments, R 2 is two R 10 where R 10 is as defined herein. In some embodiments, R 2 is three R 10 where R 10 is as defined herein. In some embodiments, R 2 is four R 10 where R 10 is as defined herein.

[0063] In some embodiments of the compounds of Formula (I), R 2 teeth, [ka] is selected from the group consisting of Here, for example, R 2 teeth, [ka] is.

[0064] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0065] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0066] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0067] As generally defined herein, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, where each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted or 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, wherein the heterocycle is optionally substituted.

[0068] In some embodiments, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted.

[0069] In some embodiments, R 7is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, where heteroaryl has 5 to 10 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl has 0 to 4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group) or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, wherein the heterocycle is 10 is substituted with an R 10 and R 11 is as defined herein.

[0070] In some embodiments, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, where heteroaryl has 5 to 10 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl is selected from 0 to 4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group), and R 11is as defined herein.

[0071] In some embodiments, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or monocyclic heteroaryl, where the heteroaryl has 5 or 6 ring atoms and has 1-2 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, and heteroaryl is selected from 0-4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group) or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, wherein the heterocycle is 10 is substituted with an R 10 and R 11 is as defined herein.

[0072] In some embodiments, R 7 is a C1-C6 alkyl, a C1-C6 heteroalkyl, a C3-C7 cycloalkyl, a phenyl, or a monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms and has 1 to 2 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, and heteroaryl is selected from 0 to 4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group), and R 11 is as defined herein.

[0073] In some embodiments, R 7is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or monocyclic heteroaryl, where the heteroaryl has 5 or 6 ring atoms and has 1-2 ring atoms that are N, and where each alkyl, heteroalkyl, phenyl, cycloalkyl, and heteroaryl is selected from 0-4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group) or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0 additional ring heteroatoms, wherein the heterocycle is 10 is substituted with an R 10 and R 11 is as defined herein.

[0074] In some embodiments, R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or monocyclic heteroaryl, where the heteroaryl has 5 or 6 ring atoms and has 1-2 ring atoms that are N, and each alkyl, heteroalkyl, phenyl, cycloalkyl, and heteroaryl is selected from 0-4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group), and R 11 is as defined herein.

[0075] In some embodiments, R 7 is selected from -Me, -Et, -CF, CHCHOMe, phenyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyridinonyl, each of which is selected from 0 to 4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group) or R 7 and R 8are taken together with the nitrogen and sulfur to which they are attached to form a 5- or 6-membered heterocycle having 0 additional ring heteroatoms, wherein the heterocycle is substituted with 0 or 1 methyl or phenyl; R 10 and R 11 is as defined herein.

[0076] In some embodiments, R 7 is selected from -Me, -Et, -CF, CHCHOMe, phenyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyridinonyl, each of which is selected from 0 to 4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group), where R 11 is as defined herein.

[0077] In some embodiments, R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or 6-membered heteroaryl, where heteroaryl has 1 or 2 nitrogen ring atoms, or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N; R 7 is 0 to 4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group), where R 11 is as defined herein.

[0078] In some embodiments, R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or 6-membered heteroaryl, where heteroaryl has 1 or 2 nitrogen ring atoms; R 7 is 0 to 4 R 11groups (i.e., 0, 1, 2, 3, or 4 R 11 group), and R 11 is as defined herein.

[0079] In some embodiments of the compounds of Formula (I), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or 6-membered heteroaryl, where the heteroaryl has 1 or 2 nitrogen ring atoms, or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N; R 7 is 0 to 4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group), where R 11 is as defined herein.

[0080] In some embodiments of the compounds of Formula (I), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or 6-membered heteroaryl, where heteroaryl has 1 or 2 nitrogen ring atoms; R 7 is 0 to 4 R 11 groups (i.e., 0, 1, 2, 3, or 4 R 11 group), and R 11 is as defined herein.

[0081] In some embodiments, R 7 is unsubstituted (i.e., 0 R 11 In some embodiments, R 7 is one R 11 In some embodiments, R 7 is two R 11In some embodiments, R 7 is three R 11 In some embodiments, R 7 is four R 11 It is substituted with an R group. 11 is as defined herein.

[0082] In some embodiments, R 7 -Me, -Et, -CF3, -CH2CH2OMe, [ka] Selected from or R 7 and R 8 are grouped together with the atoms to which they are attached, [ka] is formed.

[0083] In some embodiments, R 7 -Me, -Et, -CF3, -CH2CH2OMe, [ka] is selected from.

[0084] In some embodiments of the compounds of Formula (I), R 7 is Me, Ph, CF3, -CH2CH2OCH3, cyclopropyl, [ka] is selected from the group consisting of Here, for example, R 7 is Me.

[0085] In some embodiments, R 7 is Me or cyclopropyl.

[0086] In some embodiments of the compounds of Formula (I), R7 is Me. In some embodiments, R 7 is -Et. In some embodiments, R 7 is —CF. In some embodiments, R 7 is —CHCHOMe. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0087] As generally defined herein, R 8 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', where each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted or R7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, wherein the heterocycle is optionally substituted and R' is as defined herein.

[0088] In some embodiments, R 8 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', where the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl or heteroalkyl is substituted with 0 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is substituted with 0 to 4 R 10 or substituted with an R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is joined to 0-4 R 10 groups, where R′ and R 10 is as defined herein.

[0089] In some embodiments, R 8 is H, C1-C6 alkyl, cycloalkyl, cyano, CO-R', or CO2-R', or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0 additional ring heteroatoms, and the heterocycle is 10 groups, where R′ and R 10 is as defined herein. In some embodiments, R 8is H, C1-C6 alkyl, cycloalkyl, cyano, CO-C1-C6 alkyl, or CO2-C1-C6 alkyl, or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 5-6 membered heterocycle having 0 additional ring heteroatoms, wherein the heterocycle is 10 is substituted with an R 10 is as defined herein.

[0090] In some embodiments, R 8 is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or -CO2-t-butyl, or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 5-6 membered heterocycle having 0 additional ring heteroatoms, wherein the heterocycle is substituted with 0 or 1 methyl or phenyl.

[0091] In some embodiments, R 8 is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or -CO2-t-butyl, or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached, [ka] is formed.

[0092] In some embodiments, R 8 is H, C1-C6 alkyl, cycloalkyl, cyano, CO-R', or CO2-R', where R' is as defined herein. In some embodiments, R 8 is H, C1-C6 alkyl, cycloalkyl, cyano, CO-C1-C6 alkyl, or CO2- C1 ~C6 alkyl.

[0093] In some embodiments, R 8 is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or -CO2-t-butyl.

[0094] In some embodiments, R 8 is H. In some embodiments, R 8 is Me. In some embodiments, R 8 is Et. In some embodiments, R 8 is CN. In some embodiments, R 8 is cyclopropyl. In some embodiments, R 8 is CO-t-butyl. In some embodiments, R 8 is -CO2-t-butyl.

[0095] In some embodiments of the compounds of Formula (I), R 8 is H, Me, Et, CN, cyclopropyl, or -CO2-t-butyl, where, for example, R 8 is H.

[0096] In some embodiments of the compounds of Formula (I), R 8 is H.

[0097] In some embodiments of the compounds of Formula (I), R 7 and R 8 are linked together to form propylene (-CH-CH-CH-). In some embodiments of the compound of Formula (I), R 7 and R 8 are linked together to form ethylene (-CH2-CH2-).

[0098] In some embodiments, R 7 and R 8 are grouped together with the atoms to which they are attached, [ka] In some embodiments, R 7 and R8 are taken together with the nitrogen and sulfur to which they are attached, [ka] is formed.

[0099] In some embodiments, R 7 and R 8 are grouped together with the atoms to which they are attached, [ka] is formed.

[0100] In some embodiments, R 7 and R 8 are grouped together with the atoms to which they are attached, [ka] (e.g., including the individual enantiomers thereof).

[0101] In some embodiments, R 7 and R 8 are grouped together with the atoms to which they are attached, [ka] is formed.

[0102] In some embodiments, R 7 and R 8 are grouped together with the atoms to which they are attached, [ka] (e.g., including the individual enantiomers thereof).

[0103] As generally defined herein, each R 9is independently C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, or halogen, where each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH. 9 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, or halogen. 9 is independently selected from -Me, -Et, -iPr, -tBu, -CF, -OMe, cyclopropyl, hydroxy, cyano, -F, or -Cl. 9 is independently selected from -Me and -F.

[0104] As generally defined herein, each R 10 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl has 1 to 4 R E and optionally substituted with R C , R D , R E is as defined herein.

[0105] In some embodiments, each R 10 is phenyl, cyano, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, and CO-R Care independently selected from R C is as defined herein, and said alkyl is unsubstituted or substituted with 1 to 4 groups independently selected from halogen and OH.

[0106] In some embodiments, each R 10 is phenyl, halogen, C1-C6 alkyl, and CO-R C are independently selected from, where R C is —NH 2 , wherein the alkyl is unsubstituted or substituted with 1 to 4 groups independently selected from halogen and OH.

[0107] In some embodiments, each R 10 is halogen, C1-C6 alkyl, and CO-R C are independently selected from, where R C is —NH, and the alkyl is unsubstituted or substituted with 1 to 4 groups independently selected from halogen and OH. In some embodiments, each R 10 is halogen, C1-C6 alkyl, and CO-R C are independently selected from, where R C is —NH 2 , wherein the alkyl is unsubstituted or substituted with 1 to 4 groups independently selected from F and OH.

[0108] In some embodiments, each R 10 are independently selected from halogen and C1-C6 alkyl, where the alkyl is unsubstituted or substituted with 1 to 4 groups independently selected from halogen and OH. In some embodiments, each R 10 are independently selected from halogen and C1-C6 alkyl, where the alkyl is unsubstituted or substituted with 1 to 4 groups independently selected from F and OH. In some embodiments, each R 10 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 10is independently halogen or C1-C6 alkyl. In some embodiments, R 10 is halogen. In some embodiments, R 10 is a C1-C6 alkyl.

[0109] In some embodiments, each R 10 is independently selected from phenyl, -F, -Cl, -Me, CF, -CONH, and -CH(OH)CH. In some embodiments, each R 10 are independently selected from -F, -Cl, -Me, CF3, -CONH2, and -CH(OH)CH3.

[0110] In some embodiments, each R 10 is independently selected from -F and -Me. In some embodiments, R 10 is -F. In some embodiments, R 10 is -Me.

[0111] In some embodiments, R 10 is phenyl.

[0112] As generally defined herein, each R 11 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl has 1 to 4 R E optionally substituted with R C , R D , R Eis as defined herein.

[0113] In some embodiments, each R 11 are independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, and halogen, wherein the alkyl and heteroalkyl are optionally substituted with 1 to 4 groups independently selected from halogen and OH.

[0114] In some embodiments, each R 11 -F, -Cl, -Me, - i independently selected from —Pr, —C(═CH 2 )CH 3 , —CF 3 , —CN, —OH, —OMe, —CH 2 OCH 2 CH 2 OMe, and —CH 2 OH.

[0115] As generally defined herein, each R C are independently H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; R 12 is as defined herein. In some embodiments, each R C are independently H, OH, NH2, NHMe, NMe2, Me, Et, i Pr, t Bu, OMe, OEt, O i Pr, O t Bu, or CHCHOMe. In some embodiments, each R C are independently NH2, NHMe, NMe2, OMe, OEt, O i Pr, or O t In some embodiments, each R C are independently NH2.

[0116] As generally defined herein, each R Dare independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, C1-C6 heteroalkyl, where each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, or two R D are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, which heterocycle is optionally substituted with 1-4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH, where w is as defined herein. In some embodiments, each R D is selected from H, Me, Et, COMe, COtBu, COOMe, COOtBu, SOMe, and SO2Me, or two R D are taken together to form a heterocycle selected from azetidine, pyrrolidine, and piperidine. D is selected from H and Me, or two R D are taken together to form a heterocycle selected from azetidine, pyrrolidine, and piperidine. D is selected from H and Me. In some embodiments, two R D are taken together to form a heterocycle selected from azetidine, pyrrolidine, and piperidine. D are independently H.

[0117] As generally defined herein, each R' is independently H or C1-C6 alkyl, or two R's, together with the carbon or carbons to which they are attached, form a 3- to 6-membered cycloalkyl ring. In some embodiments, each R' is independently H or Me, or two R's, together with the carbon or carbons to which they are attached, form a 3- to 6-membered cycloalkyl ring. In some embodiments, each R' is independently H or Me, or two R's, together with the carbon or carbons to which they are attached, form a 3- to 4-membered cycloalkyl ring. In some embodiments, each R' is independently H or Me, or two R's, together with the carbon or carbons to which they are attached, form a cyclopropyl ring. In some embodiments, both R's are H. In some embodiments, one R' is Me and the remaining R' is H. In some embodiments, two R's on the same carbon atom are Me. In some embodiments, two R' together with the carbon to which they are attached form a cyclopropyl.

[0118] In some embodiments, each R' is independently H, Me, Et, i Pr, or t In some embodiments, R' is Bu. In some embodiments, R' is Me. In some embodiments, R' is t It's Bu.

[0119] As generally defined herein, each R E is independently H, halo, OH, O-C1-C6 alkyl, C1-C6 alkyl, or -C1-C6 haloalkyl. E is independently H or C1-C6 alkyl. In some embodiments, each R E is independently H, Cl, F, OH, OMe, CF, or Me. In some embodiments, each R E is H. In some embodiments, each R E is Me.

[0120] As generally defined herein, each R 12 is independently H or C1-C6 alkyl. In some embodiments, each R 12 is independently H or Me. In some embodiments, each R 12 is independently H. In some embodiments, each R 12 is, independently, Me.

[0121] As generally defined herein, w is 0, 1, or 2. In some embodiments, w is 0 or 1. In some embodiments, w is 1 or 2. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2.

[0122] In some embodiments of the compound of Formula (I), the compound has the formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 1 is N or CH, and X 2 is N or CH, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined herein.

[0123] In some embodiments of the compound of Formula (I), the compound has the formula (Ib): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0124] In some embodiments of the compound of Formula (I), the compound has the formula (Ic): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined herein.

[0125] In some embodiments of the compound of Formula (I), the compound has the formula (Id): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, and R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0126] In some embodiments of the compound of Formula (I), the compound has the formula (Ie): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 4 is N or CH, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined herein.

[0127] In some embodiments of the compound of Formula (I), the compound has the formula (If): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 4 is N or CH, and R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0128] In some embodiments, the compound has the formula (Ig): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 5 is N or CH, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined herein.

[0129] In some embodiments, the compound has formula (Ih): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 5 is N or CH, and R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0130] In some embodiments, the compound has formula (Ii): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, X 6 is N or CH, and X 7 is N or CH, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined herein.

[0131] In some embodiments, the compound has formula (Ij): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, X 6 is N or CH, and X 7 is N or CH, and R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0132] In some embodiments, X 6 is N and X 7 is CH.

[0133] In some embodiments, X 6 is CH and X 7 is N.

[0134] In some embodiments, the compound has the formula (Ik): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, X8 is N or CH, and X 9 is N or CH, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined herein.

[0135] In some embodiments, the compound has the formula (Im): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, X 8 is N or CH, and X 9 is N or CH, and R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0136] In some embodiments, X 8 is N and X 9 is CH.

[0137] In some embodiments, X 8 is CH and X 9 is N.

[0138] In some embodiments, the compound has the formula (In): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 , and R 8 is as defined herein.

[0139] In some embodiments, the compound has formula (Io): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, and R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0140] In some embodiments, the compound has the formula (Ip): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined herein.

[0141] In some embodiments, the compound has formula (Iq): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, and R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0142] In some embodiments, the compound has the formula (Ir): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is as defined herein.

[0143] In some embodiments, the compound has the formula (Is): [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, and R 2 , R 5 , R 7 , and R 8 is as defined herein.

[0144] In some embodiments, X 3 is S.

[0145] In some embodiments, X 3 is O.

[0146] In some embodiments of the compound of Formula (I), the compound is selected from the compounds disclosed in Table 1 or a pharmaceutically acceptable salt thereof, or elsewhere herein and in the figures.

[0147] In some embodiments, provided herein are compositions comprising a compound described herein and a pharmaceutically acceptable excipient.

[0148] In some embodiments, the compound is a compound identified in Table 1 below, or a pharmaceutically acceptable salt thereof.

[0149] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as shown. Compounds marked with (or) or (rel) in Table 1 and the Examples section are single enantiomers to which the absolute stereochemistry has been assigned as appropriate (e.g., based on the chiral SFC elution described in the Examples section). Compounds marked with (and) or (rac) are mixtures of enantiomers, where the relative stereochemistry is as shown. Compounds with an asymmetric center for which the configuration is not shown in the structure shown and there is no indication in the stereochemistry column of Table 1 are mixtures of enantiomers at that center. Compounds with an asymmetric center for which the configuration is shown in the structure shown and there is no indication or marked with (abs) in the stereochemistry column of Table 1 are single enantiomers, where the absolute stereochemistry is as shown.

[0150] One of ordinary skill in the art would be able to separate racemic compounds into their individual enantiomers using methods known in the art, such as chiral chromatography, chiral recrystallization, etc. Reference to a compound that is a racemic mixture is intended to encompass each individual enantiomer contained in the mixture. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

[0151] Treatment method In some embodiments, provided herein are methods for treating a disease or disorder that can be treated by inhibition of HDAC, the methods comprising administering to a patient in need thereof a compound described herein or a composition described herein.

[0152] In some embodiments, provided herein are methods of treating a human or animal subject having or diagnosed with a disease or disorder (e.g., cancer) that can be treated by inhibition of HDAC, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention (e.g., a compound of Formula (I) or a compound of Table 1) or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the disease or disorder is cancer.

[0154] In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or a sarcoma.

[0155] In some embodiments, the cancer is selected from the group consisting of brain tumors, such as astrocytoma and glioblastoma, brain metastases, medulloblastoma, meningioma, and oligodendroglioma; tumors of the peripheral or central nervous system; neuronal tumors; non-Hodgkin's lymphomas, such as low-grade non-Hodgkin's lymphoma, Burkitt's lymphoma; lymphomas (lymphosarcoma); Hodgkin's disease, non-Hodgkin's lymphoma; bone cancer; leukemias, such as acute lymphocytic leukemia / acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia; intestinal cancers, such as rectum, colon, colorectal cancer, anal cancer, and carcinoma of the large intestine; pancreatic cancer or carcinoma of the pancreas; gallbladder cancer; bile duct cancer; liver cancer; stomach cancer or gastric cancer. carcinoma); bladder cancer or carcinoma of the bladder; kidney cancer; lung cancer (bronchial carcinoma), for example, small cell bronchial carcinoma and non-small cell bronchial carcinoma (NSCLC); plate epithelial carcinoma, adenocarcinoma, and large cell bronchial carcinoma; breast cancer; uterine or endometrial cancer; ovarian cancer or ovarian carcinoma; testicular cancer; penile cancer; prostate cancer; vaginal cancer; cancer of the urethra and vulva; laryngeal cancer; head and neck tumors; throat cancer or carcinoma of the pharynx; esophageal cancer; melanoma; epidermoid carcinoma and plate epithelial carcinoma of the skin; retinoblastoma, thyroid cancer; thymoma or carcinoma of unknown primary site (CUP).

[0156] In some embodiments, the cancer is HDAC-associated glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or a sarcoma.

[0157] In some embodiments, the cancer (e.g., an HDAC-associated cancer) is cancer of unknown primary (CUP), colorectal cancer (e.g., colon cancer), cervical cancer, or non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma). In some embodiments, the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma). In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is colorectal cancer (e.g., colon cancer). In some embodiments, the cancer is cancer of unknown primary (CUP).

[0158] The compounds described herein (e.g., a compound of Formula (I) or a compound of Table 1, or a pharmaceutically acceptable salt thereof) can be used in a method comprising administering to a subject an HDAC inhibitor (e.g., a compound of Formula (I) or a compound of Table 1, or a pharmaceutically acceptable salt thereof) in an amount effective to inhibit HDAC. In one embodiment, the subject in need of treatment is suffering from a cancer selected from glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or a sarcoma.

[0159] In some embodiments, the cancer is selected from the group consisting of melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, and gastric cancer.

[0160] In another aspect, there is provided the use of a compound of the present disclosure in the manufacture of a medicament for treating cancer.

[0161] Cancer: Cancer cells grow rapidly and in hypoxic environments by activating various elements of the cellular stress response. Without wishing to be bound by theory, as the role of HDAC in cancer has recently begun to be better understood, compounds of formula (I) or its sub-formulas can also be used to treat cancer. In addition, HDAC inhibitors can be combined with one or more cancer treatments, such as chemotherapy and radiotherapy. "Cancer" in a subject refers to the presence of cells with characteristics characteristic of carcinogenic cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. In many cases, cancer cells are in the form of tumors, but such cells may exist alone in an animal or may be non-tumorigenic cancer cells, such as leukemia cells. In some cases, cancer cells are in the form of tumors, and such cells may exist locally in an animal or circulate in the bloodstream as independent cells, such as leukemia cells.

[0162] Exemplary cancers include, but are not limited to, glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or sarcoma.

[0163] Another exemplary list of cancers includes, but is not limited to, brain tumors such as astrocytoma and glioblastoma, brain metastases, medulloblastoma, meningioma, and oligodendroglioma; tumors of the peripheral or central nervous system; neuronal tumors; non-Hodgkin's lymphomas, such as low-grade non-Hodgkin's lymphoma, Burkitt's lymphoma; lymphomas (lymphosarcoma); Hodgkin's disease, non-Hodgkin's lymphoma; bone cancer; leukemias, such as acute lymphocytic leukemia / acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia; intestinal cancers, such as rectum, colon, colorectal cancer, anal cancer, carcinoma of the large intestine; pancreatic cancer or carcinoma of the pancreas; gallbladder cancer; bile duct cancer; liver cancer; stomach cancer or gastric cancer carcinoma); bladder cancer or carcinoma of the bladder; kidney cancer; lung cancer (bronchial carcinoma), for example, small cell bronchial carcinoma and non-small cell bronchial carcinoma (NSCLC); plate epithelial carcinoma, adenocarcinoma, and large cell bronchial carcinoma; breast cancer; uterine or endometrial cancer; ovarian cancer or ovarian carcinoma; testicular cancer; penile cancer; prostate cancer; vaginal cancer; cancer of the urethra and vulva; laryngeal cancer; head and neck tumors; throat cancer or carcinoma of the pharynx; esophageal cancer; melanoma; epidermoid carcinoma and plate epithelial carcinoma of the skin; retinoblastoma, thyroid cancer; thymoma or carcinoma of unknown primary origin.

[0164] In some examples, the cancer is HDAC-associated glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or a sarcoma.

[0165] In some instances, the cancer is an HDAC-associated brain tumor, such as astrocytoma and glioblastoma, brain metastases, medulloblastoma, meningioma, and oligodendroglioma; an HDAC-associated peripheral or central nervous system tumor; an HDAC-associated neuronal tumor; an HDAC-associated non-Hodgkin's lymphoma, e.g., low-grade non-Hodgkin's lymphoma, Burkitt's lymphoma; an HDAC-associated lymphoma (lymphosarcoma); an HDAC-associated Hodgkin's disease, an HDAC-associated non-Hodgkin's lymphoma; an HDAC-associated bone cancer; an HDAC-associated leukemia, such as acute lymphocytic leukemia / acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia; an HDAC-associated intestinal cancer, e.g., rectal, colon, colorectal cancer, anal cancer, and colorectal carcinoma; an HDAC-associated pancreatic cancer or carcinoma of the pancreas; an HDAC-associated gallbladder cancer; an HDAC-associated cholangiocarcinoma; an HDAC-associated liver cancer; an HDAC-associated stomach cancer. HDAC-related cancer or gastric carcinoma; HDAC-related bladder cancer or carcinoma; HDAC-related kidney cancer; HDAC-related lung cancer (bronchogenic carcinoma), e.g., small cell bronchogenic carcinoma and non-small cell bronchogenic carcinoma (NSCLC); HDAC-related plate epithelial carcinoma, adenocarcinoma, and large cell bronchogenic carcinoma; HDAC-related breast cancer; HDAC-related uterine or endometrial cancer; HDAC-related ovarian cancer or carcinoma; HDAC-related testicular cancer; HDAC-related penile cancer; HDAC-related prostate cancer; HDAC-related vaginal cancer; HDAC-related urethral and vulvar cancer; HDAC-related laryngeal cancer; HDAC-related head and neck tumors; HDAC-related throat cancer or carcinoma; HDAC-related esophageal cancer; HDAC-related melanoma; HDAC-related epidermoid carcinoma and plate epithelial carcinoma of the skin. carcinoma); HDAC-associated retinoblastoma, thyroid cancer; HDAC-associated thymoma, or carcinoma of unknown primary origin.

[0166] In some examples, the cancer (e.g., an HDAC-associated cancer) is cancer of unknown primary (CUP), colorectal cancer (e.g., colon cancer), cervical cancer, or non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma). In some embodiments, the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma). In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is colorectal cancer (e.g., colon cancer). In some embodiments, the cancer is cancer of unknown primary (CUP).

[0167] In some examples, the subject in need of treatment is suffering from a cancer selected from glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or a sarcoma.

[0168] Combination therapy Provided herein are methods of treating a disease or disorder (e.g., cancer) using a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound in Table 1, or a pharmaceutically acceptable salt thereof), in combination with a second therapeutic agent.

[0169] The term "combination" refers to either a fixed combination in one unit dosage form, or a combined administration in which a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a combination partner (e.g., another drug, described below, also referred to as a "therapeutic agent" or "co-agent") can be administered independently, simultaneously, or separately within a time interval, particularly where these time intervals allow the combination partners to exhibit a cooperative effect, e.g., a synergistic effect. The individual components can be packaged in a kit or packaged separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose before administration. As used herein, the terms "co-administration" or "co-administration," etc., are intended to include administration to a single subject (e.g., patient) of selected combination partners, and are intended to encompass treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. As used herein, the term "pharmaceutical combination" refers to a product obtained by mixing or combining two or more therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents, e.g., a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound of Table 1, or a pharmaceutically acceptable salt thereof), and a combination partner, are administered to a patient simultaneously in the form of a single entity or dosage form.The term "non-fixed combination" means that both the therapeutic agents, e.g., a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound in Table 1, or a pharmaceutically acceptable salt thereof), and the combination partner are administered to a patient as separate entities simultaneously, concurrently, or sequentially without specific time limitations, where such administration results in therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0170] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. The powders and / or liquids can be reconstituted or diluted to the desired dose before administration. In addition, such administration also encompasses the sequential use of each type of therapeutic agent, either at approximately the same time or at different times.

[0171] In certain embodiments, the compounds of the present invention are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergy agents, anti-nausea (or anti-emetic) agents, analgesics, cytoprotective agents, and combinations thereof.

[0172] Common chemotherapy drugs that may be considered for use in combination therapy include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), and carboplatin (Calmus®). cisplatin (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (ActinomycinD, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (A drucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan Ran (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), Mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, carmustine-containing polipheprosan 20 implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0173] Further compounds of particular interest for combination with the compounds of the invention include: EGFR inhibitors, such as cetuximab, panitumumab, erlotinib, gefitinib, and EGFRi NOS; MAPK pathway inhibitors, such as BRAFi, panRAFi, MEKi, ERKi; PI3K-mTOR pathway inhibitors, such as alpha-specific PI3Ki, panclass I PI3Ki, and mTOR / PI3Ki, in particular everolimus and its analogues.

[0174] Certain compounds and classes of compounds that act by specific mechanisms may be particularly effective in combination with compounds of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound in Table 1, or a pharmaceutically acceptable salt thereof). For example, PRMT5 is known to associate with the SWI / SNF chromatin remodeling complex along with other corepressor molecules, such as HDAC2. The activity of PRMT5 against its targets, H4R3 and H3R8, is enhanced when the lysine residue is deacetylated by HDAC enzymes. Thus, HDAC inhibitors may be effective (eg, synergistic) when used together with PRMT5 inhibitors (WO011 / 079236).

[0175] Thus, the compounds of formula (I) can be used in combination with other compounds, such as PRMT5 inhibitors or DNA methyltransferase inhibitors. In some embodiments, the DNA methyltransferase inhibitor is 5-azacytidine.

[0176] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a MAT2A inhibitor to a patient in need of treatment.

[0177] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, to a patient in need of treatment a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound in Table 1, or a pharmaceutically acceptable salt thereof) and an inhibitor of a protein that interacts with or is required for the function of PRMT5, including but not limited to pICIN, WDR77, or RIOK1.

[0178] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound in Table 1, or a pharmaceutically acceptable salt thereof) and an HDM2 inhibitor and / or 5-FU to a patient in need of treatment.

[0179] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, to a patient in need of treatment a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), or a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a CDK4 inhibitor, including but not limited to, LEE011 or a CDK4 / 6 inhibitor (e.g., palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio®)).

[0180] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering to a patient in need of treatment, in any order, targeted therapies depending on the dependency of the individual target tumor on relevant pathways as determined by suitable predictive markers, including, but not limited to, inhibitors of HDM2i, PI3K / mTOR-i, MAPKi, RTKi (EGFRi, FGFRi), METi, IGFIRi, JAKi, and WNTi.

[0181] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) and immunotherapy.

[0182] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order, or co-administering to a patient in need thereof a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is a cancer vaccine, such as a neoantigen. These vaccines can be developed using peptides or RNA. In some embodiments, the immunotherapeutic agent is an oncolytic virus. In some embodiments, the immunotherapeutic agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

[0183] In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody. In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need of treatment, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and an anti-CTLA-4 antibody (e.g., ipilimumab, tremelimumab).

[0184] In some embodiments, the immunotherapeutic agent is an anti-PD-1 ligand or an anti-PD-L1 ligand. In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, to a patient in need of treatment a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and an anti-PD-1 ligand (e.g., PD-L1 (e.g., B7-HI or CD274) or PD-L2 (e.g., B7-DC or CD273)). In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody (e.g., anti-PD-1 or anti-PD-L1). In some embodiments, the immunotherapeutic agent is an anti-PD-1 agent (e.g., an anti-PD-1 antibody, e.g., nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538); CT-011; AMP-224; pembrolizumab (MK-3475); pidilizumab; cemiplimab; dostallimab; prorugolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab). In some embodiments, the immunotherapeutic agent is an anti-PD-L1 agent (e.g., an anti-PD-L1 antibody, e.g., BMS936559 (i.e., MDX-1105); durvalumab (MEDI4736); avelumab (MSB0010718C); embafolimab; cosibelimab; sugemalimab, AUNP-12, or atezolizumab (MPDL-3280A), or an anti-PD-L1 small molecule (e.g., CA-170)).

[0185] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a KRAS inhibitor to a patient in need of treatment. In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor. In some embodiments, the KRAS inhibitor is sotorasib.

[0186] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, to a patient in need of treatment a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a checkpoint inhibitor antibody (e.g., anti-TIM3, anti-LAG3, anti-TIGIT, including IMP321 and MGA271).

[0187] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a checkpoint inhibitor.

[0188] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a cell therapy. In some embodiments, the cell therapy is a CAR-T therapy.

[0189] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, to a patient in need of treatment a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a costimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0190] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a disease-specific huMAB (e.g., an anti-HER3 huMAB) to a patient in need of treatment.

[0191] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, to a patient in need of treatment a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and an ADC / ADCC that depends on the expression of relevant surface targets on a target tumor of interest.

[0192] Some patients may experience allergic reactions to the compound of formula (I) and / or other anti-cancer drug(s) during or after administration. Therefore, anti-allergy medications are often administered to minimize the risk of allergic reactions. Suitable anti-allergy medications include, but are not limited to, dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, sold under the trade names Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), prednisolone (sold under the trade names Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (Deltasone®, Liquid corticosteroids, including methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the trade names Duralone, Medralone, Medrol, M-Prednisol, and Solu-Medrol); antihistamines, such as diphenhydramine (e.g., Benadryl), hydroxyzine, and cyproheptadine; and bronchodilators, such as the beta-adrenergic receptor agonists albuterol (e.g., Proventil), and terbutaline (Brethine).

[0193] Some patients may experience nausea during and after administration of the compound of formula (I) and / or other anticancer drug(s). Therefore, antiemetics are used to prevent nausea (upper stomach) and vomiting. Suitable antiemetics include aprepitant (Emend®), ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®), dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof.

[0194] To make patients more comfortable, medications are often prescribed to alleviate pain experienced during the procedure. Common over-the-counter painkillers, such as Tylenol®, are often used. However, opioid analgesics are also useful for moderate or severe pain, including, but not limited to, hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), and fentanyl (e.g., Duragesic®).

[0195] Cytoprotective agents (e.g., neuroprotective agents, free radical scavengers, cardioprotective agents, anthracycline extravasation neutralizers, nutrients, etc.) may be used as adjunctive therapy to protect normal cells from treatment toxicity and reduce organ toxicity. Suitable cytoprotective agents include amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folinic acid).

[0196] The structures of active compounds identified by code number, generic name, or trade name can be obtained from the current edition of the standard compendium "The Merck Index" or from databases such as Patents International (e.g., IMS World Publications).

[0197]

[0449] The above-mentioned compounds that may be used in combination with compounds of formula (I) may be prepared and administered as described in the art, including, but not limited to, the documents cited above.

[0198] In one embodiment, the present invention provides pharmaceutical compositions comprising at least one compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, alone or with other anti-cancer agents. In particular, the compositions are formulated together as a combination therapy or administered separately.

[0199] In combination therapy, the compound of formula (I) and other anti-cancer agent(s) may be administered simultaneously, concurrently, or sequentially without any specific time limit, where such administration results in therapeutically effective levels of the two compounds in the patient's body.

[0200] In some embodiments, the compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) and the other anticancer agent(s) are typically administered sequentially by injection or orally in any order. The administration regimen may vary depending on the stage of the disease, the patient's physical condition, the safety profile and tolerability of the individual drugs, and other criteria known to the attending physician and medical professional(s) administering the combination. The compound of the present invention and the other anticancer agent(s) may be administered minutes apart, hours apart, days apart, or even weeks apart, depending on the particular cycle used in the treatment. In addition, cycles may involve administering one drug more frequently than the other during the treatment cycle and at different dosages for each administration of the drug.

[0201] In some embodiments, kits are provided that include one or more compounds of Formula (I) (e.g., a compound of Formula (Ia), (Ib)(Ic)(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a second therapeutic agent disclosed herein. Representative kits include (a) a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof); and (b) at least one other therapeutic agent, e.g., as described above; such kits may include a package insert or other labeling containing directions for administration.

[0202] A compound of formula (I) (e.g., a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) may be used in combination with known therapeutic processes, such as the administration of hormones or, particularly, radiation. The compound of formula (I) may be used, in particular, as a radiosensitizer, especially for the treatment of tumors that are poorly sensitive to radiation therapy.

[0458] In certain instances, the compounds of the present invention are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergy agents, anti-nausea (or anti-emetic) agents, analgesics, cytoprotective agents, and combinations thereof.

[0203] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a CAAP1 inhibitor to a patient in need of treatment.

[0204] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need of treatment, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and an AKAP17A inhibitor.

[0205] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order, or co-administering to a patient in need thereof a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a BCL2L1 inhibitor. In some embodiments, the BCL2L1 inhibitor is AT-101.

[0206] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a TSC1 / 2 inhibitor.

[0207] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need of treatment, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a UBE2H inhibitor.

[0208] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and an NF2 inhibitor to a patient in need of treatment.

[0209] In some embodiments, a method of treating a disease or disorder (e.g., cancer) is provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a ZC3HC1 inhibitor to a patient in need of treatment.

[0210] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) and an MGEA5 inhibitor to a patient in need of treatment.

[0211] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) and a CNOT4 inhibitor to a patient in need of treatment.

[0212] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound of Table 1, or a pharmaceutically acceptable salt thereof) and an API5 inhibitor.

[0213] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need of treatment, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a HEXIM1 inhibitor.

[0214] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order or simultaneously administering to a patient in need of treatment, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a PTEN inhibitor.

[0215] In some embodiments, methods of treating a disease or disorder (e.g., cancer) are provided, comprising administering, in any order, or co-administering to a patient in need thereof a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is), a compound in Table 1, or a pharmaceutically acceptable salt thereof) and a DNA damage pathway inhibitor. In some embodiments, the DNA damage pathway inhibitor is selected from the group consisting of bleomycin, an ATM inhibitor (e.g., AZD1390), a USP1 inhibitor, a WEE1 inhibitor (e.g., AZD1775), and a Chk1 inhibitor (e.g., AZD7762).

[0216] definition Unless otherwise stated or implied from context, the following terms and phrases include the meanings indicated below. Unless otherwise stated or apparent from context, the following terms and phrases do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. Definitions are provided to aid in describing particular embodiments and are not intended to limit the invention as claimed, since the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms include pluralities and plural terms include the singular.

[0217] As used herein, the terms "compound" and "agent" are used interchangeably to refer to the inhibitors / antagonists / agonists of the present invention. In certain embodiments, the compound is a small organic or inorganic molecule, e.g., having a molecular weight of less than 7500 amu, preferably less than 5000 amu, and even more preferably less than 2000, 1500, 1000, 750, 600, or 500 amu. In certain embodiments, one class of small organic or inorganic molecules is non-peptidyl, containing, e.g., two, one, or zero peptide and / or saccharide linkages.

[0218] Unless otherwise specified, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." When used in conjunction with percentages, the term "about" can mean ±1%.

[0219] The singular terms "a," "an," and "the" refer to one or more than one, unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise.

[0220] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.

[0221] As used herein, the term "administration" refers to the placement of a composition into a subject by a method or route that results in at least partial localization of the composition at the intended site, so that the desired effect is produced.The compounds or compositions described herein can be administered by any suitable route known in the art, including but not limited to oral or parenteral routes, such as intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, airway (aerosol) administration, pulmonary administration, nasal administration, rectal administration, intrathecal administration, and topical administration (including buccal administration and sublingual administration).

[0222] The terms "reduce," "reduced," "reduction," "decrease," or "inhibit" are generally used herein to mean a statistically significant decrease. In some embodiments, the terms "reduced," "reduction," "decrease," or "inhibit" mean a decrease of at least 0.1% compared to the reference level, such as a decrease of at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% compared to the reference level, or a decrease of up to 100% (e.g., a non-existent level compared to the reference sample), or any decrease between 1-100%, for example, 10-100%.

[0223] The terms "increased," "increase," "enhance," or "activate" are generally used herein to mean a statistically significant increase. In some embodiments, the terms "increased," "increase," "enhance," or "activate" refer to an increase of at least 0.1% compared to the reference level, such as a decrease of at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% compared to the reference level, or an increase of up to 100% (e.g., a level that is absent compared to the reference sample), or any increase between 1 and 100%, for example, 10 and 100%.

[0224] "Treating," "preventing," or "ameliorating" a disease or disorder means delaying or preventing the onset, progression, worsening, or exacerbation of such disease or disorder, or reversing, alleviating, ameliorating, inhibiting, slowing, or halting the progression or severity of conditions associated with such disease or disorder. In one embodiment, at least one symptom of the disease or disorder is alleviated by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%.

[0225] As used herein, a "therapeutically effective amount," or "effective amount," is an amount of a compound or combination effective to treat a disorder (e.g., a disorder described herein) that is effective in treating a subject, or in treating, alleviating, ameliorating, or improving a subject with a disorder (e.g., a disorder described herein), when administered once or multiple times to a subject, beyond that expected in the absence of such treatment. Determining a therapeutically effective amount is well within the capabilities of one of ordinary skill in the art. Typically, a therapeutically effective amount may vary depending on the subject's medical history, age, condition, sex, and the severity and type of the subject's medical condition, as well as the administration of other pharmaceutically active agents.

[0226] As used herein, "subject" refers to a human or animal. Typically, an animal is a vertebrate such as a primate, rodent, domestic animal, or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys. Rodents include mice, rats, marmots, ferrets, rabbits, and hamsters. Domestic and game animals include cattle, horses, pigs, deer, bison, buffalo, feline species, such as domestic cats, canine species, such as dogs, foxes, wolves, avian species, such as chickens, emus, and ostriches, and fish, such as trout, catfish, and salmon. A patient or subject includes any subset of the foregoing, such as one or more groups or species, for example, all of the above except humans, primates, or rodents. In certain embodiments, the subject is a mammal, such as a primate, for example, a human. The terms "patient" and "subject" are used interchangeably herein. The terms "patient" and "subject" are used interchangeably herein.

[0227] As used herein, the term "nucleic acid" refers to a polymeric form of nucleotides, either ribonucleotides or deoxynucleotides, or modified forms of either type of nucleotide. This term should be understood to encompass, as equivalents, either RNA or DNA analogs made from nucleotide analogs, as well as single-stranded (e.g., sense or antisense) and double-stranded polynucleotides, as applicable to the described embodiments.

[0228] As used herein, the term "inhibitor of HDAC" refers to compounds and compositions of Formula (I) (e.g., compounds of Formulas (I), (Ia), (Ib), (Ic), and (Id), Table 1, or pharmaceutically acceptable salts thereof) that can inhibit the deacetylase activity of HDAC enzymes. These include, by way of non-limiting example, any compound that inhibits post-translational modification of a protein, the enzymatic activity of a protein, interaction with a protein complex, interaction with a substrate, etc. The term also refers to any agent that inhibits the intracellular function of an HDAC protein by either ATP-competitive inhibition of the active site, allosteric modulation of protein structure, disruption of protein-protein interactions, or inhibition of the transcription, translation, post-translational modification, or stability of the HDAC protein.

[0229] Specific Chemical Definitions At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include all individual subcombinations of the members of such groups and ranges. For example, the term "C 1~6 "Alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0230] In compounds of the invention in which a variable occurs more than once, each variable may be a different moiety selected from the Markush group defining the variable. For example, if a structure is described as having two R groups occurring simultaneously on the same compound, the two R groups may represent different moieties selected from the Markush group defined for R.

[0231] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in a single embodiment, may also be provided separately or in any suitable subcombination.

[0232] When compounds of the invention are shown in the form of chemical names and as formulas, in case of discrepancies, the formulas shall prevail.

[0233] Whether utilized as a bond or shown perpendicular to a bond, the symbol: [ka] indicates the position at which the indicated moiety is attached to the rest of the molecule, a solid support, etc.

[0234] The following terms, together with their intended meanings below, are useful in understanding the description and intended scope of the present invention.

[0235] As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each alkyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group can be an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~6 It is alkyl.

[0236] The term "alkylene" refers to the diradical of an alkyl group. An exemplary alkylene group is -CHCH-.

[0237] As used herein, the term "alkenyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C 24 In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C-C 10 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each example of an alkenyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~6 It is alkenyl.

[0238] As used herein, the term "alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C 24 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C-C 10 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-C5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-C4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-C3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each example of an alkynyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~6 It is alkynyl.

[0239] As used herein, the term "heteroalkyl" refers to a stable acyclic straight or branched chain, or combinations thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be located at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -NHCH2-, -C(O)-NH-, -C(O)N(CH3)-, -C(O)N(CH2CH3)-, -C(O)N(CH2CF3)-, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. For example, up to two or three heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. "Heteroalkyl" is recited, followed by the particular heteroalkyl group, e.g., -CHO, -NR C R D When a heteroalkyl group is mentioned, the term heteroalkyl and -CH2O or -NR C R D It will be understood that the heteroalkyl groups are not overlapping or mutually exclusive. Rather, specific heteroalkyl groups are recited for added clarity. Thus, the term "heteroalkyl" refers to specific heteroalkyl groups, e.g., -CHO, -NR C R D Nothing herein should be construed as excluding, etc. One type of heteroalkyl group is an "alkoxyl" group.

[0240] The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, alkyl substituents that make an alkyl an ether include -O-alkyl, -O-alkenyl, O-alkynyl, -O-(CH2) mm -R aaa where mm is an integer (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11), and R aaa can be halogen, haloalkyl, nitrile, -NH, -NO, -SO, Si(CH), cycloalkyl, heterocyclyl, aryl, or heteroaryl. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. For example, -O-CHF, -O-CHF, -O-CF, etc. In certain embodiments, a haloalkoxyl is an alkoxyl group substituted with at least one fluoro group. In certain embodiments, a haloalkoxyl is an alkoxyl group substituted with 1 to 6, 1 to 5, 1 to 4, 2 to 4, or 3 fluoro groups.

[0241] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared by the ring system) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C6- 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14Aryl"; for example, anthracyl). The aryl group is, for example, C6-C 10 aryl, where the term "membered" refers to a non-hydrogen ring atom within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C6-C 14 In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0242] As used herein, "heteroaryl" refers to the radical of a 5-10-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared by the ring system) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10-membered heteroaryl"). In heteroaryl groups having one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valency permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is at either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be in either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). Heteroaryl groups can be expressed, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom within the moiety.

[0243] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is a 5- to 14-membered unsubstituted heteroaryl. In certain embodiments, a heteroaryl group is a 5- to 14-membered substituted heteroaryl.

[0244] Exemplary 5-membered heteroaryl groups having one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups having two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups having three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups having four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups having one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups having two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups having three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups having one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives."Heteroaryl" also encompasses ring systems in which a heteroaryl ring, as defined above, is fused to one or more heterocycloalkyl groups, where the point of attachment is on the heteroaryl ring; in such cases, the carbon number continues to refer to the carbon number of the heteroaryl ring system. Exemplary ring systems of this type include 7,8-dihydro-5H-pyrano[4,3-b]pyridine and 1,4,6,7-tetrahydropyrano[4,3-b]pyrrole.

[0245] As used herein, "cycloalkyl" refers to a group having 3 to 10 ring carbon atoms ("C3-C6") in a non-aromatic ring system. 10 "Cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10Cycloalkyl groups may be represented, for example, as C4-C7 membered cycloalkyl, where the term "member" refers to a non-hydrogen ring atom within the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the C3-C6 cycloalkyl groups described above, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. 10 The cycloalkyl group includes, but is not limited to, the above-mentioned C3 to C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10As the above examples illustrate, in certain embodiments, cycloalkyl groups are either monocyclic ("monocyclic cycloalkyl") or contain fused, bridged, or spiro ring systems, e.g., bicyclic ring systems ("bicyclic cycloalkyl"), and can be saturated or partially unsaturated. "Cycloalkyl" also encompasses ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on the cycloalkyl ring; in such instances, the carbon number continues to refer to the carbon number of the cycloalkyl ring system. Each instance of a cycloalkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 alkyl group. 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0246] As used herein, "heterocyclyl," "heterocycle," or "heterocycloalkyl" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "3- to 10-membered heterocyclyl"). In heterocyclyl groups having one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic (a "monocyclic heterocyclyl") or fused, bridged, or spirocyclic ring systems, e.g., bicyclic ring systems (a "bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Bicyclic heterocyclyls may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also encompasses ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups, where the point of attachment is on either the cycloalkyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl, aryl, or heteroaryl ring; in such instances, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Heterocyclyl groups may be expressed, for example, as 3- to 7-membered heterocyclyls, where the term "members" refers to the non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is a 3-10 membered unsubstituted heterocyclyl. In certain embodiments, the heterocyclyl group is a 3-10 membered substituted heterocyclyl.

[0247] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0248] Exemplary 3-membered heterocyclyl groups having one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups having one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups having one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups having two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups having three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups having one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups having two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups having two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups having one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups having one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0249] As used herein, "cyano" refers to the radical --CN.

[0250] As used herein, "halo" or "halogen," independently or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0251] As used herein, "haloalkyl" can include alkyl structures substituted with one or more halo groups or combinations thereof. For example, the term "fluoroalkyl" includes haloalkyl groups in which the halo is fluorine (e.g., -C1-C6 alkyl-CF3, -C1-C6 alkyl-CH2F). Non-limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, difluoromethyl, and fluoroisopropyl.

[0252] As used herein, "hydroxy" refers to the radical --OH.

[0253] As used herein, "nitro" refers to --NO.sub.2.

[0254] As used herein, "oxo" refers to =0 where both bonds from the oxygen are connected to the same atom. For example, a carbon atom substituted with oxo forms a carbonyl group, -C=O.

[0255] Two or more substituents may be optionally linked to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are usually, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0256] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). Additionally, the present invention encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0257] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that a compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%, or more than 99.9% by weight of the enantiomer in question. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0258] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, relative to the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, relative to the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients.

[0259] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be: 1 H, 2 H (D or deuterium), and 3 H (T or tritium) and C may be in any isotopic form. 12 C. 13 C, and 14C may be in any isotopic form, including O 16 O and 18 O may be in any isotopic form, including O, etc.

[0260] A number of terms provided above may be used repeatedly in the definitions of formulae or groups and may in each case have, independently of one another, one of the meanings provided above.

[0261] It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like.

[0262] In general, the term "substituted," whether followed by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. A moiety described as "optionally substituted" (e.g., optionally substituted with a number or range of numbers of substituents selected from a list) may be unsubstituted or substituted (e.g., unsubstituted or substituted with the number of substituents indicated). For example, a moiety optionally substituted with 1 to 4 R groups may be unsubstituted, substituted with one R group, substituted with two R groups, substituted with three R groups, or substituted with four R groups. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0263] Suitable substituents for optionally substituted alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups include halogen, —O, —CN, —OR cc , -NR dd R ee , -S(O) kk R cc , -NR cc S(O)2R cc , -S(O)NR dd R ee , -C(=O)OR cc , -OC(=O)OR cc , -OC(=O)R cc , -OC(=S)ORcc , -C(=S)OR cc , -O(C=S)R cc , -C(=O)NR dd R ee , -NR cc C(-O)R cc , -C(-S)NR dd R ee , -NR cc C(=S)R cc , -NR cc (C=O)OR cc , -O(C=O)NR dd R ee , -NR cc (C=S)OR cc , -O(C=S)NR dd R ee , -NR cc (C=O)NR dd R ee , -NR cc (C=S)NR dd R ee , -C(=S)R cc , -C(=O)R cc , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6 alkylene)-carbocyclyl, (C1-C6 heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6 alkylene)-heterocyclyl, (C1-C6 heteroalkylene)-heterocyclyl, aryl, (C1-C6 alkylene)-aryl, (C1-C6 heteroalkylene)-aryl, heteroaryl, (C1-C6 alkylene)-heteroaryl, or (C1-C6 heteroalkylene)-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with halogen, OR cc , -NO2, -CN, -NR cc C(=O)W, -NR dd R ee , -S(O) k R cc , -C(=O)OR cc , -C(=O)NR dd R ee , -C(=O)R cc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; and R cc is hydrogen, hydroxy, C1-C6 alkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6 alkylene)-carbocyclyl, (C1-C6 heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6 alkylene)-heterocyclyl, (C1-C6 heteroalkylene)-heterocyclyl, aryl, (C1-C6 alkylene)-aryl, (C1-C6 heteroalkylene)-aryl, heteroaryl, (C1-C6 alkylene)-heteroaryl, or (C1-C6 heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R dd and R ee are each independently selected from hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl, and k is 0, 1, or 2. The present invention is not intended to be limited in any way to the illustrative list of substituents above.

[0264] The contemplated equivalents of the aforementioned compounds include compounds that otherwise correspond to them and have the same general properties (e.g., ability to inhibit HDAC), with one or more simple substituent modifications that do not adversely affect the efficacy of the compounds. Generally, the compounds of the present invention can be prepared using readily available starting materials, reagents, and conventional synthetic procedures, for example, by the methods illustrated in the following general reaction schemes or modifications thereof. In these reactions, it is also possible to utilize variants that are known per se but are not mentioned here.

[0265] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements (CAS system), inside cover of the Handbook of Chemistry and Physics, 67th Ed., 1986-87. Also for purposes of this invention, the term "hydrocarbon" is intended to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds, which may be substituted or unsubstituted.

[0266] Pharmaceutical Compositions and Routes of Administration Pharmaceutical compositions containing the compounds described herein, e.g., compounds of Formula (I) or pharmaceutically acceptable salts thereof, can be used to treat or ameliorate disorders described herein, e.g., neurodegenerative diseases, cancer, ophthalmic diseases (e.g., retinal diseases), or viral infections.

[0267] The amount and concentration of the compound of formula (I) in the pharmaceutical composition and the amount of the pharmaceutical composition administered to the subject can be selected based on clinically relevant factors, such as the medically relevant characteristics of the subject (e.g., age, weight, sex, other medical conditions, etc.), the solubility of the compound in the pharmaceutical composition, the potency and activity of the compound, and the method of administration of the pharmaceutical composition.For further information on administration routes and dosage regimens, see Chapter 25.3, Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press, 1990.

[0268] In some embodiments, pharmaceutical formulations (compositions) are provided in which the compounds described herein are combined with one or more pharmaceutically acceptable excipients. The compounds according to the present invention can be formulated for administration in any convenient manner used in human or veterinary medicine. In certain embodiments, the compounds included in the pharmaceutical formulations may be active themselves or may be prodrugs, e.g., capable of being converted to an active compound in a physiological environment. Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrate form, and / or pharmaceutical compositions of the present invention may be formulated into pharmaceutically acceptable dosage forms as described below or by other conventional methods known to those skilled in the art.

[0269] In some embodiments, pharmaceutically acceptable compositions are provided comprising a therapeutically effective amount of one or more of the above compounds formulated together with one or more pharmaceutically acceptable excipients. As described below and in detail herein, the pharmaceutical compositions disclosed herein can be specially formulated for administration in solid or liquid form, including those suitable for: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions or sustained-release formulations; (3) topical application, e.g., creams, ointments, or sustained-release patches, or sprays applied to the skin; (4) vaginal or rectal use, e.g., pessaries, creams, or foams; (5) sublingual use; (6) ocular use; (7) transdermal use; (8) transmucosal use; (9) nasal use; or (10) intrathecal use. Additionally, the compounds can be implanted or infused into a patient using drug delivery systems. See, e.g., Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed., "Controlled Release of Pesticides and Pharmaceuticals" (Plenum Press, New York, 1981); U.S. Pat. No. 3,773,919; and U.S. Pat. No. 353,270,960.

[0270] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, substance, or composition comprising a compound of the invention effective to produce some desired therapeutic effect, e.g., by inhibiting HDAC in at least a subpopulation of cells in an animal, thereby inhibiting the biological consequences of HDAC function in the treated cells, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0271] As used herein, the phrases "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered" refer to administration of a compound, drug, or other substance other than directly into the central nervous system, such that it enters the patient's system and is therefore subject to metabolism and other similar processes, e.g., subcutaneous administration.

[0272] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0273] As used herein, the phrase "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition, or vehicle, e.g., a liquid or solid filler, diluent, carrier, solvent, or encapsulating material, that is involved in the movement or transport of the subject antagonist from one organ or part of the body to another organ or part of the body. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable excipients include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; and (4) powdered tragacanth. (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; (21) cyclodextrins, such as Captisol®; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0274] The term "pharmaceutically acceptable salts" is intended to encompass salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound of the present invention has a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts.When a compound disclosed herein has a relatively basic functionality, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and those derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids, such as arginic acid, and organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present invention contain both basic and acidic functionalities, allowing the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable excipients known to those skilled in the art are suitable for the present invention.

[0275] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0276] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium hydrogen sulfide, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0277] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be combined with excipient materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient that may be combined with excipient materials to produce a single dosage form will generally be that amount of the compound of the present invention that produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0278] Methods of preparing these formulations or compositions include the step of admixing a compound disclosed herein with an excipient and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately admixing a compound of the present invention with a liquid excipient (e.g., carrier), or finely divided solid excipient (e.g., carrier), or both, and then, if necessary, shaping the product.

[0279] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or aqueous or non-aqueous liquid solutions or suspensions, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds disclosed herein can also be administered as a bolus, electuary, or paste.

[0280] In solid dosage forms for oral administration (such as capsules, tablets, pills, dragees, powders, granules, and the like) of the pharmaceutical compositions disclosed herein, the active ingredient is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0281] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets may be produced by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0282] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, may be optionally imprinted or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may be formulated to provide sustained or controlled release of the active ingredient contained therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions may optionally contain opacifying agents and may be composed to release the active ingredient(s) only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0283] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredients, liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and their mixtures.

[0284] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0285] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0286] Formulations of the pharmaceutical compositions disclosed herein for rectal, vaginal, or urethral administration can be prepared by mixing one or more active compounds of the invention with one or more suitable non-irritating excipients including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and can be provided as a suppository that is solid at room temperature but liquid at body temperature and will melt in the rectum or vaginal cavity and release the active compound.

[0287] Alternatively or additionally, the compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices can be particularly useful for delivery to the heart, lungs, bladder, urethra, ureters, rectum, or intestines. Furthermore, the compositions can be formulated for delivery via a dialysis port.

[0288] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0289] Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or oral ingestion. "Injection" includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracerebrospinal, and intrasternal injection and infusion. In some embodiments, the composition is administered by intravenous infusion or injection.

[0290] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intrathecal, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more active compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into a sterile solution or dispersion for injection immediately before use, which pharmaceutical compositions may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0291] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerin, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0292] These compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial activity can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include, for example, sugars, sodium chloride, etc. in the compositions of the present invention. In addition, prolonged absorption of the injectable formulation can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0293] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug after subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.In this case, the absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, the delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0294] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0295] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be administered as they are, or may be administered as pharmaceutical compositions containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable excipient.

[0296] The addition of the active compound of the present invention to animal feed is preferably achieved by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the total feed formulation. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be mixed into the feed. The methods for preparing and administering such feed premixes and total feed formulations are described in references (e.g., "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, USA, 1969, or "Livestock Feeds and Feeding", O and B books, Corvallis, Ore., USA, 1977).

[0297] The method of introduction can also be by a rechargeable or biodegradable device. In recent years, various sustained-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0298] Preferably, the subject is a mammal. The mammal may be, but is not limited to, a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse, or a cow. Non-human mammals can be advantageously used as subjects to serve as animal models for neurodegenerative diseases or disorders associated with neurodegenerative disorders, cancer, or viral infections.

[0299] In addition, the methods described herein can be used to treat domesticated animals and / or pets.The subject can be male or female.The subject can be previously diagnosed with, or confirmed to be suffering from, a neurodegenerative disease or neurodegenerative disorder, a cancer-related disease or disorder, a viral infection-related disease or disorder, or one or more complications associated with such a disease or disorder, but does not need to be already treated.

[0300] Dosage Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may vary for a particular patient, composition, and mode of administration so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response without being toxic to the patient.

[0301] The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt, or amide employed, the route of administration of the particular compound employed, the time of administration, the rate of excretion, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, health, and medical history of the patient being treated, and similar factors well known in the medical arts.

[0302] The compound and the pharmaceutically active agent can be administered in the same pharmaceutical composition or in different pharmaceutical compositions (simultaneously or at different times). When administered at different times, the compound and the pharmaceutically active agent can be administered within 5 minutes, 10 minutes, 20 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, or 24 hours of the administration of the other agent. When the inhibitor and the pharmaceutically active agent are administered in different pharmaceutical compositions, the routes of administration can be different.

[0303] The amount of compound that can be combined with excipient materials to produce a single dosage form will generally be that amount of inhibitor that produces a therapeutic effect. Generally, this amount ranges from about 0.1% to 99% of the inhibitor, preferably from about 5% to about 70%, and most preferably from 10% to about 30%.

[0304] Toxicity and therapeutic efficacy can be measured, for example, by LD 50 (lethal dose for 50% of the population) and ED 50 The LD (the dose which is therapeutically effective in 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Compositions that exhibit high therapeutic indices are preferred.

[0305] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably within the ED range with little or no toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0306] A therapeutically effective dose can be estimated initially from cell culture assays. The dose can be determined based on the IC 50Therapeutic agents can be formulated in animal models to achieve a circulating plasma concentration range that includes (i.e., the concentration of the therapeutic agent that achieves a half-maximal inhibition of symptoms). Plasma levels can be measured, for example, by high performance liquid chromatography. The effects of a particular dosage can be monitored by a suitable bioassay.

[0307] Dosage can be determined by a physician and can be adjusted, if necessary, to the observed therapeutic effect.

[0308] The present invention contemplates formulation of the subject compounds as any of the pharmaceutical compositions and preparations described above. Additionally, the present invention contemplates administration by any of the aforementioned routes of administration. One of skill in the art can select an appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated.

[0309] Specific Embodiments Embodiment 1. Formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is an optionally substituted aryl or heteroaryl; L 1 is -CR'2-, -CR'2CR'2-, or a bond; each R' is independently H or C1-C6 alkyl, or two R's together with the carbon or carbons to which they are attached form a 3- to 6-membered cycloalkyl ring; Each R 1 , R 3 , and R 4 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen; R 2 each is optionally substituted aryl or heteroaryl; R 5 is NH2 or OH, R 6is H or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted; R 8 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', where each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted, or a pharmaceutically acceptable salt thereof.

[0310] Embodiment 2. Formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is an aryl or heteroaryl having 5 to 10 ring atoms and 1 to 4 ring atoms selected from N, O, and S; ... 9 is substituted with a group, L 1 is -CR'2-, -CR'2CR'2-, or a bond; each R' is independently H or C1-C6 alkyl, or two R's together with the carbon or carbons to which they are attached form a 3- to 6-membered cycloalkyl ring; Each R 1 , R 3 , and R 4 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, heteroaryl having 5 to 10 ring atoms and having 1 to 4 ring atoms selected from N, O, and S; R 2 is 0 to 4 R 10 is substituted with a group, R 5 is NH2 or OH, R 6 is H or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, wherein the heteroaryl has 5 to 10 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl has 0 to 4 R 11 is substituted with a group, R 8 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', where the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl or heteroalkyl is substituted with 0 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is substituted with 0 to 4 R 10 or substituted with a group R 7 and R 8are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is joined to 0-4 R 10 is substituted with a group, Each R 9 are independently C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 4 groups independently selected from halogen and OH; Each R 10 and R 11 are independently C1-C6 alkyl, C1-C6 alkenyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen; heterocyclyl has 4 to 11 ring atoms, with 1 to 4 ring atoms selected from N, O, and S; each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E is optionally replaced by Each R C are independently H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 4 substituents independently selected from halogen and OH; or Two Rs attached to the same nitrogenD are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; Each R E are independently H, halo, OH, O-C1-C6 alkyl, C1-C6 alkyl, -C1-C6 haloalkyl; Each R 12 are independently H or C1-C6 alkyl, The compound or a pharmaceutically acceptable salt thereof, wherein W is 0, 1, or 2.

[0311] Embodiment 3. Formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, A is an aryl or heteroaryl having 5 to 10 ring atoms and 1 to 4 ring atoms selected from N, O, and S; ... 9 is substituted with a group, L 1 is -CR'2-, -CR'2CR'2-, or a bond; each R' is independently H or C1-C6 alkyl, or two R's together with the carbon or carbons to which they are attached form a 3- to 6-membered cycloalkyl ring; Each R 1 , R 3 , and R 4 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, heteroaryl having 5 to 10 ring atoms and having 1 to 4 ring atoms selected from N, O, and S; R 2 is 0 to 4 R10 is substituted with a group, R 5 is NH2 or OH, R 6 is H or C1-C6 alkyl, R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, -(CH2) 0~2 -phenyl, -(CH2) 0~2 -C3-C7 cycloalkyl, -(CH2) 0~2 -heteroaryl, or -(CH2) 0~2 -heterocyclyl, wherein the heteroaryl has 5 to 10 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl has 0 to 4 R 11 is substituted with a group, R 8 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R', or CO2-R', where the heterocyclyl has 4 to 11 ring atoms and has 1 to 4 ring atoms selected from N, O, and S, and each alkyl or heteroalkyl is substituted with 0 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is substituted with 0 to 4 R 10 or substituted with a group R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is joined to 0-4 R 10 is substituted with a group, Each R 9are independently C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 4 groups independently selected from halogen and OH; Each R 10 or R 11 are independently C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen; heterocyclyl has 4 to 11 ring atoms, with 1 to 4 ring atoms selected from N, O, and S; each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E is optionally replaced by Each R C are independently H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 4 substituents independently selected from halogen and OH; or Two Rs attached to the same nitrogen Dare taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; The compound or a pharmaceutically acceptable salt thereof, wherein W is 0, 1, or 2. Embodiment 4. A is phenyl or heteroaryl, wherein heteroaryl has 5, 6, or 9 ring atoms and has 1-4 ring atoms selected from N, O, and S, and A is 0-4 R 9 groups, and each R 9 is independently C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, or halogen, and each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH; or a pharmaceutically acceptable salt thereof.

[0312] Embodiment 5. A compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, benzothiophene, thienopyridine (e.g., thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3-b]pyridine), or furopyridine (e.g., furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-b]pyridine), each substituted with 0 to 9 R groups.

[0313] Embodiment 6. A is phenyl, benzofuran, or benzothiophene, each of which contains 0 to 9 R 9 or a pharmaceutically acceptable salt thereof.

[0314] Embodiment 7. A is 0 to 9 R 9 or a pharmaceutically acceptable salt thereof.

[0315] Embodiment 8. A is 0 to 9 R 9 or a pharmaceutically acceptable salt thereof.

[0316] Embodiment 9. A is 0 to 9 R 9 or a pharmaceutically acceptable salt thereof.

[0317] Embodiment 10.A is [ka] Each is selected from 0 to 9 R 9 group, wherein the left attachment point is: [ka] L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0318] Embodiment 11.A is [ka] Each is selected from 0 to 9 R 9 group, wherein the left attachment point is: [ka] L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0319] Embodiment 12. A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, or benzothiophene; For example, if A is [ka] and R with 0 to 4 As 9 or a pharmaceutically acceptable salt thereof.

[0320] Embodiment 13. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0321] Embodiment 14. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 15. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 16. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0324] Embodiment 17. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0325] Embodiment 18. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0326] Embodiment 19. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0327] Embodiment 20. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0328] Embodiment 21. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0329] Embodiment 22. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0330] Embodiment 23. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0331] Embodiment 24. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0332] Embodiment 25. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0333] Embodiment 26. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0334] Embodiment 27. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0335] Embodiment 28. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0336] Embodiment 29. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0337] Embodiment 30. A is 0 to 9 R 9 substituted with a group [ka] where the left attachment point: [ka] is L 1 represents the attachment point to the right attachment point: [ka] represents the point of attachment to the carbonyl, or a pharmaceutically acceptable salt thereof.

[0338] Embodiment 31. A is any R 9 31. The compound of any one of embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, which is not substituted with any group.

[0339] Embodiment 32.L 132. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein is a bond.

[0340] Embodiment 33.L 1 32. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein is -CR'2-.

[0341] Embodiment 34.L 1 32. The compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein is -CR'2CR'2-.

[0342] Embodiment 35. A compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein each R' is independently H.

[0343] Embodiment 36. A compound according to any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein two R' together with the carbons to which they are attached form a cyclopropyl ring.

[0344] Embodiment 37.L 1 is a bond, -CH2-, and [ka] 32. The compound of any one of embodiments 1-31, selected from: or a pharmaceutically acceptable salt thereof.

[0345] Embodiment 38.L 1 32. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein is —CH 2 —.

[0346] Embodiment 39.L 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0347] Embodiment 40.R 1 The compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof, wherein:

[0348] Embodiment 41.R 3 The compound of any one of embodiments 1-40, or a pharmaceutically acceptable salt thereof, wherein:

[0349] Embodiment 42.R 4 42. The compound of any one of embodiments 1-41, wherein is H, or a pharmaceutically acceptable salt thereof.

[0350] Embodiment 43.R 1 is H or R 3 is H or R 4 is H or R 1 , R 3 , and R 4 or a pharmaceutically acceptable salt thereof.

[0351] Embodiment 44.R 5 The compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, wherein is —NH 2 .

[0352] Embodiment 45.R 5 The compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, wherein is —OH.

[0353] Embodiment 46.R 6 The compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt thereof, wherein: Embodiment 47.R 2 is phenyl or monocyclic heteroaryl, the heteroaryl having 5 to 6 ring atoms and having 1 to 2 ring atoms selected from N, O, and S, and R 2 0 to 4 R 10 groups, and each R 10are independently C1-C6 alkyl, C1-C6 alkenyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO—R C , N.R. D 2, or halogen, and the heterocyclyl has 4 to 11 ring atoms, having 1 to 4 ring atoms selected from N, O, and S, each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E is optionally replaced by Each R C However, independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 4 substituents independently selected from halogen and OH; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 4 substituents independently selected from halogen and OH; or Two Rs attached to the same nitrogen D are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; Each R E are independently H, halo, OH, O-C1-C6 alkyl, C1-C6 alkyl, -C1-C6 haloalkyl; Each R 12 are independently H or C1-C6 alkyl; 47. The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein W is 0, 1, or 2.

[0354] Embodiment 48.R 2 0 to 4 R 10 48. The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2.

[0355] Embodiment 49.R 2 0 to 4 R 10 group, and optionally, each R 10 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl; or a pharmaceutically acceptable salt thereof.

[0356] Embodiment 50.R 2 0 to 4 R 10 or a pharmaceutically acceptable salt thereof.

[0357] Embodiment 51. The monocyclic heteroaryl is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiazole, and thiophene, each of which contains 0-4 R 10 51. The compound of embodiment 50, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0358] Embodiment 52.R 2 are selected from phenyl, pyridine, pyrimidine, pyridazine, pyrazine, thiazole, and thiophene, each of which contains 0 to 4 R 10 48. The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0359] Embodiment 53.R 2 are selected from phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, 4-pyridine, 3-pyridazine, pyrazine, 2-thiazole, 5-thiazole, 2-thiophene, and 3-thiophene, each of which is 0 to 4 R10 48. The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0360] Embodiment 54.R 2 are selected from phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, 4-pyridine, 3-pyridazine, 5-thiazole, 2-thiophene, and 3-thiophene, each of which has 0 to 4 R 10 48. The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0361] Embodiment 55.R 2 are selected from phenyl and thiophene, each of which contains 0 to 4 R 10 48. The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0362] Embodiment 56.R 2 are selected from phenyl and 2-thiophene, each of which contains 0 to 4 R 10 48. The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0363] Embodiment 57.R 2 0 to 4 R 10 48. The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R is a thiophene substituted with a group.

[0364] Embodiment 58.R 2 0 to 4 R 10 48. The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R is 2-thiophene substituted with a group.

[0365] Embodiment 59. Each R 10 is halogen, C1-C6 alkyl, and CO-R C are independently selected from R Cor a pharmaceutically acceptable salt thereof.

[0366] Embodiment 60. Each R 10 is independently selected from halogen and C1-C6 alkyl, and said alkyl is unsubstituted or substituted with 1 to 4 groups independently selected from halogen and OH; or a pharmaceutically acceptable salt thereof.

[0367] Embodiment 61. Each R 10 is independently selected from -F, -Cl, -Me, CF3, -CONH2, and -CH(OH)CH3; or a pharmaceutically acceptable salt thereof.

[0368] Embodiment 62. Each R 10 is independently selected from -F and -Me; or a pharmaceutically acceptable salt thereof.

[0369] Embodiment 63.R 2 is a monocyclic heteroaryl, wherein heteroaryl is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, or thiophene, e.g., R 2 is 2-thiophenyl, and each R 2 0 to 4 R 10 groups, and optionally, each R 10 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl; or a pharmaceutically acceptable salt thereof.

[0370] Embodiment 64.R 2 but, [ka] is selected from the group consisting of For example, R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0371] Embodiment 65.R 2 but, [ka] 47. The compound of any one of embodiments 1-46, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0372] Embodiment 66.R 2 but, [ka] 47. The compound of any one of embodiments 1-46, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0373] Embodiment 67.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0374] Embodiment 68.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0375] Embodiment 69.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0376] Embodiment 70.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0377] Embodiment 71.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0378] Embodiment 72.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0379] Embodiment 73.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0380] Embodiment 74.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0381] Embodiment 75.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0382] Embodiment 76.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0383] Embodiment 77.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0384] Embodiment 78.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0385] Embodiment 79.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0386] Embodiment 80.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0387] Embodiment 81.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0388] Embodiment 82.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0389] Embodiment 83.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0390] Embodiment 84.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0391] Embodiment 85.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0392] Embodiment 86.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0393] Embodiment 87.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0394] Embodiment 88.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0395] Embodiment 89.R 2 but, [ka] or a pharmaceutically acceptable salt thereof.

[0396] Embodiment 90.R 7 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms and has 1 to 2 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, cycloalkyl, and heteroaryl is selected from 0 to 4 R 11 or substituted with a group R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is 10 90. The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0397] Embodiment 91.R 7is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms and has 1 to 2 ring atoms that are N, and each alkyl, heteroalkyl, phenyl, cycloalkyl, and heteroaryl is selected from 0 to 4 R 11 or substituted with a group R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0 additional ring heteroatoms, and the heterocycle is 10 90. The compound of any one of embodiments 2-89, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0398] Embodiment 92.R 7 is selected from -Me, -Et, -CF, CHCHOMe, phenyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyridinonyl, each of which is selected from 0 to 4 R 11 or substituted with a group R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 5-6 membered heterocycle having 0 additional ring heteroatoms, and said heterocycle is substituted with 0 or 1 methyl or phenyl; or a pharmaceutically acceptable salt thereof.

[0399] Embodiment 93.R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, phenyl, or 6-membered heteroaryl, wherein heteroaryl has 1 or 2 nitrogen ring atoms; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N; R 7 0 to 4 R 11 90. The compound of any one of embodiments 2-89, or a pharmaceutically acceptable salt thereof, substituted with a group.

[0400] Embodiment 94. Each R 11 is independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, hydroxy, cyano, and halogen, wherein said alkyl and heteroalkyl are optionally substituted with 1 to 4 groups independently selected from halogen and OH; or a pharmaceutically acceptable salt thereof.

[0401] Embodiment 95. Each R 11 -F, -Cl, -Me, - i A compound according to any one of embodiments 2 to 93, or a pharmaceutically acceptable salt thereof, independently selected from Pr, -C(=CH2)CH3, -CF3, -CN, -OH, -OMe, -CH2OCH2CH2OMe, and -CH2OH.

[0402] Embodiment 96.R 7 , -Me, -Et, -CF3, -CH2CH2OMe, [ka] Selected from or R 7 and R 8 are grouped together with the atoms to which they are bonded, [ka] or a pharmaceutically acceptable salt thereof.

[0403] Embodiment 97.R 7 Me, Ph, CF3, -CH2CH2OCH3, cyclopropyl, [ka] is selected from the group consisting of For example, R 7 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein is Me.

[0404] Embodiment 98.R 7 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein is -Me.

[0405] Embodiment 99.R 7 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein is -Et.

[0406] Embodiment 100.R 7 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein is —CF 3 .

[0407] Embodiment 101.R 7 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein is —CH 2 CH 2 OMe.

[0408] Embodiment 102.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0409] Embodiment 103.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0410] Embodiment 104.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0411] Embodiment 105.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0412] Embodiment 106.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0413] Embodiment 107.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0414] Embodiment 108.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0415] Embodiment 109.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0416] Embodiment 110.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0417] Embodiment 111.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0418] Embodiment 112.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0419] Embodiment 113.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0420] Embodiment 114.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0421] Embodiment 115.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0422] Embodiment 116.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0423] Embodiment 117.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0424] Embodiment 118.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0425] Embodiment 119.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0426] Embodiment 120.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0427] Embodiment 121.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0428] Embodiment 122.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0429] Embodiment 123.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0430] Embodiment 124.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0431] Embodiment 125.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0432] Embodiment 126.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0433] Embodiment 127.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0434] Embodiment 128.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0435] Embodiment 129.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0436] Embodiment 130.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0437] Embodiment 131.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0438] Embodiment 132.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0439] Embodiment 133.R7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0440] Embodiment 134.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0441] Embodiment 135.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0442] Embodiment 136.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0443] Embodiment 137.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0444] Embodiment 138.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0445] Embodiment 139.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0446] Embodiment 140.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0447] Embodiment 141.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0448] Embodiment 142.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0449] Embodiment 143.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0450] Embodiment 144.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0451] Embodiment 145.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0452] Embodiment 146.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0453] Embodiment 147.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0454] Embodiment 148.R 7 but, [ka] or a pharmaceutically acceptable salt thereof.

[0455] Embodiment 149.R 7 and R 8 are grouped together with the atoms to which they are bonded, [ka] or a pharmaceutically acceptable salt thereof.

[0456] Embodiment 150.R7 and R 8 are grouped together with the atoms to which they are bonded, [ka] or a pharmaceutically acceptable salt thereof.

[0457] Embodiment 151.R 7 and R 8 are grouped together with the atoms to which they are bonded, [ka] or a pharmaceutically acceptable salt thereof.

[0458] Embodiment 152.R 7 and R 8 are grouped together with the atoms to which they are bonded, [ka] or a pharmaceutically acceptable salt thereof.

[0459] Embodiment 153.R 8 The compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or —CO2-t-butyl.

[0460] Embodiment 154.R 8 is H, Me, Et, CN, cyclopropyl, or -CO2-t-butyl, for example, R 8 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein:

[0461] Embodiment 155.R 8The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein:

[0462] Embodiment 156.R 8 The compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein is Me.

[0463] Embodiment 157.R 8 The compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein is Et.

[0464] Embodiment 158.R 8 The compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein is CN.

[0465] Embodiment 159.R 8 The compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein is cyclopropyl.

[0466] Embodiment 160.R 8 The compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein is CO-t-butyl.

[0467] Embodiment 161.R 8 The compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein is -CO2-t-butyl.

[0468] Embodiment 162.R 7 and R 8 are linked to each other to form propylene (-CH2-CH2-CH2-), or a pharmaceutically acceptable salt thereof.

[0469] Embodiment 163. Formula (Ia): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, During the ceremony, X 1 is -N- or -CH-, and X 2 is -N- or -CH-, or a pharmaceutically acceptable salt thereof.

[0470] Embodiment 164. Formula (Ib): [ka] 164. The compound of embodiment 163, or a pharmaceutically acceptable salt thereof.

[0471] Embodiment 165. Formula (Ic): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, or a pharmaceutically acceptable salt thereof.

[0472] Embodiment 166. Formula (Id): [ka] 166. The compound according to embodiment 165, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, or a pharmaceutically acceptable salt thereof.

[0473] Embodiment 167. Formula (Ie): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, In the formula, X 4 is N or CH, or a pharmaceutically acceptable salt thereof.

[0474] Embodiment 168. Formula (If): [ka] 168. The compound according to embodiment 167, or a pharmaceutically acceptable salt thereof, In the formula, X 4 is N or CH, or a pharmaceutically acceptable salt thereof.

[0475] Embodiment 169. Formula (Ig): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, In the formula, X 5 is N or CH, or a pharmaceutically acceptable salt thereof.

[0476] Embodiment 170. Formula (Ih): [ka] 169. The compound according to embodiment 169, or a pharmaceutically acceptable salt thereof, In the formula, X 5 is N or CH, or a pharmaceutically acceptable salt thereof.

[0477] Embodiment 171. Formula (Ii): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, X 6 is N or CH, X 7 is N or CH, or a pharmaceutically acceptable salt thereof.

[0478] Embodiment 172. Formula (Ij): [ka] 172. The compound of embodiment 171, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, X 6 is N or CH, X 7 is N or CH, or a pharmaceutically acceptable salt thereof.

[0479] Embodiment 173.X 6 is N and X 7 172. The compound of embodiment 170 or 171, or a pharmaceutically acceptable salt thereof, wherein is CH.

[0480] Embodiment 174.X 6 is CH and X 7 172. The compound according to embodiment 170 or 171, wherein is N; or a pharmaceutically acceptable salt thereof.

[0481] Embodiment 175. Formula (Ik): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, X 8 is N or CH, X 9 is N or CH, or a pharmaceutically acceptable salt thereof.

[0482] Embodiment 176. Formula (Im): [ka] 176. The compound according to embodiment 175, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, X 8 is N or CH, X 9 is N or CH, or a pharmaceutically acceptable salt thereof.

[0483] Embodiment 177.X 8 is N and X 9 177. The compound of embodiment 175 or 176, or a pharmaceutically acceptable salt thereof, wherein is CH.

[0484] Embodiment 178.X 8 is CH and X 9 177. The compound of embodiment 175 or 176, wherein is N; or a pharmaceutically acceptable salt thereof.

[0485] Embodiment 179. Formula (In): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, or a pharmaceutically acceptable salt thereof.

[0486] Embodiment 180. Formula (Io): [ka] 179. The compound according to embodiment 179, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, or a pharmaceutically acceptable salt thereof.

[0487] Embodiment 181. Formula (Ip): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, or a pharmaceutically acceptable salt thereof.

[0488] Embodiment 182. Formula (Iq): [ka] 182. The compound of embodiment 181, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, or a pharmaceutically acceptable salt thereof.

[0489] Embodiment 183. Formula (Ir): [ka] A compound according to any one of embodiments 1 to 3 and 40 to 162, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, or a pharmaceutically acceptable salt thereof.

[0490] Embodiment 184. Formula (Is): [ka] 184. The compound according to embodiment 183, or a pharmaceutically acceptable salt thereof, In the formula, X 3 is O or S, or a pharmaceutically acceptable salt thereof.

[0491] Embodiment 185.X 3 or a pharmaceutically acceptable salt thereof.

[0492] Embodiment 186.X 3is O; or a pharmaceutically acceptable salt thereof.

[0493] Embodiment 187. A compound disclosed in Table 1 or a pharmaceutically acceptable salt thereof, or a compound selected from elsewhere herein and in the Figures.

[0494] Embodiment 188. The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0495] Embodiment 189. A composition comprising a compound according to any one of embodiments 1 to 188, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0496] Embodiment 190. A method for treating a disease or disorder that can be treated by inhibition of histone deacetylase (HDAC), comprising administering to a patient in need thereof a compound according to any one of embodiments 1 to 188 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 189.

[0497] Embodiment 191. The method of embodiment 190, wherein the disease or disorder is cancer.

[0498] Embodiment 192. The method of embodiment 191, wherein the cancer is selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or sarcoma.

[0499] Embodiment 193. The method of embodiment 191, wherein the cancer is selected from the group consisting of melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, and gastric cancer.

[0500] Embodiment 194. The method of embodiment 191, wherein the cancer (e.g., a cancer associated with HDAC) is cancer of unknown primary (CUP), colorectal cancer (e.g., colon cancer), cervical cancer, or non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma).

[0501] Embodiment 195. The method of embodiment 191, wherein the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma).

[0502] Embodiment 196. The method of embodiment 191, wherein the cancer is cervical cancer.

[0503] Embodiment 197. The method of embodiment 191, wherein the cancer is colorectal cancer (e.g., colon cancer).

[0504] Embodiment 198. The method of embodiment 191, wherein the cancer is cancer of unknown primary (CUP).

[0505] Embodiment 199. The method of any one of embodiments 189 to 198, further comprising the use of at least one additional therapeutic agent.

[0506] Embodiment 200. The method of embodiment 199, wherein the at least one additional therapeutic agent is chemotherapy or radiation.

[0507] Embodiment 201. The method of embodiment 199, wherein the at least one additional therapeutic agent is an immunotherapeutic agent (e.g., an anti-PD-1 ligand or an anti-PD-L1 ligand).

[0508] Embodiment 202. The method of embodiment 201, wherein the immunotherapeutic agent is an anti-PD-1 antibody (e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostallimab; prorugolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).

[0509] Embodiment 203. The method of embodiment 201, wherein the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559; durvalumab; avelumab; embafolimab; cosibelimab; sugemalimab AUNP-12; or atezolizumab) or an anti-PD-L1 small molecule (e.g., CA-170).

[0510] Embodiment 204. Use of a compound according to any one of embodiments 1 to 188 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 189, in the manufacture of a medicament for treating a disease or disorder that can be treated by inhibition of histone deacetylase (HDAC).

[0511] Embodiment 205. The use of embodiment 204, wherein the disease or disorder is cancer.

[0512] Embodiment 206. The use of embodiment 205, wherein the cancer is selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or sarcoma.

[0513] Embodiment 207. The use of embodiment 205, wherein the cancer is selected from the group consisting of melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, and gastric cancer.

[0514] Embodiment 208. The use of embodiment 205, wherein the cancer (e.g., a cancer associated with HDAC) is cancer of unknown primary (CUP), colorectal cancer (e.g., colon cancer), cervical cancer, or non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma).

[0515] Embodiment 209. The use of embodiment 205, wherein the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma).

[0516] Embodiment 210. The use of embodiment 205, wherein the cancer is cervical cancer.

[0517] Embodiment 211. The use of embodiment 205, wherein the cancer is colorectal cancer (e.g., colon cancer).

[0518] Embodiment 212. The use of embodiment 205, wherein the cancer is cancer of unknown primary (CUP).

[0519] Embodiment 213. The use of any one of embodiments 204 to 212, wherein the medicament is configured for administration with at least one additional therapeutic agent.

[0520] Embodiment 214. The use of embodiment 213, wherein the at least one additional therapeutic agent is chemotherapy or radiation.

[0521] Embodiment 215. The use of embodiment 213, wherein the at least one additional therapeutic agent is an immunotherapeutic agent (e.g., an anti-PD-1 ligand or an anti-PD-L1 ligand).

[0522] Embodiment 216. The use of embodiment 215, wherein the immunotherapeutic agent is an anti-PD-1 antibody (e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostallimab; prorugolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).

[0523] Embodiment 217. The use of embodiment 215, wherein the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559; durvalumab; avelumab; embafolimab; cosibelimab; sugemalimab AUNP-12; or atezolizumab) or an anti-PD-L1 small molecule (e.g., CA-170).

[0524] Embodiment 218. Use of a compound according to any one of embodiments 1 to 188 in the manufacture of a medicament for treating cancer.

[0525] Embodiment 219. Use of a compound according to any one of embodiments 1 to 188 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 189, in the treatment of a disease or disorder that can be treated by the inhibition of histone deacetylase (HDAC).

[0526] Embodiment 220. The use described in embodiment 219, wherein the disease or disorder is cancer.

[0527] Embodiment 221. The use of embodiment 220, wherein the cancer is selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or sarcoma.

[0528] Embodiment 222. The use of embodiment 220, wherein the cancer is selected from the group consisting of melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, and gastric cancer.

[0529] Embodiment 223. The use of embodiment 220, wherein the cancer (e.g., a cancer associated with HDAC) is cancer of unknown primary (CUP), colorectal cancer (e.g., colon cancer), cervical cancer, or non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma).

[0530] Embodiment 224. The use of embodiment 220, wherein the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma).

[0531] Embodiment 225. The use of embodiment 220, wherein the cancer is cervical cancer.

[0532] Embodiment 226. The use of embodiment 220, wherein the cancer is colorectal cancer (e.g., colon cancer).

[0533] Embodiment 227. The use of embodiment 220, wherein the cancer is cancer of unknown primary (CUP).

[0534] Embodiment 228. The use of any one of embodiments 219 to 227, wherein the use further comprises administration of at least one additional therapeutic agent.

[0535] Embodiment 229. The use of embodiment 228, wherein the at least one additional therapeutic agent is chemotherapy or radiation.

[0536] Embodiment 230. The use of embodiment 228, wherein the at least one additional therapeutic agent is an immunotherapeutic agent (e.g., an anti-PD-1 ligand or an anti-PD-L1 ligand).

[0537] Embodiment 231. The use of embodiment 230, wherein the immunotherapeutic agent is an anti-PD-1 antibody (e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostallimab; prorugolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).

[0538] Embodiment 232. The use of embodiment 230, wherein the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559; durvalumab; avelumab; embafolimab; cosibelimab; sugemalimab AUNP-12; or atezolizumab) or an anti-PD-L1 small molecule (e.g., CA-170).

[0539] Embodiment 233. A compound according to any one of embodiments 1 to 188 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 189, for use in a method for treating a disease or disorder that can be treated by the inhibition of histone deacetylase (HDAC), comprising administering to a patient in need thereof a compound according to any one of embodiments 1 to 188 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 189.

[0540] Embodiment 234. The compound or composition for use according to embodiment 233, wherein the disease or disorder is cancer.

[0541] Embodiment 235. The compound or composition for use according to embodiment 234, wherein the cancer is selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or sarcoma.

[0542] Embodiment 236. The compound or composition for use according to embodiment 234, wherein the cancer is selected from the group consisting of melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, and gastric cancer.

[0543] Embodiment 237. The compound or composition for use of embodiment 235, wherein the cancer (e.g., a cancer associated with HDAC) is cancer of unknown primary (CUP), colorectal cancer (e.g., colon cancer), cervical cancer, or non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma).

[0544] Embodiment 238. The compound or composition for use according to embodiment 235, wherein the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma).

[0545] Embodiment 239. The compound or composition for use according to embodiment 235, wherein the cancer is cervical cancer.

[0546] Embodiment 240. The compound or composition for use according to embodiment 235, wherein the cancer is colorectal cancer (e.g., colon cancer).

[0547] Embodiment 241. The compound or composition for use according to embodiment 235, wherein the cancer is cancer of unknown primary (CUP).

[0548] Embodiment 242. A compound or composition for use according to any one of embodiments 233 to 241, further comprising the use of at least one additional therapeutic agent.

[0549] Embodiment 243. The compound or composition for use according to embodiment 242, wherein the at least one additional therapeutic agent is chemotherapy or radiation.

[0550] Embodiment 244. The compound or composition for use according to embodiment 242, wherein the at least one additional therapeutic agent is an immunotherapeutic agent (e.g., an anti-PD-1 ligand or an anti-PD-L1 ligand).

[0551] Embodiment 245. The compound or composition for use according to embodiment 244, wherein the immunotherapeutic agent is an anti-PD-1 antibody (e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostallimab; prorugolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).

[0552] Embodiment 246. The compound or composition for use of embodiment 244, wherein the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559; durvalumab; avelumab; embafolimab; cosibelimab; sugemalimab AUNP-12; or atezolizumab) or an anti-PD-L1 small molecule (e.g., CA-170). [Example]

[0553] To facilitate a more complete understanding of the present invention, the following examples are set forth. The following examples illustrate exemplary methods of making and practicing the present invention. However, the scope of the present invention is not limited to the specific embodiments disclosed in these examples, as alternative methods may be utilized to achieve similar results, and these examples are for illustrative purposes only.

[0554] In the following examples, chemical reagents were purchased from commercial sources (e.g., Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and used without further purification.

[0555] In some examples, purification of intermediates and final compounds was carried out using HPLC (HO-MeOH; Agilent 1260 Infinity system equipped with DAD and mass detector, Waters Sunfire C18 OBD preparative column, 100 Å, 5 μm, 19 mm × 100 mm equipped with SunFire C18 preparative guard cartridge, 100 Å, 10 μm, 19 mm × 10 mm). The material was dissolved in 0.7 mL of DMSO. Flow rate: 30 mL / min. The purity of the obtained fractions was confirmed by analytical LCMS. Spectra were recorded for each fraction, as each fraction was obtained in solution form immediately after chromatography. The solvent was evaporated by heating to 80 °C under a stream of N2. Based on the LCMS analysis after chromatography, the fractions were combined. The solid fraction was dissolved in 0.5 mL of MeOH and transferred to a pre-weighed and marked vial. The resulting solution was evaporated again by heating to 80 °C under a stream of N2. After drying, the product was subjected to lyophilization using an acetonitrile-water mixture and finally analyzed by LCMS and 1 It was characterized by 1 H NMR.

[0556] Nuclear magnetic resonance (NMR) spectra were recorded using a Bruker AVANCE DRX 500, a Bruker 400 spectrometer, or a Varian UNITYplus 400. Proton chemical shifts were reported as parts per million on the δ scale using residual solvent peaks (CHCl3: 7.27 ppm, methanol-d4: 3.31 ppm, DMSO-d6: 2.50 ppm, or tetramethylsilane: 0.00 ppm) as internal standards. 13 Chemical shifts for C NMR spectra are reported in ppm from the central peaks of CDCl3 (77.00 ppm), methanol-d4 (49.15 ppm), and DMSO-d6 (39.51 ppm) on the δ scale. Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, sp = septet, m = multiplet, br = broad line), coupling constant (J, Hz), and integral.

[0557] In certain examples, mass spectra were recorded on an Agilent 1100 Series LC / MSD system equipped with a DAD / ELSD and an Agilent LC / MSD VL (G1956A), SL (G1956B) mass spectrometer, or an Agilent 1200 Series LC / MSD system equipped with a DAD / ELSD and an Agilent LC / MSD SL (G6130A), SL (G6140A) mass spectrometer. All LC / MS data was acquired using positive / negative mode switching. Column: Zorbax SB-C18 1.8 μm 4.6 × 15 mm Rapid Resolution Cartridge (PN: 821975-932) Mobile phase A: acetonitrile, 0.1% formic acid B: Water (0.1% formic acid) Flow rate: 3ml / min Gradient: 100% B at 0 min 0.01 part 100%B 0% B for 1.5 min 1.8 min 0%B 1.81 min 100%B Injection volume: 1μl Ionization mode: atmospheric pressure chemical ionization (APCI) Scanning range: m / z 80-1000.

[0558] Other exemplary analytical LC / MS instruments and conditions are described below:

[0559] Instrument: Agilent LC1100-MS6100 series G1956B; Column: Xbridge Shield RP-18, 50*2.1mm*5μm; Mobile phase A: H2O containing 0.05% NH3-H2O (v%); Mobile phase B: MeCN; Flow rate: 1.0mL / min; Wavelength: UV 220nm, 254nm; Column temperature: 30℃; MS ionization: ESI. 0-30CD: Gradient: 0% to 30% B in 2 min and hold at 30% for 0.48 min; 0-60CD: Gradient: 0% to 60% B in 2 min and hold at 60% for 0.48 min; 10-80CD: Gradient: 10% to 80% B in 2 min and hold at 80% for 0.48 min; 30-90CD: Gradient: 30% to 90% B in 2 min and hold at 90% for 0.48 min; 50-100CD: Gradient: 50% to 100% B in 2 min and hold at 100% for 0.48 min.

[0560] Instrument: Agilent LC1100-MS6100 series G1956B; Column: Xtimate C18, 30*2.1mm*3μm; Mobile phase A: H2O containing 0.0375% TFA (v%); Mobile phase B: MeCN containing 0.01875% TFA (v%); Flow rate: 0.8mL / min; Wavelength: UV220nm, 254nm; Column temperature: 50℃; MS ionization: ESI. 0-30AB: Gradient: 0% to 30% B in 3 min and hold at 30% for 0.5 min; 0-60AB: Gradient: 0% to 60% B in 3 min and hold at 30% for 0.5 min; 10-80AB: Gradient: 10% to 80% B in 3 min and hold at 30% for 0.5 min; 30-90AB: Gradient: 0% to 30% B in 3 min and hold at 30% for 0.5 min; 50-100AB: Gradient: 50% to 100% B in 3 minutes and hold at 100% for 0.5 minutes.

[0561] Instrument: Shimadzu LC20-MS2010; Column: Agilent Pursuit 5 C18 20*2.0mm; Mobile phase A: H2O containing 0.0375% (v%) TFA; Mobile phase B: MeCN containing 0.01875% (v%) TFA; Gradient: 5 to 95% B in 0.7 min and hold at 95% for 0.4 min; Flow rate: 1.5 mL / min; Wavelength: UV 220 nm, 254 nm, 215 nm; Column temperature: 50 °C; MS ionization: ESI.

[0562] Instrument: Shimadzu LC20-MS2020; Column: Agilent Pursuit 5 C18 20*2.0mm; Mobile phase A: H2O containing 0.0375% (v%) TFA; Mobile phase B: MeCN containing 0.01875% (v%) TFA; Gradient: 5 to 95% B in 0.7 min and hold at 95% for 0.4 min; Flow rate: 1.5 mL / min; Wavelength: UV 220 nm, 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0563] Exemplary HPLC Instrumentation and Conditions Instrument: Shimadzu LC20; Column: YMC-Pack ODS-A 150*4.6mm; Mobile phase A: H2O containing 0.06875% (v%) TFA; Mobile phase B: MeCN containing 0.0625% (v%) TFA; Flow rate: 1.5mL / min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40℃. 0-30: Gradient: 0 to 30% B in 10 min and hold at 30% for 5 min; 0-60: Gradient: 0% to 60% B in 10 min and hold at 60% for 5 min; 0-95: Gradient: 0 to 95% B in 10 min and hold at 95% for 5 min; 10–80: Gradient: 10–80% B in 10 min and hold at 80% for 5 min; 30-90: Gradient: 30-90% B in 10 min and hold at 90% for 5 min; 50-100: Gradient: 50-100% B in 10 min and hold at 100% for 5 min.

[0564] Instrument: Shimadzu LC20; Column: Xbridge Shield RP-18 50*2.1mm, 5μm; Mobile phase A: H2O containing 0.01% NH3-H2O; Mobile phase B: MeCN; Flow rate: 1.2mL / min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40℃. 0-30CD: Gradient: 0 to 30% B in 6 min and hold at 30% for 2 min; 0-60CD: Gradient: 0 to 60% B in 6 min and hold at 60% for 2 min; 10-80CD: Gradient: 10 to 80% B in 6 min and hold at 80% for 2 min; 30-90CD: Gradient: 30 to 90% B in 6 min and hold at 90% for 2 min; 50-100CD: Gradient: 10 to 80% B in 6 min and hold at 100% for 2 min.

[0565] Instrument: Shimadzu LC20; Column: Ultimate C18 50*3mm, 3μm; Mobile phase A: H2O containing 0.06875% (v%) TFA; Mobile phase B: MeCN containing 0.0625% (v%) TFA; Flow rate: 1.2mL / min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40℃. 0-30AB: Gradient: 0 to 30% B in 2.5 minutes and hold at 30% for 0.75 minutes; 0-60AB: Gradient: 0 to 60% B in 2.5 minutes and hold at 60% for 0.75 minutes; 5-95AB: Gradient: 5 to 95% B in 2.5 minutes and hold at 95% for 0.75 minutes.

[0566] Instrument: Shimadzu LC20; Column: Ultimate C18 50*3mm, 3μm; Mobile phase A: H2O containing 0.06875% (v%) TFA; Mobile phase B: MeCN containing 0.0625% (v%) TFA; Flow rate: 1.2mL / min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40℃. 10-80AB: Gradient: 10 to 80% B in 4 minutes and hold at 80% for 2 minutes.

[0567] Exemplary TLC, concentration, and normal phase chromatography. Thin-layer chromatography (TLC) analysis was performed using silica gel 60 F254 aluminum plates. Visualization was performed using a UV lamp (254 nm) and immersion in iodine or ethanolic phosphomolybdic acid (PMA) or potassium permanganate (KMnO4), followed by heating using a heat gun. Organic solutions were concentrated by rotary evaporation at 20-40°C. Purification of reaction products was typically performed by flash column chromatography using 230-400 mesh silica gel or Agela flash silica columns.

[0568] Exemplary Chiral SFC Analysis Methods Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Mobile phase: A: Supercritical CO2; Mobile phase B: EtOH (0.05% DEA); Gradient: 5% to 40% B in 5 min and hold at 40% for 2.5 min, then hold at 5% B for 2.5 min; Flow rate: 2.5 ml / min; Column temperature: 35°C; ABPR: 1500 psi.

[0569] Column: Chiralpak AD-3 100 x 4.6 mm ID, 3 μm; Mobile phase: A: supercritical CO2; Mobile phase B: EtOH (0.1% ethanolamine); Gradient: 5% to 40% B in 4.5 min and hold at 40% for 2.5 min, then hold at 5% B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 40°C.

[0570] Exemplary Preparative HPLC Separation Methods Basic conditions (NH3-H2O): Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase A: H2O containing 0.05% NH3-H2O (v%); Mobile phase B: MeCN; Gradient: 22% to 52% B in 9.5 min, hold at 100% B for 1 min; Flow rate: 25 mL / min; Column temperature: 30 °C; Wavelength: 220 nm, 254 nm.

[0571] Acidic conditions (HCOOH): Equipment: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Agela Durashell C18 150*25mm 5μm; Mobile phase A: HO (0.0225% HCOOH); Mobile phase B: MeCN; Gradient: 7% to 37% B in 9 min, hold 100% B at 0 min; Flow rate: 25mL / min; Column temperature: 30℃; Wavelength: 220nm, 254nm.

[0572] Acidic conditions (HCl): Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Xtimate C18 150*25mm*5μm; Mobile phase A: H2O containing 0.05% (v%) HCl; Mobile phase B: MeCN; Gradient: 0% to 30% B in 6.5 min, hold 100% B for 2.5 min; Flow rate: 25mL / min; Column temperature: 30℃; Wavelength: 220nm, 254nm.

[0573] Neutral conditions (NH4HCO3): (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase A: H2O containing 10 mmol NH4HCO3; Mobile phase B: MeCN; Gradient: 39% to 69% B in 10 min, hold at 100% B for 2.5 min; Flow rate: 25 mL / min; Column temperature: 30 °C; Wavelength: 220 nm, 254 nm).

[0574] Exemplary Large-Scale Separation Basic conditions: Instrument: Shimadzu LC-8A Pump, Shimadzu SCL-10A VP System Controller, Shimadzu SPD-20AV UV / VIS Detector; Column: Phenomenex Gemini C18 250*50mm*10μm; Mobile phase A: Water (0.04% NH3-H2O + 10mM NH4HCO3); Mobile phase B: MeCN; Gradient: 65% to 95% B in 26 minutes, hold 100% B for 3 minutes; Flow rate: 110mL / min; Column temperature: 30℃; Wavelength: 220nm, 254nm.

[0575] Acidic conditions (TFA): Instrument: Shimadzu LC-20AP Pump, Shimadzu CBM-20A System Controller, Shimadzu SPD-20AV UV / VIS Detector; Column: Phenomenex luna C18 250 × 50 mm × 10 μm; Mobile phase A: HO containing 0.1% (v%) TFA; Mobile phase B: MeCN; Gradient: 0% to 25% B in 15 min, hold at 100% B for 4 min; Flow rate: 120 mL / min; Column temperature: 30 °C; Wavelength: 220 nm, 254 nm.

[0576] Exemplary preparative chiral SFC methods: Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0577] In one particular example, chiral separations were performed under the following conditions: Instrument: Thar 80; Column: Daicel Chiralpak AD 250 x 30 mm ID 10 μm; Mobile phase: Supercritical CO2 / MeOH (0.1% NH3-H2O, v%) = 60 / 40; Flow rate: 70 mL / min; Column temperature: 38 °C; Nozzle pressure: 100 bar; Nozzle temperature: 60 °C; Evaporator temperature: 20 °C; Trimmer temperature: 25 °C; Wavelength: 220 nm.

[0578] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0579] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group and suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0580] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details regarding the preparation of representative pyrazoles listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents.

[0581] Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19×250 mm; Mobile phase: acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3-H2O); Flow rate: 25 mL / min.

[0582] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile; Gradient: 5% to 95% B in 1.6 or 2 min; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6*50 mm, 3.5 μm, 45 °C. [Table 2-1] [Table 2-2]

[0583] Example 1 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-[rel-(1R)-1-oxo-4,5-dihydro-3H-isothiazol-1-yl]benzamide (Compound 185) and N-[2-amino-5-(4-fluorophenyl)phenyl]-4-[rel-(1S)-1-oxo-4,5-dihydro-3H-isothiazol-1-yl]benzamide (Compound 184) [ka] Step 1: Synthesis of tert-butyl N-(4-bromo-2-nitrophenyl)-N-tert-butoxycarbonyl-carbamate To a solution of 4-bromo-2-nitroaniline (30 g, 0.138 mol), tert-butoxycarbonyl tert-butyl carbonate (approximately 79 mL, 0.344 mol), and DMAP (approximately 5 g, 40.9 mmol) in DCM (approximately 300 mL) was added TEA (approximately 58 mL, 0.416 mol). The mixture was stirred at approximately 20° C. for approximately 12 hours. The mixture was concentrated under reduced pressure. The residue was triturated in approximately 300 mL of MeOH to give tert-butyl N-(4-bromo-2-nitrophenyl)-N-tert-butoxycarbonyl-carbamate (57 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (d, J = 2.3 Hz, 1 H), 8.01 (dd, J = 8.5, 2.3 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 1.33 (s, 18 H).

[0584] Step 2: Synthesis of tert-butyl N-(4-bromo-2-nitrophenyl)carbamate To a solution of tert-butyl N-(4-bromo-2-nitrophenyl)-N-tert-butoxycarbonyl-carbamate (approximately 57 g, 0.137 mol) in DCM (approximately 50 mL) was added TFA (approximately 18 mL, 0.234 mol). The mixture was stirred at approximately 20° C. for approximately 1 hour. The resulting mixture was adjusted to pH=approximately 8 with saturated aqueous NaCO solution and extracted with DCM (approximately 100 mL*3). The combined organic layer was washed with saturated aqueous NHCl solution (approximately 100 mL*2), brine (approximately 100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-(4-bromo-2-nitrophenyl)carbamate (approximately 46 g), which was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (s, 1 H), 8.12 (d, J = 2.3 Hz, 1 H), 7.86 (dd, J = 8.8, 2.4 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 1.38 (s, 9 H).

[0585] Step 3: Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-nitrophenyl]carbamate To a solution of tert-butyl N-(4-bromo-2-nitrophenyl)carbamate (46 g, 0.145 mol), (4-fluorophenyl)boronic acid (approximately 26 g, 0.186 mol), and KCO (approximately 58 g, 0.420 mol) in dioxane (approximately 300 mL) and HO (approximately 30 mL), cyclopentyl(diphenyl)phosphane dichloromethane dichloropalladium iron (approximately 9 g, 11.0 mmol) was added. The mixture was stirred under N at approximately 100 °C for approximately 12 hours. The resulting mixture was quenched by the addition of HO (approximately 200 mL) and extracted with EtOAc (approximately 150 mL). The combined organic layers were washed with brine (approximately 200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was triturated in a solution (about 500 mL, containing 450 mL of PE, 50 mL of EtOAc) to give tert-butyl N-[4-(4-fluorophenyl)-2-nitrophenyl]carbamate (about 33 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.66 (s, 1 H), 8.17 (d, J = 2.3 Hz, 1 H), 7.97 (dd, J = 8.6, 2.3 Hz, 1 H), 7.75 - 7.83 (m, 2 H), 7.71 (d, J = 8.6 Hz, 1H), 7.28 - 7.37 (m, 2H), 1.45 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ ppm - 114.395.

[0586] Step 4: Synthesis of tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-nitrophenyl]carbamate (approximately 33 g, 99.3 mmol) in MeOH (approximately 300 mL) was added Pd / C (approximately 12 g, 10% Pd / C, 50% water, wt%). The resulting mixture was sealed, degassed under reduced pressure and purged with N three times, and then stirred under H (balloon) at approximately 20° C. for approximately 12 hours. The resulting mixture was filtered and concentrated under reduced pressure to provide tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (approximately 28 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (brs, 1H), 7.52 - 7.62 (m, 2H), 7.20 - 7.37 (m, 3H), 6.95 (d, J = 2.1 Hz, 1H), 6.80 (dd, J = 8.2, 2.1 Hz, 1H), 4.97 (s, 2H), 1.47 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ ppm - 116.338.

[0587] Step 5: Synthesis of methyl 4-sulfanylbenzoate To a solution of 4-sulfanylbenzoic acid (approximately 50 g, 0.324 mol) in MeOH (approximately 300 mL) was added sulfuric acid (approximately 10 mL, 0.188 mol). The reaction mixture was stirred at approximately 70° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was triturated with MeOH (approximately 40 mL). The mixture was filtered. The filter cake was dried under reduced pressure to give the desired product (approximately 23 g). The filtrate was concentrated under reduced pressure. The residue was triturated again with MeOH (approximately 20 mL). The mixture was filtered. The filter cake was dried under reduced pressure to give the desired product (approximately 20 g). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 330 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 10% EtOAc; flow rate = 100 mL / min; 254 nm) to give the desired product (ca. 10 g). Overall, methyl 4-sulfanylbenzoate (ca. 53 g) was obtained. LCMS (ESI) [M+H] + m / z: calculated: 169.0, observed: 169.1.

[0588] Step 6: Synthesis of methyl 4-(3-chloropropylsulfanyl)benzoate To a mixture of methyl 4-sulfanylbenzoate (approximately 20 g, 0.119 mol) and 1-bromo-3-chloropropane (approximately 24 mL, 0.243 mol) in THF (approximately 100 mL) was added N,N-diethylethanamine (approximately 33 mL, 0.237 mol). The mixture was stirred at approximately 20° C. for approximately 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 330 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 20% EtOAc; 100 mL / min; 254 nm) to give methyl 4-(3-chloropropylsulfanyl)benzoate (approximately 26.6 g). 1H NMR (400 MHz, chloroform-d) δ ppm 7.94 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 3.90 (s, 3H), 3.68 (t, J = 6.1 Hz, 2H), 3.16 (t, J = 7.0 Hz, 2H), 2.13 (quin, J = 6.6 Hz, 2H). LCMS (ESI) [M+H] + m / z: calculated: 245.0, observed: 245.0.

[0589] Step 7: Synthesis of methyl 4-(3-chloropropylsulfonimidoyl)benzoate To a solution of methyl 4-(3-chloropropylsulfanyl)benzoate (approximately 26.6 g, 0.109 mol) in MeOH (approximately 200 mL) was slowly added ammonia carbamate (approximately 17 g, 0.218 mol) and acetoxy(phenyl)-iodanyl acetate (approximately 87.5 g, 0.272 mol) at 0 °C. The mixture was stirred at approximately 20 °C for approximately 2 h. The reaction mixture was diluted with H2O (approximately 100 mL) and extracted with EtOAc (approximately 100 mL*3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 330 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 100% EtOAc; 100 mL / min; 254 nm) to give methyl 4-(3-chloropropylsulfonimidoyl)benzoate (approximately 21 g). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.22 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 3.97 (s, 3H), 3.62 (t, J = 6.1 Hz, 2H), 3.25 - 3.41 (m, 2H), 2.14 - 2.30 (m, 4H). LCMS (ESI) [M+H] + m / z: calculated: 276.0, observed: 275.9.

[0590] Step 8: Synthesis of methyl 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoate A mixture of methyl 4-(3-chloropropylsulfonimidoyl)benzoate (about 19 g, 68.9 mmol) in 0.1 wt% NH—H O (about 200 mL) was stirred for about 2 hours at about 80° C. The reaction mixture was concentrated under reduced pressure to provide methyl 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoate (about 17 g), which was used directly without further purification.

[0591] Step 9: Synthesis of 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoic acid To a solution of methyl 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoate (17 g, 71.0 mmol) in MeOH (approximately 100 mL) and HO (approximately 30 mL) was added LiOH · HO (about 8.94 g, 0.213 mol) was added. The mixture was stirred at about 20° C. for about 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue (about 22 g). The residue (about 21.5 g) in HO (about 100 mL) was adjusted to pH=about 4 with 2N aqueous HCl. The mixture was concentrated under reduced pressure to give 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoic acid (about 33 g).

[0592] Step 10: Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoyl]amino]phenyl]carbamate A mixture of 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoic acid (approximately 32 g, 71.0 mmol), tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (approximately 21 g, 69.5 mmol), and EDCI (approximately 20 g, 0.104 mol) in pyridine (approximately 100 mL) was stirred at approximately 50° C. for approximately 1 hour. The resulting mixture was quenched by the addition of water (approximately 100 mL) and extracted with EtOAc (approximately 100 mL*3). The combined organic layer was washed with saturated aqueous NH4Cl (100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; ca. 330 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 100% EtOAc; 100 mL / min; 254 nm) to give tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoyl]amino]phenyl]carbamate (ca. 8 g). LCMS (ESI) [M+H] + m / z: calculated: 510.2, found: 510.2. HPLC: 98.96% at 220 nm, 99.57% at 254 nm.

[0593] Step 11: Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzamide To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoyl]amino]phenyl]carbamate (approximately 8 g, 15.7 mmol) in DCM (approximately 100 mL) was added TFA (approximately 25 mL, 0.325 mol). The mixture was stirred at approximately 20°C for approximately 2 hours. The mixture was concentrated under reduced pressure. The residue was diluted with HO (approximately 50 mL) and adjusted to pH = approximately 8 with saturated aqueous NaHCO3. The mixture was extracted with 10:1 DCM / MeOH (approximately 150 mL*3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzamide (approximately 6 g), which was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 8.20 (d, J = 8.5 Hz, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.59 (dd, J = 8.8, 5.5 Hz, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.3, 2.3 Hz, 1H), 7.22 (t, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 5.19 (s, 2H), 3.82 - 3.89 (m, 1H), 3.71 (dt, J = 10.3, 6.5 Hz, 1H), 3.41 - 3.50 (m, 2H), 2.20 - 2.32 (m, 2H). LCMS (ESI) [M+H] + m / z: calculated: 410.1, found: 410.1. HPLC: 98.22% at 220 nm, 99.14% at 254 nm.

[0594] Step 12: Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-[rel-(1R)-1-oxo-4,5-dihydro-3H-isothiazol-1-yl]benzamide and N-[2-amino-5-(4-fluorophenyl)phenyl]-4-[rel-(1S)-1-oxo-4,5-dihydro-3H-isothiazol-1-yl]benzamide N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzamide (approximately 6 g, 14.7 mmol) was purified by chiral SFC separation (instrument: Berger, MULTIGR AM-II; column: Daicel Chiralpak AS 250 × 50 mm ID 10 μm; mobile phase: supercritical CO / EtOH (0.1% NH -H O, v%) = 40 / 60; flow rate: 200 mL / min; column temperature: approximately 35 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: approximately 20 °C; trimmer temperature: 25 °C; wavelength: 220 nm) to give the product. The stereochemistry was assigned accordingly.

[0595] N-[2-amino-5-(4-fluorophenyl)phenyl]-4-[rel-(1R)-1-oxo-4,5-dihydro-3H-isothiazol-1-yl]benzamide (approximately 2.88 g, peak 1, retention time = 1.565 min, single enantiomer). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.97 (brs, 1H), 8.20 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 8.8, 5.5 Hz, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.3, 2.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 5.17 (s, 2H), 3.80 - 3.88 (m, 1H), 3.70 (dt, J = 10.3, 6.5 Hz, 1H), 3.41 - 3.48 (m, 2H), 2.20 - 2.35 (m, 2H).19 F NMR (376 MHz, DMSO-d6) δ ppm -117.464. LCMS (ESI) [M+H] + m / z: calculated: 410.1, found: 410.2. HPLC: 95.64% at 220 nm, 98.19% at 254 nm. 99.5% ee.

[0596] N-[2-amino-5-(4-fluorophenyl)phenyl]-4-[rel-(1S)-1-oxo-4,5-dihydro-3H-isothiazol-1-yl]benzamide (approximately 2.88 g, peak 2, retention time = 3.296 min, single enantiomer). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1H), 8.20 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 8.7, 5.4 Hz, 2H), 7.50 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.3, 2.2 Hz, 1H), 7.22 (t, J = 8.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 5.17 (s, 2H), 3.79 - 3.89 (m, 1H), 3.70 (dt, J = 10.3, 6.6 Hz, 1H), 3.41 - 3.49 (m, 2H), 2.19 - 2.32 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ ppm -117.456. LCMS (ESI) [M+H] + m / z: calculated: 410.1, found: 410.2. HPLC: 97.48% at 220 nm, 99.53% at 254 nm. 99.4% ee.

[0597] Example 2: Synthesis of N-[2-amino-5-(4-chlorophenyl)phenyl]-4-(methylsulfonimidoyl)benzamide (Compound 182) [ka] Step 1: Synthesis of tert-butyl N-[4-(4-chlorophenyl)-2-nitrophenyl]carbamate To a solution of tert-butyl N-(4-bromo-2-nitrophenyl)carbamate (ca. 1 g, 3.15 mmol), (4-chlorophenyl)boronic acid (ca. 591 mg, 3.78 mmol), and K2CO3 (ca. 1.09 g, 7.88 mmol) in dioxane (ca. 12 mL) / HO (ca. 1.2 mL), Pd(dppf)Cl2·DCM (ca. 257 mg, 0.315 mmol) was added, and the reaction mixture was stirred at ca. 100 °C for ca. 4 h. The resulting mixture was quenched by the addition of water (ca. 10 mL) and extracted with EtOAc (ca. 10 mL). The combined organic layers were washed with brine (ca. 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; approximately 40 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc using 0 to 100% EtOAc; flow rate = 40 mL / min) to give the compound N-[4-(4-chlorophenyl)-2-nitrophenyl] tert-butylcarbamate (approximately 0.855 g). 1H NMR (400 MHz, chloroform-d) δ ppm 9.69 (s, 1 H), 8.65 (d, J = 8.88 Hz, 1 H), 8.40 (d, J = 2.25 Hz, 1 H), 7.81 (dd, J = 8.88, 2.25 Hz, 1 H), 7.37 - 7.57 (m, 4 H), 1.57 (s, 9 H).

[0598] Step 2: Synthesis of tert-butyl N-[2-amino-4-(4-chlorophenyl)phenyl]carbamate A solution of tert-butyl N-[4-(4-chlorophenyl)-2-nitrophenyl]carbamate (approximately 855 mg, 2.45 mmol), Fe (approximately 684 mg, 12.3 mmol), and NHCl (approximately 655 mg, 12.3 mmol) in EtOH (approximately 20 mL) / HO (approximately 4 mL) was stirred at approximately 80° C. for approximately 2 hours. The resulting mixture was quenched by the addition of water (approximately 10 mL) and extracted with EtOAc (approximately 10 mL*3). The combined organic layers were washed with brine (approximately 10 mL*3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The compound tert-butyl N-[2-amino-4-(4-chlorophenyl)phenyl]carbamate (approximately 366 mg) was obtained. LCMS (ESI) [M+H] + m / z: calculated: 319.1, found: 319.1.

[0599] Step 3: Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(4-chlorophenyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate A solution of tert-butyl N-[2-amino-4-(4-chlorophenyl)phenyl]carbamate (approximately 100 mg, 0.313 mmol), 4-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzoic acid (approximately 94 mg, 0.313 mmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (approximately 60 mg, 0.313 mmol) in pyridine (approximately 5 mL) was stirred at approximately 50° C. for approximately 1 hour. The resulting mixture was quenched by the addition of water (approximately 10 mL) and extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (approximately 10 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 50% EtOAc; flow rate = 35 mL / min; 254 nm) to give the compound tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(4-chlorophenyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate (approximately 106 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 9.70 (br s, 1 H), 8.10 (d, J = 8.53 Hz, 3 H), 7.98 (d, J = 8.53 Hz, 2 H), 7.43 (d, J = 8.53 Hz, 2 H), 7.26 - 7.34 (m, 3H), 3.16 (s, 3H), 1.47 (s, 18H). LCMS (ESI) [M+H] + m / z: calculated: 600.2, observed: 600.2.

[0600] Step 4: Synthesis of N-[2-amino-5-(4-chlorophenyl)phenyl]-4-(methylsulfonimidoyl)benzamide A solution of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(4-chlorophenyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate (about 90 mg, 0.150 mmol) in HFIP (about 5 mL) was heated in a microwave at about 90° C. for about 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; column: Durashell 150 × 25 mm × 5 μm; mobile phase A: HO containing 0.05% NH—HO (v%); mobile phase B: MeCN; gradient: 39% to 69% B in 10 min, hold at 100% B for 2.5 min; flow rate: 25 mL / min; column temperature: 30 °C; wavelength: 220 nm, 254 nm) to give N-[2-amino-5-(4-chlorophenyl)phenyl]-4-(methylsulfonimidoyl)benzamide (15.8 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.17 (s, 2 H), 8.07 - 8.13 (m, 2 H), 7.98 (br s, 1 H), 7.65 (s, 1 H), 7.48 (d, J = 8.5 Hz, 2 H), 7.38 (d, J = 8.5 Hz, 3 H), 6.96 (d, J = 8.3 Hz, 1 H), 3.16 (s, 3 H). LCMS (ESI) [M+H] + m / z: Calculated: 400.1, Found: 400.2. HPLC: 97.13% @ 254 nm, 97.05% @ 254 nm. 96.5%.

[0601] Example 3 Synthesis of rel-(R)-N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide (Compound 181) and rel-(S)-N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide (Compound 183) [ka] Step 1: Synthesis of methyl 4-pyrimidin-5-ylsulfanylbenzoate A mixture of 5-bromopyrimidine (approximately 2.83 g, 17.8 mmol), methyl 4-sulfanylbenzoate (approximately 1 g, 5.94 mmol), KPO (approximately 3.78 g, 17.8 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (approximately 690 mg, 1.19 mmol), and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (approximately 545 mg, 0.595 mmol) in dioxane (approximately 20 mL) was stirred at approximately 100 °C under a N atmosphere for approximately 12 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; ca. 20 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 12% EtOAc; flow rate = 30 mL / min; 254 nm) to give methyl 4-pyrimidin-5-ylsulfanylbenzoate (ca. 1.42 g). LCMS (ESI) [M+H] + m / z: calculated: 247.0, observed: 247.0.

[0602] Step 2: Synthesis of methyl 4-pyrimidin-5-ylsulfinylbenzoate To a solution of methyl 4-pyrimidin-5-ylsulfanylbenzoate (approximately 1.42 g, 5.77 mmol) in DCM (approximately 50 mL) was added 3-chlorobenzenecarboperoxoic acid (approximately 1.3 g, 6.40 mmol, 85 wt%). The mixture was stirred at approximately 0°C for approximately 1 hour. The resulting mixture was quenched by the addition of saturated aqueous NaSO (approximately 30 mL) and adjusted to pH = approximately 8 with saturated aqueous NaHCO (approximately 10 mL). The mixture was extracted with DCM (approximately 20 mL * 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; ca. 20 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 35% EtOAc; flow rate = 40 mL / min; 254 nm) to give methyl 4-pyrimidin-5-ylsulfinylbenzoate (ca. 1.15 g). LCMS (ESI) [M+H] + m / z: calculated: 263.0, observed: 263.0.

[0603] Step 3: Synthesis of methyl 4-(pyrimidin-5-ylsulfonimidoyl)benzoate A mixture of methyl 4-pyrimidin-5-ylsulfinylbenzoate (approximately 1.15 g, 4.38 mmol), acetoxy(phenyl)-iodanyl acetate (approximately 3.53 g, 11.0 mmol), ammonia carbamate (approximately 690 mg, 8.84 mmol), and MeOH (approximately 50 mL) was stirred at approximately 20 °C for approximately 12 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; approximately 12 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 40% EtOAc; flow rate = 30 mL / min; 254 nm) to give methyl 4-(pyrimidin-5-ylsulfonimidoyl)benzoate (approximately 570 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 1H), 9.14 (s, 2H), 8.11 - 8.14 (m, 2H), 8.00 (d, J = 8.5 Hz, 2H), 3.87 (s, 3H). LCMS (ESI) [M+H] + m / z: calculated: 278.1, observed: 278.1.

[0604] Step 4: Synthesis of 4-(pyrimidin-5-ylsulfonimidoyl)benzoic acid To a solution of methyl 4-(pyrimidin-5-ylsulfonimidoyl)benzoate (approximately 350 mg, 1.26 mmol) in HO (approximately 2 mL) and MeOH (approximately 6 mL) was added lithium hydroxide hydrate (approximately 530 mg, 12.6 mmol). The mixture was stirred at approximately 0° C. for approximately 3 hours. The mixture was adjusted to pH=approximately 5 with 2N aqueous HCl (approximately 10 mL). The resulting mixture was extracted with EtOAc (approximately 20 mL*3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4-(pyrimidin-5-ylsulfonimidoyl)benzoic acid (approximately 270 mg). LCMS (ESI) [M+H] + m / z: calculated: 264.0, observed: 264.0.

[0605] Step 5: Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(pyrimidin-5-ylsulfonimidoyl)benzoyl]amino]phenyl]carbamate A mixture of 4-(pyrimidin-5-ylsulfonimidoyl)benzoic acid (about 270 mg, 1.03 mmol), tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 370 mg, 1.22 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (about 300 mg, 1.56 mmol), and pyridine (about 6 mL) was stirred at about 50° C. for about 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; approximately 12 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 50% EtOAc; flow rate = 35 mL / min; 254 nm) to give tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(pyrimidin-5-ylsulfonimidoyl)benzoyl]amino]phenyl]carbamate (approximately 330 mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.98 - 10.05 (m, 1H), 9.34 (d, J = 3.8 Hz, 1H), 9.16 (s, 1H), 8.76 (s, 1H), 8.00 - 8.29 (m, 4H), 7.76 (s, 1H), 7.63 - 7.72 (m, 3H), 7.51 (dd, J = 8.4, 2.1 Hz, 1H), 7.28 (t, J = 8.9 Hz, 2H), 3.71 (s, 1H), 1.43 (s, 9H). LCMS (ESI) [M+H] + m / z: calculated: 548.2, observed: 548.2.

[0606] Step 6: Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide and N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(pyrimidin-5-ylsulfonimidoyl)benzoyl]amino]phenyl]carbamate (approximately 300 mg, 0.548 mmol) in DCM (approximately 6 mL) was added TFA (approximately 1 mL, 13.0 mmol). The mixture was stirred at approximately 20°C for approximately 2 hours. The resulting mixture was adjusted to pH = approximately 8 with saturated aqueous NaHCO3 (approximately 10 mL) and extracted with EtOAc (approximately 20 mL * 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; column: Durashell 75 × 40 mm × 3 μm; mobile phase A: HO containing 10 mmol NH4HCO3 (v%); mobile phase B: MeCN; gradient: 35% to 65% B in 7.8 min, hold at 100% B for 2 min; flow rate: 30 ml / min; column temperature: approximately 30 °C; wavelength: 220 nm, 254 nm) to give racemic N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide (compound 186). The compound was further purified by chiral SFC (instrument: Thar800Q; column: Chiralpak AD 250 × 30 mm ID 10 μm; mobile phase: supercritical CO / EtOH (0.1% NH - H O, v%) = 70 / 30; flow rate: 80 mL / min; column temperature: ca. 38 ° C; nozzle pressure: 100 bar; nozzle temperature: ca. 60 ° C; evaporator temperature: ca. 20 ° C; trimmer temperature: ca. 25 ° C; wavelength: 220 nm). The fractions were concentrated under reduced pressure and then lyophilized overnight to give the product. The stereochemistry was assigned accordingly.

[0607] rel-(R)-N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide (approximately 9.8 mg, single enantiomer, peak 1, retention time: 3.068 min). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.89 (s, 1H), 9.41 (s, 1H), 9.35 (s, 2H), 8.10 - 8.26 (m, 4H), 7.56 (dd, J = 8.8, 5.5 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.21 (t, J = 8.9 Hz, 2H), 6.84 (d, J = 8.3 Hz, 1H), 5.78 (s, 1H), 5.15 (s, 2H). 19 F NMR (376 MHz, DMSO-d6) δ ppm - 117.469. LCMS (ESI) [M+H] + m / z: calculated: 448.1, found: 448.2. HPLC: 94.32% at 220 nm, 99.72% at 254 nm. 99.3% ee.

[0608] rel-(S)-N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide was further purified by chiral SFC (instrument: Sepiatec Prep SFC100; column: Chiralpak AD 250 × 30 mm ID 10 μm; mobile phase: supercritical CO / EtOH (0.1% NH -H O, v%) = 70 / 30; flow rate: 80 mL / min; column temperature: ca. 38 ° C; nozzle pressure: 100 bar; nozzle temperature: ca. 60 ° C; evaporator temperature: ca. 20 ° C; trimmer temperature: ca. 25 ° C; wavelength: 220 nm). The fractions were concentrated under reduced pressure and then lyophilized overnight to give N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide.

[0609] N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide (approximately 9.1 mg, single enantiomer, peak 2, retention time: 2.042 min). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.89 (s, 1H), 9.41 (s, 1H), 9.35 (s, 2H), 8.13 - 8.25 (m, 4H), 7.56 (dd, J = 8.6, 5.5 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.3, 2.1 Hz, 1H), 7.21 (t, J = 8.9 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 5.78 (s, 1H), 5.15 (s, 2H). 19 F NMR (376 MHz, DMSO-d6) δ ppm - 117.471. LCMS (ESI) [M+H] + m / z: calculated: 448.1, found: 448.2. HPLC: 92.25% at 220 nm, 98.72% at 254 nm. 98.3% ee.

[0610] Example 4: Synthesis of N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4-fluorophenyl)phenyl]carbamoyl]benzothiophen-5-yl]-methyl-oxo-sulfanylidene]carbamic acid (Compound 173) [ka] Step 1: Synthesis of methyl 5-bromobenzothiophene-2-carboxylate To a mixture of 5-bromo-2-fluoro-benzaldehyde (approximately 5 g, 24.6 mmol), K2CO3 (approximately 13.6 g, 98.4 mmol) in DMF (approximately 50 mL) was added methyl 2-sulfanylacetate (approximately 2.9 g, 27.3 mmol). The mixture was stirred at approximately 60°C for approximately 15 hours. The resulting mixture was quenched by the addition of water (approximately 100 mL) and extracted with EtOAc (approximately 100 mL*3). The combined organic layers were washed with brine (approximately 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give methyl 5-bromobenzothiophene-2-carboxylate (approximately 6 g). 1H NMR (400 MHz, chloroform-d) δ ppm 7.96 (d, J = 1.6 Hz, 1H), 7.91 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.46 - 7.49 (m, 1H), 3.89 (s, 3H). LCMS (ESI) [M+H] + m / z: calculated: 270.9, observed: 270.9.

[0611] Step 2: Synthesis of methyl 5-(3-methoxy-3-oxo-propyl)sulfanylbenzothiophene-2-carboxylate A mixture of methyl 5-bromobenzothiophene-2-carboxylate (ca. 1 g, 3.69 mmol), methyl 3-sulfanylpropanoate (ca. 488 mg, 4.06 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (ca. 338 mg, 0.369 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (ca. 427 mg, 0.738 mmol), and N-ethyl-N-isopropyl-propan-2-amine (ca. 1.4 g, 10.8 mmol) in dioxane (ca. 10 mL) was stirred at ca. 100° C. for ca. 12 h. The resulting mixture was quenched by the addition of water (ca. 100 mL) and extracted with EtOAc (ca. 100 mL*3). The combined organic layers were washed with brine (ca. 100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; ca. 12 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 30% EtOAc; flow rate = 30 mL / min; 254 nm) to give methyl 5-(3-methoxy-3-oxo-propyl)sulfanylbenzothiophene-2-carboxylate (ca. 1 g). LCMS (ESI) [M+H] + m / z: calculated: 311.0, observed: 311.0.

[0612] Step 3: Synthesis of methyl 5-sulfanylbenzothiophene-2-carboxylate A mixture of methyl 5-(3-methoxy-3-oxopropyl)sulfanylbenzothiophene-2-carboxylate (approximately 1 g, 3.22 mmol) and sodium methanolate (approximately 697 mg, 12.9 mmol) in MeOH (approximately 10 mL) was stirred at approximately 65°C for approximately 1 hour. The mixture was basified with Na2CO3 to pH = approximately 6. The resulting mixture was quenched by the addition of water (approximately 100 mL) and extracted with EtOAc (approximately 100 mL * 3). The combined organic layers were washed with brine (approximately 100 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / EtOAc = 0 to 30%, 254 nm) to give methyl 5-sulfanylbenzothiophene-2-carboxylate (approximately 210 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.88 (s, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.27-7.32 (m, 1H), 3.88 (s, 3H), 3.51 (s, 1H). LCMS (ESI) [M+H] + m / z: calculated: 225.0, observed: 225.0.

[0613] Step 4: Synthesis of methyl 5-methylsulfanylbenzothiophene-2-carboxylate A mixture of methyl 5-sulfanylbenzothiophene-2-carboxylate (approximately 180 mg, 0.803 mmol), iodomethane (approximately 0.1 mL, 1.61 mmol), and K2CO3 (approximately 333 mg, 2.41 mmol) in MeCN (approximately 3 mL) was stirred at approximately 60 °C for approximately 12 h. The resulting mixture was quenched by the addition of water (approximately 100 mL) and extracted with EtOAc (approximately 100 mL * 3). The combined organic layers were washed with brine (approximately 100 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / EtOAc = 0 to 60%, 254 nm) to give methyl 5-methylsulfanylbenzothiophene-2-carboxylate (approximately 130 mg). 1H NMR (400 MHz, chloroform-d) δ ppm 7.91 (s, 1H), 7.61 - 7.72 (m, 2H), 7.31 - 7.37 (m, 1H), 3.84 - 3.91 (m, 3H), 2.48 (s, 3H). LCMS (ESI) [M+H] + m / z: calculated: 239.0, observed: 239.0.

[0614] Step 5: Synthesis of methyl 5-methylsulfinylbenzothiophene-2-carboxylate To a mixture of methyl 5-methylsulfanylbenzothiophene-2-carboxylate (approximately 125 mg, 0.524 mmol) in DCM (approximately 3 mL) was added 3-chlorobenzenecarboperoxoic acid (approximately 136 mg, 0.788 mmol, 85 wt%) at approximately 0°C. The mixture was stirred at approximately 20°C for approximately 1 hour. The resulting mixture was quenched by the addition of water (approximately 100 mL) and extracted with EtOAc (approximately 100 mL*3). The combined organic layers were washed with brine (approximately 100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / EtOAc = 0-60%, 254 nm) to give methyl 5-methylsulfinylbenzothiophene-2-carboxylate (approximately 130 mg). LCMS (ESI) [M+H] + m / z: calculated: 255.0, observed: 255.0.

[0615] Step 6: Synthesis of methyl 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzothiophene-2-carboxylate A mixture of methyl 5-methylsulfinylbenzothiophene-2-carboxylate (approximately 120 mg, 0.472 mmol), diacetoxyrhodium (approximately 10 mg, 0.0236 mmol), [acetoxy(phenyl)-iodanyl] acetate (approximately 228 mg, 0.708 mmol), oxomagnesium (approximately 95 mg, 2.36 mmol), and tert-butyl carbamate (approximately 111 mg, 0.944 mmol) in DCM (approximately 3 mL) was stirred at approximately 40° C. for approximately 12 hours. The resulting mixture was quenched by the addition of water (approximately 100 mL) and extracted with EtOAc (approximately 100 mL*3). The combined organic layers were washed with brine (approximately 100 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / EtOAc=0-80%, 254 nm) to give methyl 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzothiophene-2-carboxylate (about 100 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.49 (d, J = 1.6 Hz, 1H), 7.85 - 8.12 (m, 3H), 3.88 - 3.94 (m, 3H), 3.19 - 3.27 (m, 3H), 1.55 (s, 9H). LCMS (ESI) [M+H] + m / z: calculated: 370.1, observed: 370.0.

[0616] Step 7: Synthesis of 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzothiophene-2-carboxylic acid A mixture of methyl 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzothiophene-2-carboxylate (approximately 90 mg, 0.244 mmol) and lithium hydroxide hydrate (approximately 51 mg, 1.22 mmol) in MeOH (approximately 3 mL) and HO (approximately 2 mL) was stirred at approximately 20°C for approximately 1 hour. The resulting mixture was quenched by the addition of water (approximately 100 mL) and extracted with EtOAc (approximately 100 mL*3). The mixture was acidified with 2N HCl to pH = approximately 2-3 and extracted with EtOAc (approximately 10 mL*3). The combined organic layers were then washed with brine (approximately 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzothiophene-2-carboxylic acid (approximately 86 mg). LCMS (ESI) [M+H] + m / z: calculated value: 356.1, observed value: 300.0 (mass of cleaved t-Bu).

[0617] Step 8: Synthesis of tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4-fluorophenyl)phenyl]carbamoyl]benzothiophen-5-yl]-methyl-oxo-sulfanylidene]carbamate A mixture of 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzothiophene-2-carboxylic acid (about 70 mg, 0.197 mmol), tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 65 mg, 0.217 mmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (about 45 mg, 0.236 mmol) in pyridine (about 2 mL) was stirred at about 50° C. for about 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / EtOAc = 10:0 to 0:10, 254 nm) to give tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4-fluorophenyl)phenyl]carbamoyl]benzothiophen-5-yl]-methyl-oxo-sulfanylidene]carbamate (approximately 120 mg). 1H NMR (400 MHz, Chloroform-d) δ ppm 9.93 (brs, 1H), 8.43 (s, 1H), 7.85 - 8.09 (m, 4H), 7.45 - 7.53 (m, 2H), 7.25 - 7.35 (m, 1H), 7.07 - 7.17 (m, 1H), 6.95 - 7.05 (m, 2H), 6.72 (s, 1H), 3.24 (s, 3H), 1.52 (s, 9H), 1.33 (s, 9H). LCMS (ESI) [M+H] + m / z: calculated: 640.2, found: 640.2.

[0618] Step 9: Synthesis of N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4-fluorophenyl)phenyl]carbamoyl]benzothiophen-5-yl]-methyl-oxo-sulfanylidene]carbamic acid A mixture of tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4-fluorophenyl)phenyl]carbamoyl]benzothiophen-5-yl]-methyl-oxo-sulfanylidene]carbamate (about 100 mg, 0.156 mmol) in TFA (about 1.5 mL) and DCM (about 5 mL) was stirred for 1 hour at about 25° C. The mixture was concentrated. The residue was purified by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; column: Durashell 75 × 40 mm × 3 μm; mobile phase A: HO containing NH₄HCO₃ (v%); mobile phase B: MeCN; gradient: 40% to 70% B in 7.8 min, hold at 100% B for 2 min; flow rate: 30 ml / min; column temperature: ca. 30 °C; wavelength: 220 nm, 254 nm) to give N-[2-amino-5-(4-fluorophenyl)phenyl]-5-(methylsulfonimidoyl)benzothiophene-2-carboxamide (ca. 30 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (s, 1H), 8.42 - 8.59 (m, 2H), 8.29 (d, J = 8.28 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.57 - 7.61 (m, 2H), 7.50 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.19 - 7.24 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 5.21 (brs, 2H), 4.37 (s, 1H), 3.14 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ ppm - 117.395. LCMS (ESI) [M+H] + m / z: Calculated: 440.1, Found: 440.1. HPLC: 99.11% @ 254 nm, 99.83% @ 254 nm.

[0619] Example 5: Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(3-pyridylsulfonimidoyl)benzamide (Compound 172) [ka] Step 1: Synthesis of methyl 4-(3-pyridylsulfanyl)benzoate A mixture of 3-iodopyridine (approximately 1.1 g, 5.35 mmol), methyl 4-sulfanylbenzoate (approximately 300 mg, 1.78 mmol), KPO (approximately 1.13 g, 5.34 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (approximately 210 mg, 0.363 mmol), and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (approximately 170 mg, 0.186 mmol) in dioxane (approximately 3 mL) was stirred at approximately 100 °C under a N atmosphere for approximately 12 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; ca. 12 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 14% EtOAc; flow rate = 30 mL / min; 254 nm) to give methyl 4-(3-pyridylsulfanyl)benzoate (ca. 400 mg). LCMS (ESI) [M+H] + m / z: calculated: 246.1, found: 246.1.

[0620] Step 2: Synthesis of methyl 4-(3-pyridylsulfinyl)benzoate A mixture of methyl 4-(3-pyridylsulfanyl)benzoate (ca. 400 mg, 1.63 mmol) and 3-chlorobenzenecarboperoxoic acid (ca. 497 mg, 2.45 mmol, 85 wt%) in DCM (ca. 4 mL) was stirred at 25° C. for 1 h. The mixture was quenched with saturated NaSO solution (ca. 8 mL) and NaHCO (ca. 10 mL). The combined organic layer was extracted with DCM (ca. 10 mL*3), washed with brine (ca. 10 mL), dried over anhydrous NaSO, filtered, and concentrated to give methyl 4-(3-pyridylsulfinyl)benzoate (ca. 360 mg). LCMS (ESI) [M+H] + m / z: calculated: 262.0, observed: 262.0.

[0621] Step 3: Synthesis of methyl 4-(3-pyridylsulfonimidoyl)benzoate A mixture of methyl 4-(3-pyridylsulfinyl)benzoate (approximately 260 mg, 0.995 mmol), acetoxy(phenyl)-iodanyl acetate (approximately 805 mg, 2.50 mmol), ammonia carbamate (approximately 163 mg, 2.09 mmol), and MeOH (approximately 10 mL) was stirred at approximately 20 °C for approximately 2 h. The resulting mixture was quenched by the addition of water (approximately 10 mL) and extracted with EtOAc (approximately 30 mL). The combined organic layers were washed with brine (approximately 30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; ca. 20 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 70% EtOAc; flow rate = 30 mL / min; 254 nm) to give methyl 4-(3-pyridylsulfonimidoyl)benzoate (310 mg). LCMS (ESI) [M+H] + m / z: calculated: 277.1, observed: 277.0.

[0622] Step 4: Synthesis of 4-(3-pyridylsulfonimidoyl)benzoic acid To a solution of methyl 4-(3-pyridylsulfonimidoyl)benzoate (approximately 310 mg, 1.12 mmol) in MeOH (approximately 1 mL) was added a solution of LiOH·HO (approximately 474 mg, 11.3 mmol) in HO (approximately 0.5 mL). The mixture was stirred at approximately 20° C. for approximately 1 hour. The mixture was concentrated, and then the mixture was adjusted to pH=approximately 5 with 2N aqueous HCl. The resulting mixture was diluted with water (approximately 10 mL) and extracted with EtOAc (approximately 20 mL*3). The combined organic layers were washed with brine (approximately 20 mL), dried over anhydrous NaSO, filtered, and concentrated to give 4-(3-pyridylsulfonimidoyl)benzoic acid (approximately 261 mg). LCMS (ESI) [M+H] + m / z: calculated: 263.0, observed: 263.0.

[0623] Step 5: Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(3-pyridylsulfonimidoyl)benzoyl]amino]phenyl]carbamate A mixture of 4-(3-pyridylsulfonimidoyl)benzoic acid (about 198 mg, 0.755 mmol), tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 251 mg, 0.830 mmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (about 174 mg, 0.908 mmol) in pyridine (about 4 mL) was stirred at about 50° C. for about 2 hours. The resulting mixture was quenched by the addition of water (about 10 mL) and extracted with EtOAc (about 20 mL*3). The combined organic layer was washed with brine (about 20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; ca. 20 g AgelaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 65% EtOAc; flow rate = 30 mL / min; 254 nm) to give tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(3-pyridylsulfonimidoyl)benzoyl]amino]phenyl]carbamate (ca. 361 mg). LCMS (ESI) [M+H] + m / z: calculated: 547.2, observed: 547.2.

[0624] Step 6: Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(3-pyridylsulfonimidoyl)benzamide A mixture of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(3-pyridylsulfonimidoyl)benzoyl]amino]phenyl]carbamate (approximately 361 mg, 0.660 mmol) and TFA (approximately 10.8 mL, 0.140 mol) in DCM (approximately 30 mL) was stirred at approximately 20° C. for approximately 2 hours. The reaction mixture was concentrated under reduced pressure. The mixture was adjusted to a pH of approximately 8 with 25% (wt%) NH—H O. The mixture was purified by preparative HPLC (instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; column: 2_Phenomenex Gemini C18 75*40mm*3μm; mobile phase A: water (NH4HCO3); mobile phase B: MeCN; gradient: 35% to 65% B in 9.5 min, hold at 100% B for 2 min; flow rate: 30 ml / min; column temperature: 30 °C; wavelength: 220 nm, 254 nm) to give N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(3-pyridylsulfonimidoyl)benzamide (approximately 103.8 mg). 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1 H), 9.15 (d, J = 2.4 Hz, 1 H), 8.79 (dd, J = 4.8, 1.4 Hz, 1 H), 8.31 - 8.44 (m, 1 H), 8.15 (s, 4 H), 7.53 - 7.65 (m, 3 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.25 - 7.32 (m, 1 H), 7.15 - 7.23 (m, 2 H), 6.85 (d, J = 8.4 Hz, 1 H), 5.51 (brs, 1 H), 5.16 (s, 2H). 19 F NMR (376 MHz, DMSO-d6) δ ppm - 117.479. LCMS (ESI) [M+H] + m / z: calculated: 447.1, found: 447.2. HPLC: 99.82% at 220 nm, 99.80% at 254 nm.

[0625] Example 6: Synthesis of N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(S-methylsulfonimidoyl)benzofuran-2-carboxamide (Compound 171) [ka] Step 1: Synthesis of tert-butyl N-(4-bromo-2-nitrophenyl)-N-tert-butoxycarbonyl-carbamate To a solution of 4-bromo-2-nitroaniline (approximately 5 g, 23.0 mmol), TEA (approximately 9.5 mL, 68.2 mmol), and DMAP (approximately 1.40 g, 11.5 mmol) in DCM (approximately 50 mL) was added BocO (approximately 13.5 mL, 58.75 mmol) at approximately 20° C., and the reaction mixture was stirred at approximately 20° C. for approximately 16 hours. The resulting mixture was quenched by the addition of water (approximately 100 mL) and extracted with DCM (approximately 100 mL*3). The combined organic layer was washed with brine (approximately 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; approximately 220 g SepaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 10% EtOAc; flow rate = 100 mL / min; 254 nm) to give tert-butyl N-(4-bromo-2-nitrophenyl)-N-tert-butoxycarbonyl-carbamate (approximately 7.7 g). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.21 (d, J = 2.26 Hz, 1H), 7.76 (dd, J = 8.53, 2.26 Hz, 1H), 7.19–7.28 (m, 1H), 1.41 (s, 18H).

[0626] Step 2: Synthesis of tert-butyl (4-bromo-2-nitrophenyl)carbamate To a solution of tert-butyl N-(4-bromo-2-nitrophenyl)-N-tert-butoxycarbonyl-carbamate (about 7.4 g, 17.7 mmol) in DCM (about 75 mL) was added TFA (about 2.1 mL, 27.26 mmol) at about 20° C., and the mixture was stirred at about 20° C. for about 1 hour. The reaction mixture was quenched at about 20° C. by the addition of water (about 100 mL) and extracted with DCM (about 100 mL*3). The combined organic layer was washed with brine (50 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; approximately 4 g SepaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 10% EtOAc; flow rate = 80 mL / min; 254 nm) to give tert-butyl (4-bromo-2-nitrophenyl)carbamate (approximately 130 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 9.61 (br s, 1H), 8.51 (d, J=9.13 Hz, 1H), 8.33 (d, J=2.38 Hz, 1H), 7.69 (dd, J = 9.13, 2.13 Hz, 1H), 1.54 (s, 9H). LCMS (ESI) [M+H] + m / z: calculated value: 217.0, observed value: 217.0 (mass of Boc and t-Bu cleaved).

[0627] Step 3: Synthesis of tert-butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate To a solution of tert-butyl N-(4-bromo-2-nitrophenyl)carbamate (approximately 500 mg, 1.58 mmol), (4-fluorophenyl)boronic acid (approximately 265 mg, 1.89 mmol), and KCO (approximately 545 mg, 3.94 mmol) in HO (approximately 1 mL) and dioxane (approximately 10 mL), Pd(dppf)Cl (approximately 57 mg, 0.079 mmol) was added at approximately 20° C., and the mixture was stirred at approximately 100° C. for approximately 4 hours. The reaction mixture was quenched at approximately 20° C. by the addition of water (approximately 30 mL) and extracted with EtOAc (approximately 30 mL). The combined organic layer was washed with brine (approximately 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; approximately 80 g SepaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 10% EtOAc; flow rate = 60 mL / min; 254 nm) to give tert-butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate (approximately 500 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 9.68 (s, 1H), 8.64 (d, J = 8.88 Hz, 1H), 8.38 (d, J = 2.25 Hz, 1H), 7.80 (dd, J = 8.88, 2.25 Hz, 1H), 7.52 - 7.59 (m, 2H), 7.17 (t, J = 8.63 Hz, 2H), 1.57 (s, 9H). LCMS (ESI) [M+H] + m / z: calculated value: 233.1, observed value: 233.1 (mass of Boc and t-Bu cleaved).

[0628] Step 4: Synthesis of tert-butyl (3-amino-4'-fluoro[1,1'-biphenyl]-4-yl)carbamate To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-nitrophenyl]carbamate (approximately 500 mg, 1.50 mmol) in THF (approximately 10 mL) was added Pd / C (approximately 100 mg, 0.823 mmol) (10 wt% Pd, 50 wt% water) at approximately 20°C, and the mixture was stirred under H2 (from a balloon) at approximately 20°C for approximately 16 hours. The reaction was filtered, and the filter cake containing Pd / C was washed with water. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (3-amino-4'-fluoro[1,1'-biphenyl]-4-yl)carbamate (approximately 497 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.47 - 7.57 (m, 2H), 7.36 (br d, J = 7.78 Hz, 1H), 7.08 - 7.17 (m, 2H), 6.93 - 7.05 (m, 2H), 6.25 (br s, 1H), 1.55 (s, 9H). LCMS (ESI) [M+H] + m / z: calculated: 303.2, observed: 303.1.

[0629] Step 5: Synthesis of methyl 5-(methylthio)benzofuran-2-carboxylate To a solution of 2-hydroxy-5-methylsulfanyl-benzaldehyde (about 500 mg, 2.97 mmol) and dicesium carbonate (about 1.94 g, 5.94 mmol) in DMF (about 5 mL) / MeCN (about 5 mL) was added 2-bromomethyl acetate (about 0.33 mL, 3.57 mmol) at about 20° C., and the mixture was stirred at about 85° C. for about 16 hours. The reaction mixture was quenched at about 20° C. by the addition of water (about 30 mL) and extracted with EtOAc (about 30 mL*3). The combined organic layer was washed with brine (about 30 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; ca. 20 g SepaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 10% EtOAc; flow rate: 35 mL / min at 254 nm) to give methyl 5-methylsulfanylbenzofuran-2-carboxylate (ca. 374 mg). LCMS (ESI) [M+H] + m / z: calculated: 223.0, observed: 223.1.

[0630] Step 6: Synthesis of methyl 5-(methylsulfinyl)benzofuran-2-carboxylate To a solution of methyl 5-methylsulfanylbenzofuran-2-carboxylate (approximately 300 mg, 1.35 mmol) in DCM (approximately 10 mL) was added m-CPBA (approximately 329 mg, 1.62 mmol, 85% purity) at approximately 0° C., and the mixture was stirred at approximately 0° C. for approximately 1 hour. The reaction mixture was quenched by adding saturated sodium thiosulfate solution. The reaction mixture was quenched at approximately 20° C. by the addition of water (approximately 30 mL) and extracted with DCM (approximately 30 mL*3). The combined organic layer was washed with brine (approximately 20 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; approximately 20 g SepaFlash® Silica Flash Column; petroleum ether / EtOAc with 50 to 100% EtOAc; flow rate = 35 mL / min; 254 nm) to give methyl 5-methylsulfinylbenzofuran-2-carboxylate (approximately 181 mg).1 H NMR (400 MHz, chloroform-d) δ ppm 8.10 (d, J = 1.13 Hz, 1H), 7.72 - 7.78 (m, 1H), 7.65 - 7.71 (m, 1H), 7.60 (s, 1H), 4.01 (s, 3H), 2.78 (s, 3H). LCMS (ESI) [M+H] + m / z: calculated: 239.0, observed: 239.0.

[0631] Step 7: Synthesis of methyl 5-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)benzofuran-2-carboxylate To a solution of methyl 5-methylsulfinylbenzofuran-2-carboxylate (approximately 140 mg, 0.588 mmol), PhI(OAc) (approximately 284 mg, 0.882 mmol), NHBOC (approximately 138 mg, 1.18 mmol), and MgO (approximately 121 mg, 2.93 mmol) in DCM (approximately 10 mL) was added Rh(OA) (approximately 26 mg, 0.059 mmol) at approximately 20° C., and the mixture was stirred at approximately 40° C. for approximately 12 hours. The reaction mixture was quenched at approximately 20° C. by the addition of water (approximately 20 mL) and extracted with DCM (approximately 20 mL). The combined organic layer was washed with brine (approximately 15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; approximately 12 g SepaFlash® Silica Flash Column; petroleum ether / EtOAc with 30 to 50% EtOAc; flow rate = 50 mL / min; 254 nm) to give methyl 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzofuran-2-carboxylate (approximately 182 mg). 1H NMR (400 MHz, chloroform-d) δ ppm 8.43 (d, J = 1.63 Hz, 1H), 8.04 (dd, J = 8.88, 2.00 Hz, 1H), 7.79 (d, J = 8.88 Hz, 1H), 7.63 (d, J = 0.88 Hz, 1H), 3.97 - 4.08 (m, 3H), 3.29 - 3.36 (m, 3H), 1.40 (s, 9H). LCMS (ESI) [M+H] + m / z: calculated: 354.1, observed: 354.0.

[0632] Step 8: Synthesis of 5-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)benzofuran-2-carboxylic acid To a solution of methyl 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzofuran-2-carboxylate (approximately 200 mg, 0.566 mmol) in THF (approximately 5 mL) / HO (approximately 5 mL) was added LiOH·HO (approximately 238 mg, 5.67 mmol) at approximately 20°C, and the mixture was stirred at approximately 20°C for approximately 1 hour. The mixture was concentrated under reduced pressure. The residue was diluted with HO (4 mL). The mixture was adjusted to pH approximately 4 with 0.5 M aqueous HCl and extracted with EtOAc (approximately 50 mL*2). The combined organic layer was concentrated under reduced pressure. The compound 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzofuran-2-carboxylic acid (approximately 190 mg) was obtained. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.46 (d, J = 1.76 Hz, 1H), 8.06 (dd, J = 9.03, 2.01 Hz, 1H), 7.81 (d, J = 8.78 Hz, 1H), 7.66 (s, 1H), 3.31 (s, 3H), 1.42 (s, 9H). LCMS (ESI) [M+Na] + m / z: calculated: 340.1, observed: 340.0.

[0633] Step 9: Synthesis of tert-butyl (3-(5-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)benzofuran-2-carboxamido)-4'-fluoro[1,1'-biphenyl]-4-yl)carbamate To a solution of 5-(N-tert-butoxycarbonyl-S-methylsulfonimidoyl)benzofuran-2-carboxylic acid (about 100 mg, 0.295 mmol) and tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 89 mg, 0.294 mmol) in pyridine (about 2 mL) was added EDCI (about 68 mg, 0.355 mmol) at about 20° C., and the mixture was stirred at about 50° C. for about 1 hour. The reaction mixture was quenched at about 20° C. by the addition of water (about 20 mL) and extracted with EtOAc (about 20 mL*3). The combined organic layer was washed with brine (about 15 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; approximately 12 g SepaFlash® Silica Flash Column; petroleum ether / EtOAc with 0 to 100% EtOAc; flow rate: 30 mL / min at 254 nm) to give tert-butyl (3-(5-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)benzofuran-2-carboxamido)-4′-fluoro[1,1′-biphenyl]-4-yl)carbamate (approximately 180 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.52 (s, 1H), 8.21 (s, 1H), 8.10 - 8.16 (m, 1H), 7.74 - 7.86 (m, 3H), 7.67 (br dd, J = 8.63, 5.25 Hz, 3 H), 7.50 (br d, J = 9.01 Hz, 2 H), 3.42 (s, 3 H), 1.50 (s, 18 H). LCMS (ESI) [M+Na] + m / z: calculated: 646.2, found: 646.2.

[0634] Step 10: Synthesis of N-(4-amino-4'-fluoro[1,1'-biphenyl]-3-yl)-5-(S-methylsulfonimidoyl)benzofuran-2-carboxamide To a solution of tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4-fluorophenyl)phenyl]carbamoyl]benzofuran-5-yl]-methyl-oxo-sulfanylidene]carbamate (about 180 mg, 0.289 mmol) in DCM (about 5 mL) was added TFA (about 329 mg, 2.89 mmol) at about 20° C., and the mixture was stirred at about 20° C. for 12 hours. The mixture was adjusted to pH about 8 with saturated aqueous NaCO solution. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Durashell 75 × 40 mm × 3 μm; Mobile phase A: HO containing 10 mm NH₄HCO₃ (v%); Mobile phase B: ACN; Gradient: 6% to 65% B in 9.5 min, hold at 100% B at 0 min; Flow rate: 30 mL / min; Column temperature: 30 °C; Wavelength: 220 nm, 254 nm) to give N-(4-amino-4′-fluoro[1,1′-biphenyl]-3-yl)-5-(S-methylsulfonimidoyl)benzofuran-2-carboxamide (approximately 32 mg). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.46 (d, J = 1.63 Hz, 1H), 8.38 (s, 1H), 8.15 (dd, J = 8.63, 1.88 Hz, 1H), 7.69 - 7.76 (m, 3H), 7.52 (dd, J = 8.76, 5.38 Hz, 2H), 7.11 (t, J = 8.69 Hz, 3H), 6.96 (d, J = 8.25 Hz, 2H), 3.19 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ ppm -116.38. LCMS (ESI) [M+H] + m / z: calculated: 424.1, found: 424.1. HPLC: 94.62% at 220 nm, 94.66% at 254 nm.

[0635] Example 7: Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-5-[(methylsulfonimidoyl)methyl]benzofuran-2-carboxamide (Compound 170) [ka] Step 1: Synthesis of methyl 5-methylbenzofuran-2-carboxylate To a mixture of 2-hydroxy-5-methylbenzaldehyde (approximately 9 g, 66.1 mmol) in CHCN (approximately 120 mL) and DMF (approximately 30 mL) was added CsCO (approximately 43.1 g, 132 mmol) and methyl 2-bromoacetate (approximately 12.1 g, 79.3 mmol) under N at approximately 20 °C. The mixture was heated to approximately 85 °C and stirred for approximately 16 hours. The mixture was filtered and concentrated under reduced pressure at approximately 50 °C. The residue was poured into ice water (approximately 30 mL) and stirred for approximately 10 minutes. The aqueous phase was extracted with ethyl acetate (approximately 50 mL*2). The combined organic phase was washed with H0 (approximately 50 mL*2), brine (approximately 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate=100 / 1, 20 / 1) to give methyl 5-methylbenzofuran-2-carboxylate (approximately 6.2 g, 32.6 mmol). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.38 - 7.61 (m, 3 H), 7.13 - 7.35 (m, 1 H), 3.86 - 4.07 (m, 3 H), 2.34 - 2.56 (m, 3 H).

[0636] Step 2: Synthesis of methyl 5-(bromomethyl)benzofuran-2-carboxylate To a mixture of methyl 5-methylbenzofuran-2-carboxylate (approximately 6.2 g, 32.6 mmol) in CCl4 (approximately 120 mL) was added NBS (approximately 5.80 g, 32.6 mmol) and 2,2'-azobis(isobutyronitrile) (approximately 535 mg, 3.26 mmol). The reaction was heated to approximately 80 °C and stirred for approximately 16 hours. The mixture was filtered, and the filtrate was evaporated. The residue was triturated with MeOH (approximately 20 mL) to give methyl 5-(bromomethyl)benzofuran-2-carboxylate (approximately 7.0 g). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.73 (d, J = 1.5 Hz, 1 H), 7.56 - 7.60 (m, 1 H), 7.48 - 7.53 (m, 2 H), 4.57 - 4.68 (m, 2 H), 3.99 - 4.02 (m, 3 H).

[0637] Step 3: Synthesis of methyl 5-(methylsulfanylmethyl)benzofuran-2-carboxylate A mixture of methyl 5-(bromomethyl)benzofuran-2-carboxylate (approximately 7.0 g, 26.0 ...

Claims

1. Formula (I): 【Chemical 501】 or a pharmaceutically acceptable salt thereof, During the ceremony, A is an optionally substituted aryl or heteroaryl; L １ is -CR' ２ -, -CR' ２ CR' ２ - or a bond, Each R' is independently H or C １ ~C ６ alkyl, or two R' together with the carbon or carbons to which they are attached form a 3- to 6-membered cycloalkyl ring; Each R １ , R ３ , and R ４ are independently H, C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, or halogen; R ２ each is optionally substituted aryl or heteroaryl; R ５ is NH ２ or OH, R ６ is H or C １ ~C ６ is alkyl, R ７ is C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, -(CH ２ ) ０～２ -phenyl, -(CH ２ ) ０～２ -C ３ ~C ７ Cycloalkyl, -(CH ２ ) ０～２ -heteroaryl, or -(CH ２ ) ０～２ -heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted; R ８ is H, C １ ~C ６ Alkyl, C １ ~C ６ heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO—R′, or CO ２ -R', where each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted or R ７ and R ８ are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted, or a pharmaceutically acceptable salt thereof.

2. A is phenyl or heteroaryl, heteroaryl having 5, 6, or 9 ring atoms and having 1 to 4 ring atoms selected from N, O, and S, and A is 0 to 4 R ９ is substituted with a group, Each R ９ But independently, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH.

3. A is, 【Chemical 502】 each of which is selected from 0 to 9 R ９ group, wherein the left attachment point is: 【Chemical 503】 L １ Represents a connection point to the right of the 【Chemical 504】 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein represents the point of attachment to the carbonyl.

4. A is, 【Chemical 505】 each of which is selected from 0 to 9 R ９ group, wherein the left attachment point is: 【Chemical 506】 L １ Represents a connection point to the right of the 【Chemical 507】 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein represents the point of attachment to the carbonyl.

5. R with 0 to 9 A ９ substituted with a group 【Chemical 508】 where the left attachment point: 【Chemical 509】 L １ Represents a connection point to the right of the 【Chemical 510】 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein represents the point of attachment to the carbonyl.

6. A is either R ９ 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, which is not substituted with any group.

7. L １ is a bond, -CH ２ - and 【Chemical 511】 2. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

8. L １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is a bond.

9. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

10. R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

11. R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

12. R ５ But NH ２ 2. The compound of claim 1, wherein:

13. R ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

14. R ２ is phenyl or monocyclic heteroaryl, the heteroaryl having 5 to 6 ring atoms and having 1 to 2 ring atoms selected from N, O, and S; R ２ 0 to 4 R １０ is substituted with a group, Each R １０ But independently, C １ ~C ６ Alkyl, C １ ~C ６ Alkenyl, C １ ~C ６ Heteroalkyl, phenyl, C ３ ~C ７ Cycloalkyl, heterocyclyl, C １ ~C ６ Alkylene-phenyl, C １ ~C ６ Alkylene-C ３ ~C ７ Cycloalkyl, C １ ~C ６ Alkylene-heterocyclyl, hydroxy, cyano, CO—R Ｃ , N.R. Ｄ ２ or halogen, wherein the heterocyclyl has 4 to 11 ring atoms, having 1 to 4 ring atoms selected from N, O, and S, each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R Ｅ is optionally replaced by Each R Ｃ are independently H, OH, NR １２ ２ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; Each R Ｄ However, independently, H, C １ ~C ６ Alkyl, CO-C １ ~C ６ Alkyl, CO ２ -C １ ~C ６ Alkyl, SO ｗ -C １ ~C ６ Alkyl, C １ ~C ６ heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; or Two Rs attached to the same nitrogen Ｄ are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ optionally substituted with 1 to 4 substituents independently selected from alkoxy, and OH; Each R Ｅ are independently H, halo, OH, O—C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, —C １ ~C ６ is haloalkyl, Each R １２ are independently H or C １ ~C ６ is alkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is 0, 1, or 2.

15. R ２ 0 to 4 R １０ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

16. R ２ 0 to 4 R １０ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, which is a monocyclic heteroaryl substituted with a group.

17. R ２ are selected from phenyl, pyridine, pyrimidine, pyridazine, pyrazine, thiazole, and thiophene, each of which has 0 to 4 R １０ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, substituted with a group.

18. R ２ are selected from phenyl and thiophene, each of which contains 0 to 4 R １０ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, substituted with a group.

19. Each R １０ But halogen, C １ ~C ６ Alkyl, and CO-R Ｃ and R Ｃ But -NH ２ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein said alkyl is unsubstituted or substituted with 1 to 4 groups independently selected from halogen and OH.

20. Each R １０ -F, -Cl, -Me, CF ３ , -CONH ２ , and —CH(OH)CH ３ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, independently selected from:

21. Each R １０ is independently selected from -F and -Me, or a pharmaceutically acceptable salt thereof.

22. R ２ but, 【Chemical 512】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

23. R ２ but, 【Chemical 513】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

24. R ７ But C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ７ cycloalkyl, phenyl, or monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms and has 1 to 2 ring atoms selected from N, O, and S, and each alkyl, heteroalkyl, phenyl, and heteroaryl has 0 to 4 R １１ or substituted with a group R ７ and R ８ are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is １０ is substituted with a group, Each R １０ and R １１ But independently, C １ ~C ６ Alkyl, C １ ~C ６ Alkenyl, C １ ~C ６ Heteroalkyl, phenyl, C ３ ~C ７ Cycloalkyl, heterocyclyl, C １ ~C ６ Alkylene-phenyl, C １ ~C ６ Alkylene-C ３ ~C ７ Cycloalkyl, C １ ~C ６ Alkylene-heterocyclyl, hydroxy, cyano, CO—R Ｃ , N.R. Ｄ ２ or halogen, wherein the heterocyclyl has 4 to 11 ring atoms, having 1 to 4 ring atoms selected from N, O, and S, each alkyl or heteroalkyl is optionally substituted with 1 to 4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R Ｅ is optionally replaced by Each R Ｃ are independently H, OH, NR １２ ２ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; Each R Ｄ However, independently, H, C １ ~C ６ Alkyl, CO-C １ ~C ６ Alkyl, CO ２ -C １ ~C ６ Alkyl, SO ｗ -C １ ~C ６ Alkyl, C １ ~C ６ heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; or Two Rs attached to the same nitrogen Ｄ are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ optionally substituted with 1 to 4 substituents independently selected from alkoxy, and OH; Each R Ｅ are independently H, halo, OH, O—C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, —C １ ~C ６ is haloalkyl, Each R １２ are independently H or C １ ~C ６ is alkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein w is 0, 1, or 2.

25. R ７ But C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ７ cycloalkyl, phenyl, or monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms and 1-2 ring atoms that are N, and each alkyl, heteroalkyl, phenyl, cycloalkyl, and heteroaryl has 0-4 R １１ or substituted with a group R ７ and R ８ are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle having 0 additional ring heteroatoms, and said heterocycle is １０ 25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, substituted with a group.

26. R ７ is -Me, -Et, -CF ３ , C.H. ２ CH ２ OMe, phenyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyridinonyl, each of which is selected from 0 to 4 R １１ or substituted with a group R ７ and R ８ are taken together with the nitrogen and sulfur to which they are attached to form a 5-6 membered heterocycle having 0 additional ring heteroatoms, said heterocycle being substituted with 0 or 1 methyl or phenyl, or a pharmaceutically acceptable salt thereof.

27. Each R １１ But C １ ~C ６ Alkyl, C １ ~C ６ Alkenyl, C １ ~C ６ Heteroalkyl, C ３ ~C ７ 25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein said alkyl and heteroalkyl are optionally substituted with 1 to 4 groups independently selected from cycloalkyl, hydroxy, cyano, and halogen, and wherein said alkyl and heteroalkyl are optionally substituted with 1 to 4 groups independently selected from halogen and OH.

28. Each R １１ -F, -Cl, -Me, - ｉ Pr, -C(=CH ２ ) CH ３ , -CF ３ , -CN, -OH, -OMe, -CH ２ OCH ２ CH ２ OMe, and -CH ２ 25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from OH.

29. 2 ７ が、-Me、-Et、-CF ３ 、-CH ２ CH ２ OMe、 【Chemical Formula 514】 Selected from or R ７ and R ８ are grouped together with the atoms to which they are bonded, 【Chemical 515】 2. The compound of claim 1, wherein the compound is formed as follows:

30. R ７ The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein is -Me.

31. R ８ is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or —CO ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -t-butyl.

32. R ８ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

33. The compound of formula (Ia): 【Chemical 516】 or a pharmaceutically acceptable salt thereof, In the formula, X １ is N or CH, and X ２ is N or CH, or a pharmaceutically acceptable salt thereof.

34. The compound of formula (Ic): 【Chemical 517】 or a pharmaceutically acceptable salt thereof, In the formula, X ３ is O or S, or a pharmaceutically acceptable salt thereof.

35. The compound of claim 35, wherein the compound has formula (Ie): 【Chemical 518】 or a pharmaceutically acceptable salt thereof, In the formula, X ４ is N or CH, or a pharmaceutically acceptable salt thereof.

36. The compound of formula (Ig): 【Chemical 519】 or a pharmaceutically acceptable salt thereof, In the formula, X ５ is N or CH, or a pharmaceutically acceptable salt thereof.

37. The compound of claim 37, wherein the compound has formula (Ii): 【Chemical 520】 or a pharmaceutically acceptable salt thereof, In the formula, X ３ is O or S, X ６ is N or CH, X ７ is N or CH, or a pharmaceutically acceptable salt thereof.

38. The compound of claim 37, wherein the compound has the formula (Ik): 【Chem.521】 or a pharmaceutically acceptable salt thereof, In the formula, X ３ is O or S, X ８ is N or CH, X ９ is N or CH, or a pharmaceutically acceptable salt thereof.

39. The compound of claim 39, wherein the compound has the formula (In): 【Chemical 522】 or a pharmaceutically acceptable salt thereof, In the formula, X ３ is O or S, or a pharmaceutically acceptable salt thereof.

40. The compound of formula (Ip): 【Chemical 523】 or a pharmaceutically acceptable salt thereof, In the formula, X ３ is O or S, or a pharmaceutically acceptable salt thereof.

41. The compound of formula (Ir): 【Chemical 524】 or a pharmaceutically acceptable salt thereof, In the formula, X ３ is O or S, or a pharmaceutically acceptable salt thereof.

42. The compound is 【Chemical 525-1】 【Chemical 525-2】 【Chemistry 525-3】 【Chemical 525-4】 【Chemistry 525-5】 【Chemistry 525-6】 【Chemistry 525-7】 【Chemistry 525-8】 【Chemistry 525-9】 【Chemical 525-10】 2. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

43. The compound of claim 1, 【Chemical 526】 43. The compound of claim 42, wherein:

44. The compound of claim 1, 【Chemical Formula 527】 43. The compound of claim 42, wherein:

45. 45. A composition comprising a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

46. 45. A composition comprising a compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, or a composition comprising a compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, for use in treating a disease or disorder that can be treated by inhibition of histone deacetylase (HDAC).

47. 47. The composition for use according to claim 46, wherein the disease or disorder is cancer.

48. 48. The composition for use of claim 47, wherein the cancer is selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or sarcoma.

49. 48. The composition for use of claim 47, wherein the cancer is selected from the group consisting of melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, and gastric cancer.

50. 48. The composition for use of claim 47, wherein the cancer is cancer of unknown primary (CUP), colorectal cancer, cervical cancer, or non-small cell lung cancer (NSCLC).

51. The composition for use according to claim 46, wherein the composition is configured to be administered together with an additional therapeutic agent.

52. 52. The composition for use of claim 51, wherein the additional therapeutic agent is chemotherapy or radiation.

53. 52. The composition for use of claim 51, wherein the additional therapeutic agent is an immunotherapeutic agent.

54. 54. The composition for use of claim 53, wherein the immunotherapeutic agent is an anti-PD-1 antibody.

55. The composition for use according to claim 54, wherein the anti-PD-1 antibody is pembrolizumab.

56. 54. The composition for use of claim 53, wherein the immunotherapeutic agent is an anti-PD-L1 antibody or an anti-PD-L1 small molecule.

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