Novel regulators of EHMT1 and EHMT2 and their therapeutic uses

Abstract

Described herein are novel compounds, compositions, and methods for modulating EHMT1 and EHMT2, and the treatment of diseases, including cancer, using such compounds, compositions, and methods.

Description

[Technical Field]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 256,057, filed October 15, 2021, and U.S. Provisional Patent Application No. 63 / 390,438, filed July 19, 2022, the entire contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present invention relates to compounds, compositions, and methods for modulating EHMT1 and EHMT2 and for treating diseases, including cancer. [Background technology]

[0003] Important advances have been made in cancer treatment, particularly in immunotherapy. Immune checkpoint inhibitors, including anti-PD-1 and anti-CTLA-4 biologics, have demonstrated clinical efficacy against some tumors but not many others, including CRC (Topalian et al. N. Engl. J. Med. 2012, 366(26): 2443-2454; Brahmer et al. N. Engl. J. Med. 2012, 366 (26): 2455-2465; Chung et al. J. Clin. Oncol. 2010, 28(21): 3845-3490). Immune checkpoint inhibitors reactivate antitumor immunity through various parameters, including tumor immunogenicity and the presence of tumor-infiltrating T cells (Ribas et al. Science 2018, 359(6382): 1350-1355), known as T cell inflammation or a hot tumor microenvironment (TME). The hot TME is further characterized by high interferon (IFN) pathway activity (Garris et al. Clin. Cancer Res. 2020, 26(15): 3901-3907). In contrast, a low T cell infiltration, or "cold" TME, is typically associated with poor response to immune checkpoint blockade (ICB) therapy. While mechanisms of poor response or resistance to current checkpoint blockade have been described (Sharma et al. Cell 2017, 168(4): 707-723), many more mechanisms for tumor immunomodulation remain to be discovered. Epigenetic modifications of histones have been shown to be malignant drivers of several cancer types and to be associated with immune-cold signatures (Topper et al. Nature Rev. Clin. Oncol. 2020, 17:75-90). Because epigenetic changes are dynamic, it may be possible to reverse both the malignant process and / or the therapy-resistant phenotype by targeting epigenetic processes that cause malignancy and resistance to checkpoint inhibitor blockade.

[0004] Histone methyltransferases (HMTs) have recently emerged as targets of potential therapeutic value. They catalyze the methylation of histone lysine and arginine, utilizing S-adenosyl-methionine (SAM) as a substrate. This process can result in either transcriptional activation or repression (Jones, et. al. Cell 2007, 128(4):683-692). Two related HMTs, EHMT1 and EHMT2 (euchromatic histone-lysine N-methyltransferases 1 and 2 (EHMT1 / 2, also known as GLP and G9a, respectively), share approximately 80% sequence identity in their SET domains and play important roles in catalyzing mono- and dimethylation at the lysine 9 residue of histone H3 (H3K9me1 / H3K9me2) in euchromatic regions. These histone marks are generally associated with transcriptional repression of target genes. The involvement of EHMT1 and / or EHMT2 in many biological processes, including embryonic development, repairing DNA damage, and tumor cell growth and metastasis, has been reported (Tachibana et al. Genes Dev. 2005, 19(7):815-826; Yokochi et al. Proc Natl Acad Sci 2009, 106(46):19363-19368; Huang et al. J Biol Chem 2010 285(13):9636-9641). Their dysregulation has also been shown to be associated with many human diseases, such as cancer, inflammatory diseases, hematological diseases, and neurodegenerative diseases (Shanker, et. al. Epigenetics, 2013 8(1):16-22; Chen et al. Cancer Res. 2010, 70(20):7830-7840; Chaturvedi et al. Proc Natl Acad Sci 2009, 106:18303-18308; Renneville et al. 2015 Blood 126(16): 1930-1939). Thus, EHMT1 and / or EHMT2 can be targeted for modulation, thereby providing therapeutic opportunities for treating various diseases. Over the past several decades, several EHMT1 / 2 tool compounds have been discovered and demonstrated antitumor efficacy in several preclinical mouse xenograft models, both as monotherapy and in combination with anti-PD-L1 therapy in several cancer types (Segovia et al., Nat Med. 2019;25:1073-1081, Kato et al. Cancer Discovery 2020 10:980-987). Therefore, there is a need to develop clinical-grade EHMT1 / 2 inhibitors for the treatment of human cancers, including immune-mediated cold tumors, with or without the addition of immune checkpoint blockade, and / or for the treatment of other diseases such as sickle cell anemia and hematological disorders. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Topalian et al.N. Engl.J.Med.2012, 366(26): 2443-2454 [Non-patent document 2] Brahmer et al. N. Engl.J.Med.2012, 366 (26):2455-2465 [Non-patent document 3] Chung et al. J. Clin. Oncol. 2010, 28(21):3845-3490 [Non-patent document 4] Ribas et al. Science 2018, 359(6382): 1350-1355 [Non-Patent Document 5] Garris et al. Clin. Cancer Res.2020, 26(15): 3901-3907 [Non-patent document 6] Sharma et al.Cell 2017, 168(4): 707-723 [Non-Patent Document 7] Topper et al.Nature Rev.Clin. Oncol. 2020, 17:75-90 [Non-patent document 8] Jones, et. al Cell 2007, 128(4):683-692 [Non-Patent Document 9] Tachibana et al.Genes Dev.2005, 19(7):815-826 [Non-Patent Document 10] Yokochi et al.Proc Natl Acad Sci 2009, 106(46):19363-19368 [Non-Patent Document 11] Huang et al. J Biol Chem 2010 285(13):9636-9641 [Non-Patent Document 12] Shanker, et. al. Epigenetics, 2013 8(1):16-22 [Non-Patent Document 13] Chen et al. Cancer Res.2010, 70(20):7830-7840 [Non-Patent Document 14] Chaturvedi et al. Proc Natl Acad Sci 2009, 106:18303-18308 [Non-Patent Document 15] Renneville et al.2015 Blood 126(16): 1930-1939 [Non-Patent Document 16] Segovia et al., Nat Med.2019;25:1073-1081 [Non-Patent Document 17] Kato et al.Cancer Discovery 2020 10:980-987 Summary of the Invention

[0006] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is an optionally substituted 5- or 6-membered oxygen-containing heterocycle; G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Wis 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0007] In one aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] wherein X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl, and each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R.D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted, and each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0008] In one aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3are independently H, 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, C1-C6 alkoxy, hydroxy, cyano, CO—R C , N.R. D 2, or halogen, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 alkoxy, 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 each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen Dtogether with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, C-C heteroalkyl, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0009] In one aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, 3-heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, deuterium, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 5 deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0010] The present invention also provides a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] wherein X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12-C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R Dare independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0011] In one aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12-C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, C1-C6 alkoxy, hydroxy, cyano, CO—R C , N.R. D 2, or halogen, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 alkoxy, 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 each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R C are independently H, OH, N(R 12)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, C-C heteroalkyl, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR'; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, wherein C-C alkyl is optionally substituted with one or more deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R Eis independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0013] In one aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen; R 4is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, wherein C-C alkyl is optionally substituted with one or more deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R Eis independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0014] In one aspect, the present invention provides a compound of formula (IIIa-2), or a pharmaceutically acceptable salt thereof, wherein: [ka] R 2 is selected from H, C1-C6 alkyl, and halogen; R 6 is selected from C1-C6 alkyl and C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 5 instances of deuterium; R 7 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and halogen, each alkyl optionally substituted with 1 to 5 instances of deuterium; R 8 is C1-C6 alkyl, optionally substituted with 1 to 5 deuterium atoms; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, and OH; R E is optionally substituted with 1 to 5 deuterium atoms, m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0015] In one aspect, the present invention provides a compound of formula (IIIb-2), or a pharmaceutically acceptable salt thereof, wherein: [ka] R 2 is selected from H, C1-C6 alkyl, and halogen; R 6is selected from C1-C6 alkyl and C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 5 instances of deuterium; R 7 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and halogen, each alkyl optionally substituted with 1 to 5 instances of deuterium; R 8 is C1-C6 alkyl, optionally substituted with 1 to 5 deuterium atoms; Each R 11 are independently selected from H, C-C alkyl, hydroxy, and halogen, or two R 11 together with the carbons to which they are attached form a spiro-fused C3-C7 cycloalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, and OH; R E is optionally substituted with 1 to 5 deuterium atoms, m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0016] In one aspect, the present invention provides a compound of formula (IVb-2), or a pharmaceutically acceptable salt thereof, wherein: [ka] X is O or C(R 11 )2, R 2 is selected from H, C1-C6 alkyl, and halogen; R 6 is selected from C1-C6 alkyl and C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 5 instances of deuterium; R 7 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and halogen, each alkyl optionally substituted with 1 to 5 instances of deuterium; R 8is C1-C6 alkyl, optionally substituted with 1 to 5 deuterium atoms; Each R 11 are independently selected from H, C-C alkyl, hydroxy, and halogen, or two R 11 together with the carbons to which they are attached form a spiro-fused C3-C7 cycloalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, and OH; R E is optionally substituted with 1 to 5 deuterium atoms, m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0017] In one aspect, the present invention provides a compound of formula (IIIc-2), or a pharmaceutically acceptable salt thereof, wherein: [ka] R 2 is selected from H, C1-C6 alkyl, and halogen; R 6 is selected from C1-C6 alkyl and C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 5 instances of deuterium; R 7 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and halogen, each alkyl optionally substituted with 1 to 5 instances of deuterium; R 8 is C1-C6 alkyl, optionally substituted with 1 to 5 deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, or halogen; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, and OH; R E is optionally substituted with 1 to 5 deuterium atoms, m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0018] In one aspect, the present invention provides a compound of formula (IIId-2), or a pharmaceutically acceptable salt thereof, wherein: [ka] R 2 is selected from H, C1-C6 alkyl, and halogen; R 6 is selected from C1-C6 alkyl and C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 5 instances of deuterium; R 7 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and halogen, each alkyl optionally substituted with 1 to 5 instances of deuterium; R 8 is C1-C6 alkyl, optionally substituted with 1 to 5 deuterium atoms; Each R 11 are independently selected from H, C-C alkyl, hydroxy, and halogen, or two R 11 together with the carbons to which they are attached form a spiro-fused C3-C7 cycloalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, and OH; R E is optionally substituted with 1 to 5 deuterium atoms, m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0019] In one aspect, the present invention provides a compound of formula (IVa-2), or a pharmaceutically acceptable salt thereof, wherein: [ka] X is O or C(R 11 )2, R2 is selected from H, C1-C6 alkyl, and halogen; R 6 is selected from C1-C6 alkyl and C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 5 instances of deuterium; R 7 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and halogen, each alkyl optionally substituted with 1 to 5 instances of deuterium; R 8 is C1-C6 alkyl, optionally substituted with 1 to 5 deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, or halogen; Each R 11 are independently selected from H, C-C alkyl, hydroxy, and halogen, or two R 11 together with the carbons to which they are attached form a spiro-fused C3-C7 cycloalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, and OH; R E is optionally substituted with 1 to 5 deuterium atoms, m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0020] In one aspect, the present invention provides a composition comprising any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0021] In another aspect, the present invention provides a method for treating a disease or disorder that can be treated by modulating EHMT1 or EHMT2, the method comprising administering a compound described herein or a composition described herein to a patient in need thereof.

[0022] In one aspect, the present invention provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder that can be treated by modulation of EHMT1 or EHMT2.

[0023] In one aspect, the present invention provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a composition disclosed herein, for the treatment of a disease or disorder that can be treated by modulation of EHMT1 or EHMT2.

[0024] In one aspect, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a composition disclosed herein, for use in treating a disease or disorder that can be treated by modulation of EHMT1 or EHMT2.

[0025] In another aspect, there is provided the use of a compound of the present disclosure in the manufacture of a medicament for the treatment of cancer.

[0026] Still other objects and advantages of the present invention will be apparent to those skilled in the art from the disclosure herein, which is illustrative only and not limiting. Accordingly, other embodiments may be devised by those skilled in the art without departing from the spirit and scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0027] Generally, as described herein, the present invention provides compounds (e.g., compounds of Formula (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIa-1), (IIb-1), (IIc-1), (IId-1), (IIIa-1), (IIIb-1), (IIIc-1), (IIId-1), (IIIa-2), (IIIb-2), (IIIc-2), (IIId-2), (IVa), (IVb), (IVa-1), (IVb-1), (IVa-2), and (IVb-2), or compounds of Table 1, or pharmaceutically acceptable salts thereof) useful for disorders associated with the regulation of EHMT1 or EHMT2 (e.g., cancer).

[0028] compound In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is an optionally substituted 5- or 6-membered oxygen-containing heterocycle; G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0029] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is an optionally substituted 5- or 6-membered oxygen-containing heterocycle; G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, A is an optionally substituted 5-membered oxygen-containing heterocycle. In some embodiments, A is an optionally substituted 6-membered oxygen-containing heterocycle. In some embodiments, A has 1 or 2 oxygens as the only ring heteroatom. In some embodiments, A has 1 oxygen as the only ring heteroatom.

[0031] In one aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] wherein X is C(R 11)2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 Or Or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; and R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C However, independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0032] In one aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] wherein X is C(R 11 )2, O, S(O) w , or NR12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 Or Or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; and R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C However, independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, a compound of formula (II) [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, wherein 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 optionally replaced by R4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each RC However, independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; W is 0, 1, or 2.

[0034] In certain embodiments, a compound of formula (II), or a pharmaceutically acceptable salt thereof, [ka] wherein X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E and R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R C However, independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; R Eis optionally substituted with one or more deuterium atoms, W Also provided herein are compounds, or pharmaceutically acceptable salts thereof, wherein is 0, 1, or 2.

[0035] In one aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R3 are independently H, 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, C1-C6 alkoxy, hydroxy, cyano, CO—R C , N.R. D 2, or halogen, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 alkoxy, 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-RC , N.R. D 2, or halogen, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, C-C heteroalkyl, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the compound of formula (II) is [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, and OH.

[0037] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] wherein X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, and Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, where E is C3-C 10cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 5 deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, and OH; R E is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0038] In one aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, 3-heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, deuterium, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 5 deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, G is CR 7 In some embodiments, G is CH. In some embodiments, G is N.

[0040] In certain embodiments, a compound of formula (III), or a pharmaceutically acceptable salt thereof, [ka] wherein X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12-C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; and R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C However, independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w-C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0041] In certain embodiments, a compound of formula (III), or a pharmaceutically acceptable salt thereof, [ka] wherein X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; and R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R.D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; Each R C However, independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w-C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the compound of formula (III) is [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R C However, independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; W is 0, 1, or 2.

[0043] In certain embodiments, provided herein is a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] wherein X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 11 and R 13are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R C However, independently, H, OH, and NR 122. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0044] In one aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, C1-C6 alkoxy, hydroxy, cyano, CO—R C , N.R. D2, or halogen, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 alkoxy, 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 each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen Dtogether with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, C-C heteroalkyl, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the compound of formula (III) is [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12-C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR'; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 11 and R 13are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; or Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; W is 0, 1, or 2.

[0046] In certain embodiments, provided herein is a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR'; E is C3-C 10cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl, and each R 2 and R 3 are independently H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, wherein C-C alkyl is optionally substituted with one or more deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 11 and R 13are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0047] In one aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR'; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, wherein C-C alkyl is optionally substituted with one or more deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; or R9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the compound of formula (III) is [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12-C1-C6 alkylene-E, or E; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 11 and R 13are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, and OH.

[0049] In certain embodiments, provided herein is a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is selected from 1 to 4 R E and each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; R 4 is H, or C1-C6 alkyl, and each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, wherein C-C alkyl is optionally substituted with one or more deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R Eis independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, and OH, wherein C1-C6 alkyl is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0050] In one aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, wherein C-C alkyl is optionally substituted with one or more deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R Eis independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0051] Generally, as defined herein, X is C(R 11 )2, O, S(O) w , or NR 12 and R 11 , R 12 , and w are as defined herein.

[0052] In some embodiments, X is C(R 11 )2, O, or NR 12 is.

[0053] In some embodiments, X is C(R 11 )2, or O. In some embodiments, X is CHR 11 , CH2, or O. In some embodiments, X is CH(CH3), CH2, or O. In some embodiments, X is CH(CH3), or O. In some embodiments, X is CH2, or O.

[0054] In some embodiments, X is C(R 11 )2.

[0055] In some embodiments, X is CH. In some embodiments, X is CH(CH).

[0056] In other embodiments, X is O.

[0057] In other embodiments, X is NR 12 is.

[0058] Generally, as defined herein, Y is a bond, C(R 13)2, or C(R 13 )2-C(R 13 )2 and R 11 and R 13 is as defined herein.

[0059] In some embodiments, Y is C(R 13 )2. In some embodiments, Y is a bond or C(R 13 )2. In some embodiments, Y is a bond or CH2.

[0060] In some embodiments, Y is CH2.

[0061] In other embodiments, Y is a bond.

[0062] In some embodiments, XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 and R 9 , R 10 , R 11 , and R 13 is as defined herein.

[0063] In some embodiments, XY is CH=CH.

[0064] In some embodiments, XYZ is CH=CH.

[0065] In some embodiments, X is C(R 11 )2 (e.g., CH2), and Y is C(R 13 )2 (e.g., CH2).

[0066] In some embodiments, X is CH2 and Y is CH2.

[0067] In other embodiments, X is C(R 11 )2 (e.g., CH2) and Y is a bond.

[0068] In some embodiments, X is O and Y is C(R 13 )2 (e.g., CH2).

[0069] In some embodiments, X is O and Y is CH2.

[0070] In other embodiments, X is O and Y is a bond.

[0071] Generally, as defined herein, Z is CR 9 R 10 and R 9 and R 10 is as defined herein. In some embodiments, Z is CR 9 R 10 and each R 9 and R 10 is independently H, C1-C6 alkyl, or halogen. In some embodiments, Z is CR 9 R 10 and each R 9 and R 10 are independently H, Me, or F.

[0072] In some embodiments, Z is selected from CH2, CF2, and CMe2.

[0073] In some embodiments, Z is selected from C=O, CF2, and CH2. In some embodiments, Z is =O. In some embodiments, Z is CH2. In some embodiments, Z is CF2.

[0074] In some embodiments, XYZ is C(R 11 )=C(R 13 ) and R 9 , R 10 , R 11 , R 13 is as defined herein.

[0075] Generally, as defined herein, E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted.

[0076] In some embodiments, E is C3-C 10 Cycloalkyl, or C3-C 10 heterocycloalkyl, each of which is selected from 1 to 4 R E (i.e., 0, 1, 2, 3, or 4 R E ), and each R E is as defined herein. In some embodiments, C3-C 10 Cycloalkyl, or C3-C 10 The heterocycloalkyl is unsubstituted. In some embodiments, C-C 10 Cycloalkyl, or C3-C 10 Heterocycloalkyl is a group consisting of one R E In some embodiments, C3-C 10 Cycloalkyl, or C3-C 10 Heterocycloalkyl is a group consisting of two R E In some embodiments, C3-C 10 Cycloalkyl, or C3-C 10 Heterocycloalkyl is a group consisting of three R E In some embodiments, C3-C 10 Cycloalkyl, or C3-C 10 Heterocycloalkyl is a group consisting of four R E is replaced by

[0077] In some embodiments, E is C3-C 10 cycloalkyl, and 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0078] In some embodiments, E is cyclohexyl or cyclohexenyl and 1 to 4 RE (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0079] In other embodiments, E is heterocycloalkyl and has 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0080] In some embodiments, E is C3-C 10 heterocycloalkyl, and 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0081] In some embodiments, heterocycloalkyl has 3 to 10 ring atoms, including 1 to 3 ring heteroatoms selected from N, O, and S.

[0082] In some embodiments, heterocycloalkyl has 5 to 8 ring atoms, including 1 to 3 ring heteroatoms selected from N, O, and S.

[0083] In some embodiments, heterocycloalkyl has 5 to 8 ring atoms, including 1 or 2 nitrogen heteroatoms.

[0084] In some embodiments, heterocycloalkyl has 5 to 8 ring atoms, including one nitrogen heteroatom.

[0085] In some embodiments, heterocycloalkyl has 6 to 8 ring atoms, including 1 to 3 ring heteroatoms selected from N, O, and S.

[0086] In some embodiments, heterocycloalkyl has 6 to 8 ring atoms, including 1 or 2 nitrogen heteroatoms.

[0087] In some embodiments, heterocycloalkyl has 6 to 8 ring atoms, including one nitrogen heteroatom.

[0088] In some embodiments, E is selected from pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, azepanyl, diazepanyl, tetrahydro-1H-azepinyl, 2,6-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.4]octanyl, hexahydrocyclopenta[c]pyrrolyl, 1,8-diazaspiro[4.5]decanyl, 1,7-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[4.5]decanyl, 2,7-diazaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,7-diazaspiro[4.5]decanyl, cyclohexenyl, octahydrocyclopenta[c]pyrrolyl, and octahydropyrrolo[3,4-c]pyrrolyl, each of which is selected from 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0089] In some embodiments, E is selected from pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, azepanyl, diazepanyl, tetrahydro-1H-azepinyl, cyclohexenyl, hexahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[c]pyrrolyl, and octahydropyrrolo[3,4-c]pyrrolyl, each of which is selected from 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0090] In some embodiments, E is selected from pyrrolidinyl and tetrahydro-1H-azepinyl, each of which is selected from 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0091] In some embodiments, E is pyrrolidinyl and 1 to 4 R E(i.e., 0, 1, 2, or 3 R E is replaced by ).

[0092] In some embodiments, E is tetrahydro-1H-azepinyl and 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0093] In some embodiments, E is pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl, tetrahydropyridin-4-yl, azepan-4-yl, 1,4-diazepan-1-yl, 2,3,4,7-tetrahydro-1H-azepin-5-yl, cyclohexen-1-yl, 2,6-diazaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.4]octan-2-yl, 1,8-diazaspiro[4.5]decan-8-yl, 1,7-diazaspiro[4.4]nonane-7-yl, 1,8-diazaspiro[4.5]decan-8-yl, 1,7-diazaspiro[4.4]nonane-7-yl, 1,8-diazaspiro[4.5]decane-8 ... yl, 1,7-diazaspiro[4.5]decan-7-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 2,8-diazaspiro[4.5]decan-2-yl, 2,7-diazaspiro[4.5]decan-2-yl, 2,3,6,7-tetrahydro-1H-azepin-4-yl, 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl, octahydrocyclopenta[c]pyrrol-5-yl, and octahydropyrrolo[3,4-c]pyrrol-2-yl, each of which is selected from 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0094] In some embodiments, E is selected from pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl, tetrahydropyridin-4-yl, azepan-4-yl, 1,4-diazepan-1-yl, 2,3,4,7-tetrahydro-1H-azepin-5-yl, cyclohexen-1-yl, 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl, octahydrocyclopenta[c]pyrrol-5-yl, and octahydropyrrolo[3,4-c]pyrrol-2-yl, each of which is selected from 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0095] In some embodiments, E is selected from pyrrolidin-1-yl and 2,3,4,7-tetrahydro-1H-azepin-5-yl, each of which is selected from 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0096] In some embodiments, E is pyrrolidin-1-yl and 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0097] In some embodiments, E is 2,3,4,7-tetrahydro-1H-azepin-5-yl and 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0098] In some embodiments, E is [ka] and 1 to 3 R E is optionally replaced by

[0099] In some embodiments, E is [ka] and 1 to 3 R E is optionally replaced by

[0100] In some embodiments, E is [ka] and 1 to 3 R E is optionally replaced by

[0101] In some embodiments, E is [ka] and 1 to 3 R E is optionally replaced by

[0102] In some embodiments, E is [ka] and 1 to 3 R E is optionally replaced by

[0103] In some embodiments, E is [ka] and 1 to 3 R E is optionally replaced by

[0104] In some embodiments, E is [ka] and 1 to 3 R E In some embodiments, E is optionally substituted with [ka] and 1 to 3 R EIn some embodiments, E is optionally substituted with [ka] and 1 to 3 R E In some embodiments, E is optionally substituted with [ka] and 1 to 3 R E In some embodiments, E is optionally substituted with [ka] and 1 to 3 R E In some embodiments, E is optionally substituted with [ka] and 1 to 3 R E is optionally replaced by

[0105] In some embodiments, E is [ka] is.

[0106] In some embodiments, E is [ka] is.

[0107] In some embodiments, E is [ka] is.

[0108] In some embodiments, E is [ka] is.

[0109] In some embodiments, E is [ka] is.

[0110] In some embodiments, E is [ka] is.

[0111] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] is.

[0112] In some embodiments, E is [ka] where: [ka] is a single bond and A is CH or N, or [ka] is a double bond, A is C, and E is one to three additional R E where n is 1 or 2 and n' is 1 or 2.

[0113] Generally, as defined herein, each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, C-C heteroalkyl, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuteriums (ie, substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0114] In some embodiments, each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; R E is optionally substituted with one or more deuteriums (ie, substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0115] In some embodiments, each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, and OH; R E is optionally substituted with one or more deuteriums (ie, substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0116] In some embodiments, each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C heteroalkyl, C-C hydroxyalkyl, NH, and OH; R Eis optionally substituted with 1 to 5 deuteriums (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0117] In some embodiments, each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; R E is optionally substituted with 1 to 5 deuteriums (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums). E is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH.

[0118] In some embodiments, each R E is independently selected from C1-C6 alkyl, and OH; R E is optionally substituted with 1 to 5 deuteriums (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0119] In some embodiments, each R E is independently selected from halogen, C-C alkyl, and OH; R E is optionally substituted with 1 to 5 deuteriums (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0120] In some embodiments, each R E are independently selected from Me, CD, Et, iPr, F, OH, OMe, CHOH, CHCHF, CHF, CHF, CHCHOMe, and NH.

[0121] In some embodiments, each R E is independently selected from Me, CD3, Et, F, and OH.

[0122] In some embodiments, each R E is independently selected from Me, CD3, and OH.

[0123] In some embodiments, each R E is independently selected from Me, and OH.

[0124] In some embodiments, each R E is independently F. In some embodiments, each R E is independently CD3. In some embodiments, each R E is independently Me. In some embodiments, each R E are independently OH.

[0125] In some embodiments, R E is bonded to a carbon atom.

[0126] In some embodiments, R E is bonded to the nitrogen atom.

[0127] Generally, as defined herein, each R' is independently selected from H and C1-C6 alkyl. In some embodiments, each R' is independently selected from H and Me. In some embodiments, R' is H. In some embodiments, R' is Me.

[0128] Generally, as defined herein, R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 (i.e., 0, 1, 2, or 3) independently selected halo or C1-C6 alkyl; R 12 and R' is as defined herein.

[0129] In some embodiments, R 1 -O-C1-C6 alkylene-E, -NR 12-C1-C6 alkylene-E, or E, where each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR'.

[0130] In some embodiments, R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E.

[0131] In some embodiments, R 1 is -O-C1-C6 alkylene-E.

[0132] In some embodiments, R 1 is -NR 12 -C1-C6 alkylene-E.

[0133] In some embodiments, R 1 is selected from E, and —O—C1-C6 alkylene-E.

[0134] In some embodiments, R 1 is selected from —O—CH—CH—CH—E, —O—CH—CH—E, and E.

[0135] In some embodiments, R 1 is selected from —O—(CH 2 ) 2 —E, and —O—(CH 2 ) 3 —E.

[0136] In some embodiments, R 1 is E.

[0137] In some embodiments, R 1 is -O-CH2-CH2-CH2-E.

[0138] In some embodiments, R 1 teeth,

[0139] [ka] is selected from.

[0140] In some embodiments, R 1 teeth, [ka] is.

[0141] In some embodiments, R 1 teeth, [ka] Selected from 1 to 3 R E (i.e., 0, 1, 2, or 3 R E (replaced by), each R E is as defined herein.

[0142] In some embodiments, R 1 teeth, [ka] and 1 to 3 R E (i.e., 0, 1, 2, or 3 R E (replaced by), each R E is as defined herein.

[0143] In some embodiments, R 1 teeth, [ka] and 1 to 3 R E and each R E is as defined herein.

[0144] In some embodiments, R 1 teeth, [ka] and 1 to 3 R E and each R Eis as defined herein. In some embodiments, R 1 teeth, [ka] and 1 to 3 R E and each R E is as defined herein. In some embodiments, R 1 teeth, [ka] and 1 to 3 R E and each R E is as defined herein. In some embodiments, R 1 teeth, [ka] and 1 to 3 R E and each R E is as defined herein. In some embodiments, R 1 teeth, [ka] and 1 to 3 R E and each R E is as defined herein. In some embodiments, R 1 teeth, [ka] and 1 to 3 R E and each R E is as defined herein.

[0145] In some embodiments, R 1 teeth, [ka] is.

[0146] In some embodiments, R 1 teeth, [ka] [ka] is.

[0147] In some embodiments, R 1 teeth, [ka] [ka] is.

[0148] In some embodiments, R 1 teeth, [ka] is.

[0149] In some embodiments, R 1 teeth, [ka] is.

[0150] In some embodiments, R 1 teeth, [ka] is.

[0151] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0152] Generally, as defined herein, each R 2 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylenephenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 groups) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E(i.e., 0, 1, 2, or 3 R E substituted with ), R C , R D , and R E is as defined herein.

[0153] In some embodiments, each R 2 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylenephenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 groups) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0154] In some embodiments, each R 2 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R C and R D is as defined herein.

[0155] In some embodiments, each R 2 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D2, or halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R C and R D is as defined herein.

[0156] In some embodiments, each R 2 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen.

[0157] In some embodiments, each R 2 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen.

[0158] In some embodiments, R 2 is C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylenephenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 groups) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0159] In some embodiments, R 2 is C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D2, or halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 groups) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0160] In some embodiments, R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen.

[0161] In some embodiments, R 2 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen.

[0162] In some embodiments, R 2 is H, C1-C6 alkyl, or halogen. In some embodiments, R 2 is C1-C6 alkyl, or halogen.

[0163] In some embodiments, R 2 is a halogen.

[0164] In some embodiments, R 2 is C1-C6 alkyl.

[0165] In some embodiments, R 2 is selected from H, Me, F, and Cl.

[0166] In some embodiments, R 2 is selected from Me, F, and Cl.

[0167] In some embodiments, R 2is selected from F and Cl.

[0168] In some embodiments, R 2 is H. In some embodiments, R 2 is Me. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F.

[0169] Generally, as defined herein, each R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylenephenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 groups) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E substituted with ), R C , R D , and R E is as defined herein.

[0170] In some embodiments, each R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylenephenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D2, or halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 groups) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0171] In some embodiments, each R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R C and R D is as defined herein.

[0172] In some embodiments, each R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R C and R D is as defined herein.

[0173] In some embodiments, each R 3 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen.

[0174] In some embodiments, each R 3is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen.

[0175] In some embodiments, each R 3 is H.

[0176] In some embodiments, each R 2 and R 3 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen.

[0177] In some embodiments, R 2 and R 3 Each of is H.

[0178] Generally, as defined herein, R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl.

[0179] In some embodiments, R 4 is H, or C1-C6 alkyl.

[0180] In some embodiments, R 4 is H or Me.

[0181] In some embodiments, R 4 is H.

[0182] Generally, as defined herein, each R 5 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E substituted with ), R E is as defined herein.

[0183] In some embodiments, each R 5 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted.

[0184] In some embodiments, R 5 is H.

[0185] Generally, as defined herein, each R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E substituted with ), R E is as defined herein.

[0186] In some embodiments, each R 6is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted.

[0187] In some embodiments, R 5 and R 6 together with the nitrogen to which they are attached form a 3- to 7-membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, wherein the heterocycle is optionally substituted.

[0188] In some embodiments, R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E (i.e., 0, 1, 2, or 3 R E substituted with ), R E is as defined herein.

[0189] In some embodiments, R 6 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, C3-C 10 heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, and C1-C6 alkylene-C3-C 10 and heterocyclyl, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is selected from 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0190] In some embodiments, R 6is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, C3-C 10 Heterocyclyl, C1-C6 alkylene-C3-C7 cycloalkyl, and C1-C6 alkylene-C3-C 10 and heterocyclyl, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH, and each cycloalkyl or heterocyclyl is selected from 1 to 4 R E is optionally replaced by

[0191] In some embodiments, R 6 is selected from C1-C6 alkyl, and C1-C6 heteroalkyl, where each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH.

[0192] In some embodiments, R 6 is selected from C1-C6 alkyl, and C1-C6 heteroalkyl, each alkyl or heteroalkyl optionally substituted with 1 to 5 instances of deuterium (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0193] In some embodiments, R 6 is C1-C6 alkyl, optionally substituted with one or more deuterium atoms. In some embodiments, R 6 is C1-C6 alkyl.

[0194] In some embodiments, R 6 is a C1-C6 alkyl, optionally substituted with 1 to 5 instances of deuterium (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0195] In some embodiments, R 6is selected from Me, CD3, Et, CH2CD3, CH2CH2OMe, CH2CH2CH2OMe, CH2CF3, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, CH2-tetrahydropyranyl, CH2-tetrahydrofuran-2-yl, N-iPr-piperidin-4-yl.

[0196] In some embodiments, R 6 is selected from Me, CD3, Et, CH2CD3, CH2CH2OMe, and CH2CH2CH2OMe.

[0197] In other embodiments, R 6 are C3-C7 cycloalkyl, or heterocyclyl, each of which is selected from 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0198] In some embodiments, R 6 is selected from Me, and CD3. In some embodiments, R 6 is Me. In some embodiments, R 6 is CD3.

[0199] In some embodiments, R 5 and R 6 are each C1-C6 alkyl, optionally substituted with one or more deuterium atoms. In some embodiments, R 5 and R 6 are each C1-C6 alkyl.

[0200] In some embodiments, R 5 is H and R 6 is not H.

[0201] In some embodiments, R 5 and R 6 are Me, respectively.

[0202] Generally, as defined herein, each R 7are independently H, C1-C6 alkyl, C1-C6 alkoxy, 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, and halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E substituted with ), R C , R D , and R E is as defined herein.

[0203] In some embodiments, each R 7 are independently H, 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, and halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0204] In some embodiments, each R 7are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, and halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted.

[0205] In some embodiments, each R 7 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, and halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted.

[0206] In some embodiments, each R 7 is independently selected from H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, and halogen, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 deuteriums (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0207] In some embodiments, each R 7 is independently selected from H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, and halogen, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 deuteriums (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0208] In some embodiments, R 7 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, C3-C 10Heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, and halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0209] In some embodiments, R 7 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and halogen, each alkyl optionally substituted with 1 to 5 instances of deuterium (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0210] In some embodiments, R 7 is selected from H, F, Cl, Me, Et, and OMe.

[0211] In some embodiments, R 7 is selected from H, F, and Me. In some embodiments, R 7 is H, or F. In some embodiments, R 7 is H. In some embodiments, R 7 is F.

[0212] Generally, as defined herein, each R 8 are independently H, C1-C6 alkyl, C1-C6 alkoxy, 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, and halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E substituted with ), R C , R D , and R E is as defined herein.

[0213] In some embodiments, each R 8 are independently H, 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, and halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0214] In some embodiments, each R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, and halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted.

[0215] In some embodiments, each R 8are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, and halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted.

[0216] In some embodiments, each R 8 is independently selected from H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, and halogen, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 deuteriums (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0217] In some embodiments, each R 8 is independently selected from H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, and halogen, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 deuteriums (i.e., substituted with 0, 1, 2, 3, 4, or 5 deuteriums).

[0218] In some embodiments, R 8 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, C3-C 10 Heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, C1-C6 alkylene-heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, and halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, 4, or 5 substituents) independently selected from deuterium, halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 RE is replaced by ).

[0219] In some embodiments, R 8 is C1-C6 alkyl, C3-C7 cycloalkyl, heterocyclyl, where each alkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from deuterium, halogen, and OH, and each cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0220] In some embodiments, R 8 is C1-C6 alkyl, C3-C7 cycloalkyl, heterocyclyl, where each alkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen and OH, and each cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E is replaced by ).

[0221] In some embodiments, R 8 is C1-C6 alkyl and is substituted with 1 to 5 deuteriums (i.e., 0, 1, 2, 3, 4, or 5 deuteriums). 8 is C1-C6 alkyl.

[0222] In some embodiments, R 8 is selected from methyl, ethyl, CH2D, iPr, cyclopropyl, cyclohexyl, and CH2CF3.

[0223] In some embodiments, R 8 is selected from methyl and CH2D. In some embodiments, R 8 is Me. In some embodiments, R 8 is CH2D.

[0224] Generally, as defined herein, each R 9 and R 10 are independently H, 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, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E substituted with ), R C , R D , and R E is as defined herein, or R 9 and R 10 can combine with the carbon to which they are attached to form CO.

[0225] In some embodiments, each R 9 and R 10 are independently H, 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, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R Esubstituted with ), R C , R D , and R E is as defined herein.

[0226] In some embodiments, each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted.

[0227] In some embodiments, each R 9 and R 10 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen.

[0228] In some embodiments, each R 9 and R 10 are independently H, C1-C6 alkyl, or halogen, or R 9 and R 10 combine with the carbon to which they are attached to form CO.

[0229] In some embodiments, each R 9 and R 10 are independently H, C1-C6 alkyl, or halogen.

[0230] In some embodiments, each R 9 and R 10 are independently H, C1-C6 alkyl, or halogen.

[0231] In some embodiments, each R 9 and R 10 are independently H, Me, or F.

[0232] In some embodiments, each R 9 and R 10、 are independently H. Generally, as defined herein, each R 11 are independently H, 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, and halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E substituted with ), R C , R D , and R E is as defined herein, or two R 11 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl.

[0233] In some embodiments, each R 11 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, and halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted or has two R 11 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl.

[0234] In some embodiments, each R 11are independently selected from H, C1-C6 alkyl, hydroxy, and halogen, each alkyl optionally substituted with 1 to 4 substituents (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen and OH, or two R 11 taken together with the carbon to which they are attached form CO or a spiro-fused C3-C7 cycloalkyl.

[0235] In some embodiments, each R 11 is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen.

[0236] In some embodiments, each R 11 are independently selected from H, C-C alkyl, hydroxy, and halogen, or two R 11 together with the carbons to which they are attached form a spiro-fused C3-C7 cycloalkyl,

[0237] In some embodiments, each R 11 are independently selected from H, Me, hydroxy, and F, or two R 11 together with the carbon to which they are attached to form a spiro-fused cyclopropyl.

[0238] In some embodiments, each R 11 is independently selected from H and Me.

[0239] In some embodiments, each R 11 is independently selected from hydroxy and Me.

[0240] In some embodiments, each R 11 is independently H. In some embodiments, each R 11 is independently Me. In some embodiments, each R 11 are independently F.

[0241] In some embodiments, two R 11 together with the carbon to which they are attached to form a spiro-fused cyclopropyl.

[0242] Generally, as defined herein, each R 12 are independently selected from H, C-C alkyl, C-C heteroalkyl, phenyl, C-C cycloalkyl, heterocyclyl, C-C alkylene-phenyl, C-C alkylene-C-C cycloalkyl, or C-C alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, and OH; E (i.e., 0, 1, 2, or 3 R E substituted with ), or two R attached to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and the heterocycle is E (i.e., 0, 1, 2, or 3 R E substituted with ), R C , R D , and R E is as defined herein.

[0243] In some embodiments, each R 12 are independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, and heterocyclyl, and each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted or has two R attached to the same nitrogen. 12 together with the nitrogen to which they are attached form a 3- to 7-membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, wherein the heterocycle is optionally substituted.

[0244] In some embodiments, each R 12 is independently selected from H, C-C alkyl, C-C haloalkyl, and C-C heteroalkyl. 12 is independently selected from H, C1-C6 alkylene-phenyl, and C1-C6 alkyl.

[0245] In some embodiments, each R 12 is independently H, or C1-C6 alkyl. In some embodiments, each R 12 is H.

[0246] Generally, as defined herein, each R 13 are independently H, 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, and halogen, each alkyl or heteroalkyl is optionally substituted (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E (i.e., 0, 1, 2, or 3 R E substituted with ), R C , R D , and R E is as defined herein, or two R 11 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl.

[0247] In some embodiments, each R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C, N.R. D 2, and halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted or has two R 11 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl.

[0248] In some embodiments, each R 13 are independently selected from H, C-C alkyl, C-C heteroalkyl, hydroxy, cyano, and halogen, where each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen and OH, or two R 13 taken together with the carbon to which they are attached form CO or a spiro-fused C3-C7 cycloalkyl.

[0249] In some embodiments, each R 13 are independently selected from H, C-C alkyl, hydroxy, and halogen, or two R 13 together with the carbons to which they are attached form a spiro-fused C3-C7 cycloalkyl,

[0250] In some embodiments, each R 13 is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen.

[0251] In some embodiments, each R 13 are independently selected from H, Me, hydroxy, and F, or two R 13 together with the carbon to which they are attached to form a spiro-fused cyclopropyl.

[0252] In some embodiments, each R 13 are independently H.

[0253] Generally, as defined herein, each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, and heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted.

[0254] In some embodiments, each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, and heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH.

[0255] In some embodiments, each R C are independently H, OH, and NR 12 2, C1-C6 alkyl, or C1-C6 alkoxy.

[0256] Generally, as defined herein, each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, and heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally being substituted or having two R attached to the same nitrogen. Dtogether with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted; W is 0, 1, or 2.

[0257] In some embodiments, each R D are independently D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, and heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH, or two R D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, the heterocycle being optionally substituted with 1-4 substituents (i.e., substituted with 0, 1, 2, 3, or 4 substituents) independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; W is 0, 1, or 2.

[0258] In some embodiments, each R D is independently H, or C1-C6 alkyl.

[0259] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIa): [ka] The variables are as defined herein.

[0260] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIb): [ka] The variables are as defined herein.

[0261] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIc): [ka] The variables are as defined herein.

[0262] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IId): [ka] The variables are as defined herein.

[0263] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIIa): [ka] The variables are as defined herein.

[0264] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIIb): [ka] The variables are as defined herein.

[0265] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIIc): [ka] The variables are as defined herein.

[0266] In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIId): [ka] The variables are as defined herein.

[0267] In certain embodiments, provided herein is a compound of formula (IVa), or a pharmaceutically acceptable salt thereof: [ka] The variables are as defined herein.

[0268] In certain embodiments, provided herein is a compound of formula (IVb), or a pharmaceutically acceptable salt thereof: [ka] The variables are as defined herein.

[0269] In certain embodiments, provided herein is a compound of formula (IIa-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, RE Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0270] In certain embodiments, provided herein is a compound of formula (IIb-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0271] In certain embodiments, provided herein is a compound of formula (IIc-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0272] In certain embodiments, provided herein is a compound of formula (IId-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0273] In certain embodiments, provided herein is a compound of formula (IIIa-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0274] In certain embodiments, provided herein is a compound of formula (IIIb-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0275] e [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0276] In certain embodiments, provided herein is a compound of formula (IIId-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0277] In certain embodiments, provided herein is a compound of formula (IVa-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0278] In certain embodiments, provided herein is a compound of formula (IVb-1), or a pharmaceutically acceptable salt thereof: [ka] where m is 0, 1, 2, 3, or 4, and the remainder of the variables are as defined herein. For clarity, R E Each instance of can be attached to either a carbon atom or a nitrogen atom.

[0279] In some embodiments, m is 0. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0280] In some embodiments, the compound is a compound of formula (I), wherein A is an optionally substituted 5-membered oxygen-containing heterocycle. [ka] is selected from the group consisting of:

[0281] In some embodiments, the compound is a compound of formula (I), wherein A is an optionally substituted 6-membered oxygen-containing heterocycle. [ka] is selected from the group consisting of:

[0282] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] is selected from.

[0283] In some embodiments, the compound is [ka] [ka] [ka] [ka] is selected from.

[0284] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0285] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0286] In some embodiments, provided herein is a composition comprising a compound described herein and a pharmaceutically acceptable carrier.

[0287] In some embodiments, the compound is a compound shown in Table 1 below, or a pharmaceutically acceptable salt thereof.

[0288] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as shown. Compounds marked with (or) are single enantiomers for which the absolute stereochemistry has been arbitrarily assigned (e.g., based on the chiral SFC elution described in the Examples section). Compounds marked with (and) are mixtures of enantiomers, with the relative stereochemistry as shown. Compounds with stereocenters whose configuration is not shown in the depicted structure and are not marked in the "Stereochemistry" column are mixtures of enantiomers. Compounds marked with (abs) are single enantiomers, with the absolute stereochemistry as shown.

[0289] One skilled in the art will be able to separate racemic compounds into their individual enantiomers using art-known methods such as chiral chromatography, chiral recrystallization, etc. Reference to a compound that is a racemic mixture is intended to include each individual enantiomer contained within 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

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

[0290] Treatment methods In certain embodiments, provided herein are methods for treating a disease or disorder that can be treated by modulation of EHMT1 or EHMT2, the method comprising administering a compound described herein or a composition described herein to a patient in need thereof.

[0291] In some embodiments, the disease or disorder is selected from the group consisting of cancer, sickle cell disease, and beta thalassemia.

[0292] In some embodiments, the disease or disorder is cancer (e.g., colorectal cancer).

[0293] In some embodiments, the cancer is breast cancer, melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchial cancer, blastoma, carcinoma, chondrosarcoma, oral or pharyngeal cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, liver cancer, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmic cancer, osteosarcoma, ovarian cancer, pancreatic cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small intestine or appendix cancer, small cell lung cancer, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, bladder cancer, uterine or endometrial cancer, and vulvar cancer.

[0294] In some embodiments, the cancer is selected from the group consisting of ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, adrenocortical carcinoma, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, ophthalmic cancer, Hodgkin's lymphoma, Kaposi's sarcoma, renal cancer, liver cancer, lung cancer (small cell and / or non-small cell), malignant ascites, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, chorionic neoplasm, uterine cancer, vaginal cancer, vulvar cancer, or Wilms' tumor.

[0295] In some embodiments, the cancer is a lymphoma. In some embodiments, the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma (e.g., diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt's lymphoma, or the like). lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma), and T-cell lymphoma (e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g., smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, nasal type (ENKL), enteropathy-associated intestinal T-cell lymphoma (EATL) (e.g., type I EATL and type II EATL), and anaplastic large cell lymphoma (ALCL)).

[0296] 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.

[0297] In some embodiments, the method further comprises the use of at least one additional therapeutic agent, hi some embodiments, the at least one additional therapeutic agent is chemotherapy or radiation.

[0298] In another aspect, there is provided the use of a compound of the present disclosure in the manufacture of a medicament for the treatment of cancer.

[0299] Cancer: Cancer cells grow rapidly in hypoxic environments by activating various elements of the cellular stress response. Without wishing to be bound by theory, a deeper understanding of the role of EHMT in cancer has recently begun to emerge, and therefore, compounds of formula (I) can also be used to treat cancer. Furthermore, EHMT modulators can be combined with one or more cancer therapies, such as chemotherapy and radiation therapy.

[0300] "Cancer" in a subject refers to the presence of cells that possess typical characteristics of cancer-causing 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 a tumor, but such cells may exist alone in an animal or may be non-tumorigenic cancer cells, such as leukemia cells. In some situations, cancer cells are in the form of a tumor, and such cells may exist locally in an animal or circulate in the bloodstream as independent cells, such as leukemia cells. Examples of cancer include, but are not limited to, breast cancer, melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchial cancer, blastoma, carcinoma, chondrosarcoma, oral or pharyngeal cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, liver cancer, hepatic cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmic cancer, osteosarcoma, ovarian cancer, pancreatic cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small intestine or appendix cancer, small cell lung cancer, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, bladder cancer, uterine or endometrial cancer, vulvar cancer, and the like.

[0301] Other exemplary cancers include ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, adrenocortical carcinoma, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, ophthalmic cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small These include, but are not limited to, ovarian cancer, ovarian (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, chorionic lining neoplasm, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, and the like.

[0302] Exemplary lymphomas include Hodgkin's lymphoma and non-Hodgkin's lymphoma. Further exemplary non-Hodgkin's lymphomas include B-cell lymphomas (e.g., diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt's lymphoma, and the like). lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma), and T-cell lymphomas (e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g., smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, nasal type (ENKL), enteropathy-associated intestinal T-cell lymphoma (EATL) (e.g., type I EATL and type II EATL), and anaplastic large cell lymphoma (ALCL)).

[0303] definition Unless otherwise stated or implied from context, the following terms and phrases have the meanings set forth 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 relevant art. Definitions are provided to help describe particular embodiments and are not intended to limit the claimed invention, since the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0304] As used herein, the terms "compound" and "agent" are used interchangeably to refer to inhibitors / antagonists / agonists of the present invention. In certain embodiments, compounds are small organic or inorganic molecules, 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, e.g., containing two, one, or no peptide and / or sugar linkages.

[0305] Unless otherwise indicated, 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 connection with percentages, the term "about" can mean ±1%.

[0306] 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.

[0307] 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.

[0308] As used herein, the term "administering" refers to placing a composition into a subject by a method or route that results in at least partial localization of the composition at a desired site so that a desired effect occurs. The compounds or compositions described herein can be administered by any suitable route known in the art, including oral or parenteral routes, including, but not limited to, intravenous, intramuscular, subcutaneous, transdermal, respiratory (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration.

[0309] The terms "reduce," "reduced," "reduction," "reduce," or "inhibit" are all used herein to generally mean a reduction by a statistically significant amount. In some embodiments, the terms "reduced," "reduction," "reduction," or "inhibition" refer to a reduction of at least 0.1% compared to a reference level, for example, a reduction 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%, or up to a 100% reduction (e.g., a reduction in the level of deficiency compared to a reference sample), or any reduction between 1 and 100%, for example, 10 and 100%.

[0310] The terms "increased," "increase," "enhancement," or "activation" are all generally used herein to mean a statically significant increase. In some embodiments, the terms "increased," "increase," "enhancement," or "activation" refer to an increase of at least 0.1% compared to a reference level, e.g., an increase 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%, or up to a 100% increase (e.g., a deficiency level compared to a reference sample), or any increase between 1 and 100%, e.g., 10 and 100%.

[0311] "Treating," "preventing," or "ameliorating" a disease or disorder means delaying or preventing the onset of such disease or disorder, or reversing, alleviating, ameliorating, inhibiting, slowing, or halting the progression or worsening or worsening of the severity of the 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%.

[0312] As used herein, a "therapeutically effective amount" or "effective amount" refers to the amount of a compound or combination that, upon single or multiple administration(s) to a subject, is effective in treating the subject or in treating, alleviating, ameliorating, or improving a subject having a disorder (e.g., a disorder described herein) beyond that expected in the absence of such treatment. Determining a therapeutically effective amount is within the capabilities of one of ordinary skill in the art. Generally, a therapeutically effective amount may vary depending on the subject's medical history, age, condition, sex, and the severity and type of medical condition in the subject, as well as the administration of other pharmaceutically active agents.

[0313] As used herein, "subject" refers to a human or an animal. Typically, an animal is a vertebrate such as a primate, rodent, livestock, or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., rhesus monkeys. Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Livestock and game animals include cattle, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cats, canine species, e.g., dogs, foxes, wolves, avian species, e.g., chickens, emus, ostriches, and fish, e.g., trout, catfish, and salmon. A patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species, such as humans, primates, or rodents. In certain embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms "patient" and "subject" are used interchangeably herein. The terms "patient" and "subject" are used interchangeably herein.

[0314] The term "nucleic acid" as used herein refers to a polymeric form of nucleotides, either ribonucleotides or deoxynucleotides, or modified forms of either type of nucleotide. The term should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, as well as analogs of single-stranded (e.g., sense or antisense) and double-stranded polynucleotides, as applicable to the described embodiments.

[0315] As used herein, the term "modulators of EHMTs" refers to compounds and compositions of formula (I) that modulate the activity of EHMTs, eg, EHMT1 and EHMT2.

[0316] Selected chemical substance 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 each and every individual subcombination of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0317] For 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, when a structure is described with 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.

[0318] It is 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 the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0319] When a compound of the present invention is shown in the form of a chemical name and a formula, in the event of any discrepancy, the formula shall prevail.

[0320] symbol [ka] indicates the point at which the displayed moiety is attached to the remainder of the molecule, solid support, etc., whether utilized as a bond or displayed perpendicular to a bond.

[0321] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention.

[0322] As used herein, "alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having from 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C-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), iso-butyl (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 is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-6 It is alkyl.

[0323] The term "alkylene" refers to the diradical of an alkyl group. An exemplary alkylene group is -CH2CH2-.

[0324] As used herein, "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 2- -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 (e.g., 2-butenyl) or terminal (e.g., 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 aforementioned 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 instance 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 C2-C6 10 In certain embodiments, the alkenyl group is a substituted C2-C6 alkenyl.

[0325] As used herein, the term "alkynyl" refers to a 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 ("C 2- -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 (such as 2-butynyl) or terminal (such as 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 instance of alkynyl 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.

[0326] As used herein, the term "heteroalkyl" means acyclic, stable, straight or branched chains, 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, wherein the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) O, N, P, S, and Si can be placed 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. Up to two or three heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. "Heteroalkyl" is shown followed by -CHO, -NR C R D When specific heteroalkyl groups such as -CHO or -NR are recited, the heteroalkyl and -CHO or -NR are also recited. C R D It will be understood that the terms are not overlapping or mutually exclusive. Rather, specific heteroalkyl groups are recited for clarity. Thus, the term "heteroalkyl" is used herein to include, but is not limited to, -CHO, -NR C R D This should not be construed as excluding certain heteroalkyl groups such as, for example, aryl, aryloxy ...

[0327] 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, the substituent on an alkyl that makes it an ether is or resembles an alkoxyl, and includes -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, -NH2, -NO2, -SO2, Si(CH3)3, cycloalkyl, heterocyclyl, aryl, or heteroaryl, as described above. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Examples include -O-CH2F, -O-CHF2, and -O-CF3. In certain embodiments, the haloalkoxyl is an alkoxyl group substituted with at least one fluoro group. In certain embodiments, the haloalkoxyl is an alkoxyl group substituted with 1 to 6, 1 to 5, 1 to 4, 2 to 4, or 3 fluoro groups.

[0328] The term "hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (e.g., 1, 2, or 3) hydrogen atoms are independently replaced with a hydroxyl group (-OH). Exemplary hydroxyalkyl groups include -CHOH, CHCHOH, C(CH)OH, and the like.

[0329] 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 in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-C 14In 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, an aryl group has 14 ring carbon atoms ("C 14 Aryl groups include, for example, C-C 10 aryl, the term "membered" referring to a non-hydrogen ring atom within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group can 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 C-C 14 In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0330] As used herein, "heteroaryl" refers to a radical of a 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-10-membered heteroaryl"). For heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which the heteroaryl ring, as defined above, is fused with one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.) can have the attachment point in either ring, i.e., either the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl). Heteroaryl groups can be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom within the moiety.

[0331] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems 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 some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems 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 ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems 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 ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0332] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives. "Heteroaryl" further includes ring systems in which the heteroaryl ring defined above is fused to one or more heterocycloalkyl groups, and the point of attachment is on the heteroaryl ring; in such instances, the number of carbons continues to designate the number of carbons in 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.

[0333] 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 10 Cycloalkyl groups may be described, for example, as C4-C7 membered cycloalkyl, where the term "membered" refers to a non-hydrogen ring atom within the moiety. Exemplary C3-C6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 carbocyclyl groups include, without limitation, the aforementioned C3-C6 carbocyclyl groups 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 Carbocyclyl groups include, without limitation, the aforementioned C3-C8 carbocyclyl 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 10), and the like. While the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or includes a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic cycloalkyl"), and can be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which the cycloalkyl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on the cycloalkyl ring; in such instances, the number of carbons continues to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group can 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 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0334] As used herein, "heterocyclyl," "heterocycle," or "heterocycloalkyl" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl" or "C-C 10Heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valency allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups, and the point of attachment is on either the cycloalkyl ring or the heterocyclyl ring or ring system; and a heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, and the point of attachment is on the heterocyclyl or aryl or heteroaryl ring; in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, where the term "membered" refers to the non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Alternatively, a heterocyclyl group containing 3 to 10 non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, is described as a "C3-C 10 A heterocyclyl group containing 3 to 7 non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, can be described as a "C3-C7 heterocyclyl." Each instance of heterocyclyl can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, a heterocyclyl group can be an unsubstituted 3- to 10-membered heterocyclyl (i.e., an unsubstituted C3-C7 heterocyclyl). 10 In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl (i.e., a substituted C-C 10 heterocyclyl).

[0335] 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, each 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, each 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, each 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, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0336] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, azacyclohexenyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, azacycloheptenyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0337] As used herein, "cyano" refers to the radical --CN.

[0338] 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.

[0339] 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., -C-C alkyl-CF, -C-C alkyl-CF). Non-limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, difluroylmethyl, and fluoroisopropyl.

[0340] As used herein, "hydroxy" refers to the radical --OH.

[0341] As used herein, "nitro" refers to --NO.sub.2.

[0342] As used herein, "oxo" refers to =O where both bonds from the oxygen are attached to the same atom. For example, a carbon atom substituted with oxo forms a carbonyl group, -C=O.

[0343] Two or more substituents may optionally combine to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are typically, 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 create 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 create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0344] 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 mixtures 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-pressure 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 sp. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0345] 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 a 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 the 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 an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0346] In the compositions provided herein, the enantiomerically pure compounds may be present 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 comprise, for example, at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound, based on 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 comprise, for example, at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0347] The compounds described herein may also contain one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium), and 3 H (T or tritium), and C can be in any isotopic form.12 C. 13 C, and 14 C can be any isotopic form, including O 16 O and 18 It may be in any isotopic form, including O, and the like.

[0348] Many of the terms given above may be used repeatedly in the definitions of formulae or groups and in each case have, independently of one another, one of the meanings given above.

[0349] 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 that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, etc.

[0350] In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if 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. Optionally substituted moieties may be substituted with groups that form a ring together with the atoms to which they are attached (e.g., 3- to 10-membered cycloalkyl or heterocyclyl). Unless otherwise specified, substituents on one "optionally substituted" moiety cannot be combined with substituents on a second, separate "optionally substituted" moiety to form a ring. Combinations of substituents envisioned under 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 are not substantially altered when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0351] 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)OR cc , -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 selected from the group consisting of 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; R cc is hydrogen, hydroxy, C-C alkyl, C-C heteroalkyl, carbocyclyl, (C-C alkylene)-carbocyclyl, (C-C heteroalkylene)-carbocyclyl, heterocyclyl, (C-C alkylene)-heterocyclyl, (C-C heteroalkylene)-heterocyclyl, aryl, (C-C alkylene)-aryl, (C-C heteroalkylene)-aryl, heteroaryl, (C-C alkylene)-heteroaryl, or (C-C heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halogen, hydroxy, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R dd and R eeare each independently selected from hydrogen, C-C alkyl, or C-C heteroalkyl, and k is 0, 1, or 2. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0352] Conceivable equivalents of the above compounds include compounds that otherwise correspond thereto and have the same general properties (e.g., the ability to modulate EHMT1 or EHMT2), with one or more simple modifications of the substituents that do not adversely affect the efficacy of the compound. 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 shown in the general reaction schemes described below, or by modifications thereof. In these reactions, it is also possible to utilize variants that are known per se but are not mentioned here.

[0353] For purposes of this invention, they are identified according to the endpapers of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds, which may be substituted or unsubstituted.

[0354] Pharmaceutical Compositions and Routes of Administration Pharmaceutical compositions comprising the compounds described herein, such as a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, can be used to treat or ameliorate a disorder described herein, e.g., a neurodegenerative disease, cancer, an ocular disease (e.g., a retinal disease), or a viral infection.

[0355] The amount and concentration of the compound of formula (I) or (II) 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 subject's medically relevant characteristics (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.

[0356] Although it is possible to administer the compounds of the present invention alone, it is preferable to administer the compounds as pharmaceutical formulations (compositions), in which the compounds are combined with one or more pharmaceutically acceptable diluents, excipients, or carriers. The compounds according to the present invention can be formulated for administration in any convenient manner for use in human or veterinary medicine. In certain embodiments, the compounds included in the pharmaceutical formulation may be active per se or may be, for example, prodrugs that can be converted to active compounds in a physiological environment. Regardless of the selected route of administration, the compounds of the present invention, which may be used in a suitable hydrated form, and / or pharmaceutical compositions of the present invention can be formulated into pharmaceutically acceptable dosage forms as described below or by other conventional methods known to those skilled in the art.

[0357] Accordingly, another aspect of the present invention provides a therapeutically effective amount of a pharmaceutically acceptable composition comprising one or more of the compounds described above formulated together with one or more pharmaceutically acceptable carriers (excipients) and / or diluents. As described in detail below, the pharmaceutical compositions of the present invention 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), troches, dragees, capsules, pills, tablets (e.g., buccal, sublingual, and those targeted for systemic absorption), boluses, powders, granules, pastes for application to the tongue, and the like; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, as sterile aqueous solutions or suspensions, or as sustained-release formulations; (3) topical application, e.g., as creams, ointments, or controlled-release patches or sprays applied to the skin; (4) vaginal or rectal administration, e.g., as pessaries, creams, or foams; (5) sublingual administration; (6) ophthalmic administration; (7) transdermal administration; (8) transmucosal administration; (9) nasal administration; or (10) intrathecal administration. Additionally, compound drug delivery systems can be used to implant or inject into patients. 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. Patent No. 3,773,919; and U.S. Patent No. 353,270,960.

[0358] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, material, or composition, including a compound of the present invention, that is effective to produce some desired therapeutic effect, at a reasonable benefit / risk ratio applicable to any treatment, e.g., by modulating EHMT1 or EHMT2 in at least some cell populations of an animal, thereby blocking the biological consequences of its function in the treated cells.

[0359] As used herein, the phrases "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered" refer to the administration of a compound, drug, or other substance other than directly to the central nervous system, where it enters the patient's system and thus is subject to metabolism and other similar processes, e.g., subcutaneous administration.

[0360] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of safe medical judgment and commensurate with a reasonable benefit / risk ratio.

[0361] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a subject antagonist from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) celluloses and their derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (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; and (10) 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 solutions, (21) cyclodextrins such as Captisol®, and (22) other non-toxic, compatible substances used in pharmaceutical formulations.

[0362] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein.When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds 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, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds 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, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galactunolonic 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 functional groups that allow 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 carriers known to those skilled in the art are suitable for the present invention.

[0363] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the compositions.

[0364] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0365] 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 methods well known in the art of pharmacy. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0366] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0367] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, sweetened tablets (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0368] In solid dosage forms of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, 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, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) sorbents, such as sorbitol, ... Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, for example, paraffin; (6) absorption accelerators, for example, quaternary ammonium compounds; (7) wetting agents, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, for example, kaolin and bentonite clay; (9) lubricants, for example, 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 employed as fillers in soft- and hard-filled gelatin capsules using lactose or milk sugar, high molecular weight polyethylene glycols, and similar excipients.

[0369] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can 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 can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0370] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of a sterile solid composition that can be dissolved in sterile water or other injectable sterile medium immediately before use. These compositions can also optionally contain opacifying agents, and can be compositions that 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 can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0371] 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 ingredient, 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, oils (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0372] 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.

[0373] 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.

[0374] Formulations of pharmaceutical compositions of the present invention for rectal, vaginal, or urethral administration may be provided as suppositories, which can be prepared by mixing one or more active compounds of the present invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature and will melt in the rectal or vaginal cavity to release the active compound(s).

[0375] Alternatively or additionally, the composition can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such a device can be particularly useful for delivery to the heart, lungs, bladder, urethra, ureter, rectum, or intestine. Furthermore, the composition can be formulated for delivery via a dialysis port.

[0376] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present disclosure.

[0377] Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or 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.

[0378] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more 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 sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0379] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0380] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. 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.

[0381] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug can then depend on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of the drug form of parenterally administered dosage form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0382] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0383] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they can be administered by themselves or, for example, in combination with a pharmaceutically acceptable carrier, as a pharmaceutical composition containing 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient.

[0384] The active compound of the present invention is preferably added to animal feed by preparing a suitable feed premix containing an effective amount of the active compound, and incorporating the premix into the complete ration. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The methods for preparing and administering such feed premixes and complete rations are described in references (e.g., "Applied Animal Nutrition", WH Freedman and CO., San Francisco, USA, 1969 or "Livestock Feeds and Feeding", O and B books, Corvallis, Ore., USA, 1977).

[0385] The method of introduction may be provided by a rechargeable or biodegradable device. A variety of sustained-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0386] 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 represent animal models of neurodegenerative diseases or disorders, cancer, or disorders associated with viral infections.

[0387] Furthermore, the methods described herein can be used to treat livestock and / or pets.The subject can be male or female.The subject can be previously diagnosed with or identified as suffering from a neurodegenerative disease or 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 no longer need to be treated.

[0388] Dosage Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being harmful to the patient.

[0389] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds of the present invention, or esters, salts, or amides thereof, being used, the route of administration, the time of administration, the excretion rate of the particular compound being used, the duration of treatment, other drugs, compounds, and / or materials being used in combination with the particular compound being used, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0390] The compound and the pharmaceutically active agent can be administered to a subject 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.

[0391] The amount of compound which can be combined with a carrier material to produce a single dosage form will generally be that amount of inhibitor which produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 0.1% to 99% of the inhibitor, preferably from about 5% to about 70%, and most preferably from 10% to about 30%.

[0392] 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 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 large therapeutic indices are preferred.

[0393] 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 administered at an ED400 dose 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.

[0394] A therapeutically effective dose can be estimated initially from cell culture assays. The dose can be determined by 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 suppression of symptoms). Plasma levels can be measured, for example, by high performance liquid chromatography. The effect of any particular dose can be monitored by a suitable bioassay.

[0395] Dosage will be determined by the physician and may be adjusted, if necessary, to suit the observed effects of the treatment.

[0396] The present invention contemplates formulating the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Additionally, the present invention contemplates administration via 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.

[0397] Selected Embodiments Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, A is an optionally substituted 5- or 6-membered oxygen-containing heterocycle; G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R Care independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0398] Embodiment 2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, A is an optionally substituted 5- or 6-membered oxygen-containing heterocycle; G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0399] Embodiment 3. A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered oxygen-containing heterocycle.

[0400] Embodiment 4. A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 5-membered oxygen-containing heterocycle.

[0401] Embodiment 5. A compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0402] Embodiment 6. A compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] wherein X is C(R 11 )2, O, S(O)w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 Or Or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; and R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R C independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0403] Embodiment 7. A compound of formula (II): [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, wherein 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 optionally replaced by R 4is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R Cindependently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached 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, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; W is 0, 1, or 2.

[0404] Embodiment 8. A compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached 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, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, and OH; R Eis optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0405] Embodiment 9. A compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3are independently H, 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, C1-C6 alkoxy, hydroxy, cyano, CO—R C , N.R. D 2, or halogen, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 alkoxy, 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 each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R C are independently H, OH, N(R 12 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 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, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen Dtogether with the nitrogen to which they are attached 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, C-C alkyl, C-C haloalkyl, C-C alkoxy, and OH; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C cycloalkyl, heterocyclyl, C-C heteroalkyl, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0406] Embodiment 10. A compound of formula (II): [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, and OH.

[0407] Embodiment 11. A compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 5 deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R E is independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, and OH; R E is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0408] Embodiment 12. A compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, or NR 12 and Y is a bond or C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and G is N or CR 7 and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E; E is C3-C 10 cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, cyano, or halogen; R 4 is H or C1-C6 alkyl; Each R 5 and R 6are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, 3-heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, deuterium, and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C heteroalkyl, hydroxy, cyano, or halogen, each alkyl or heteroalkyl optionally substituted with 1 to 5 deuterium atoms; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; or R 9 and R 10 can combine with the carbon to which they are attached to form CO, Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, hydroxy, cyano, or halogen; Each R 12 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; Each R Eis independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C hydroxyalkyl, NH, and OH; R E is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

[0409] Embodiment 13.G is CR 7 13. The compound of any one of embodiments 1-12, wherein:

[0410] Embodiment 14. A compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein G is CH.

[0411] Embodiment 15. A compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein G is N.

[0412] Embodiment 16. A compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R 13 ) and R 1-O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0413] Embodiment 17. A compound of formula (III), or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11)=C(R 13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is optionally substituted; R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R 7 and R 8 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C1-C6 alkoxy, hydroxy, cyano, CO-RC , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 9 and R 10 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R 11 and R 13 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO-R C , N.R. D 2, or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R C are independently H, OH, N(R 12)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SO w -C1-C6 alkyl, CO2-C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; W is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0414] Embodiment 18. A compound of formula (III): [ka] During the ceremony, X is C(R 11 )2, O, S(O) w , or NR 12 can be, Y is a bond, C(R 13 )2, or C(R 13 )2-C(R 13 )2, Z is CR 9 R 10 or XY is C(R 11 )=C(R 13 ) and Z is CR 9 R 10 or XYZ is C(R 11 )=C(R13 ) and R 1 -O-C1-C6 alkylene-E, -NR 12 -C1-C6 alkylene-E, or E, wherein each methylene group of the C1-C6 alkylene is individually optionally substituted with O or NR', and the C1-C6 alkylene is optionally substituted with 1 to 3 independently selected halo or C1-C6 alkyl; E is C3-C 10 Cycloalkyl or C3-C 10 heterocycloalkyl, each of which is 1 to 4 R E optionally replaced by R' is H or C1-C6 alkyl; Each R 2 and R 3 are independently H, 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, wherein 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 optionally replaced by R 4 is H, C1-C6 alkyl, or C1-C6 heteroalkyl; Each R 5 and R 6 are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-C3-C 10 heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R Eoptionally replaced by, or R 5 and R 6 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R 7 and R 8 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 9 and R 10 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by Each R 11 and R 13 are independently H, 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, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or 2 R's 11 Or two R's 13 can be taken together with the carbon to which they are attached to form CO or a spiro-fused C3-C7 cycloalkyl; Each R 12 is H, C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 alkylene-phenyl, C1-C6 alkylene-C3-C7 cycloalkyl, or C1-C6 alkylene-heterocyclyl, each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R E optionally replaced by, or Two Rs bonded to the same nitrogen 12 together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, and said heterocycle is E optionally replaced by Each R C independently, H, OH, and NR 12 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, phenyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; Each R D are independently H, C1-C6 alkyl, CO-C1-C6 alkyl, CO2-C1-C6 alkyl, SOw -C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and OH; or Two Rs bonded to the same nitrogen D together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms s...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Hua 321】 During the ceremony, A is an optionally substituted 5- or 6-membered oxygen-containing heterocycle; G is N or CR ７ and R １ But -O-C １ -C ６ Alkylene-E, -NR １２ -C １ -C ６ alkylene-E, or E, and C １ -C ６ each methylene group of the alkylene is individually optionally substituted with O or NR'; C １ -C ６ Alkylene is selected from 1 to 3 independently selected halo or C １ -C ６ optionally substituted with alkyl; E is C ３ -C １０ Cycloalkyl or C ３ -C １０ heterocycloalkyl, each of which is optionally substituted; R' is H or C １ -C ６ is alkyl, Each R ２ and R ３ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ Cycloalkyl, heterocyclyl, C １ -C ６ Alkoxy, hydroxy, cyano, CO-R Ｃ , N.R. Ｄ ２ or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R ４ But H, C １ -C ６ Alkyl, or C １ -C ６ is heteroalkyl, Each R ５ and R ６ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or R ５ and R ６ together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R ７ and R ８ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C １ -C ６ Alkoxy, hydroxy, cyano, CO-R Ｃ , N.R. Ｄ ２ or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R １２ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen １２ together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R Ｃ are independently H, OH, N(R １２ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; 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, CO ２ -C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen Ｄ together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Ｗ is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (II), or a pharmaceutically acceptable salt thereof: 【Hua 322】 wherein X is C(R １１ ) ２ , O, S(O) ｗ , or NR １２ can be, Y is a bond, C(R １３ ) ２ , or C(R １３ ) ２ -C(R １３ ) ２ and Z is CR ９ R １０ Or Or X-Y is C(R １１ ) = C(R １３ ) and Z is CR ９ R １０ or X-Y-Z is C(R １１ ) = C(R １３ ) and G is N or CR ７ and R １ But -O-C １ -C ６ Alkylene-E, -NR １２ -C １ -C ６ alkylene-E, or E, and C １ -C ６ each methylene group of the alkylene is individually optionally substituted with O or NR'; C １ -C ６ Alkylene is selected from 1 to 3 independently selected halo or C １ -C ６ optionally substituted with alkyl; E is C ３ -C １０ Cycloalkyl or C ３ -C １０ heterocycloalkyl, each of which is optionally substituted; R′ is H or C １ -C ６ is alkyl, Each R ２ and R ３ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ Cycloalkyl, heterocyclyl, C １ -C ６ Alkoxy, hydroxy, cyano, CO-R Ｃ , N.R. Ｄ ２ or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; R ４ But H, C １ -C ６ Alkyl, or C １ -C ６ is heteroalkyl, Each R ５ and R ６ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or R ５ and R ６ together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Each R ７ and R ８ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, cycloalkyl, heterocyclyl, C １ -C ６ Alkoxy, hydroxy, cyano, CO-R Ｃ , N.R. Ｄ ２ or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R ９ and R １０ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO—R Ｃ , N.R. Ｄ ２ or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; Each R １１ and R １３ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, cycloalkyl, heterocyclyl, hydroxy, cyano, CO—R Ｃ , N.R. Ｄ ２ or halogen, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or Two R's １１ Or two R's １３ together with the carbon to which they are attached to form a C-O or spiro-fused C ３ -C ７ can form a cycloalkyl, Each R １２ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen １２ together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; 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, phenyl, C ３ -C ７ cycloalkyl, or heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; 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, CO ２ -C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, phenyl, C ３ -C ７ cycloalkyl, or heterocyclyl, each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl optionally substituted; or Two Rs bonded to the same nitrogen Ｄ together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle being optionally substituted; Ｗ is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G is CH.

4. A compound of formula (III), or a pharmaceutically acceptable salt thereof: 【Hua 323】 During the ceremony, X is C(R １１ ) ２ , O, or NR １２ and Y is a bond or C(R １３ ) ２ and Z is CR ９ R １０ or X-Y is C(R １１ ) = C(R １３ ) and Z is CR ９ R １０ or X-Y-Z is C(R １１ ) = C(R １３ ) and R １ But -O-C １ -C ６ Alkylene-E, -NR １２ -C １ -C ６ alkylene-E, or E; E is C ３ -C １０ cycloalkyl or heterocycloalkyl, each of which is 1 to 4 R Ｅ optionally replaced by Each R ２ and R ３ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C １ -C ６ alkoxy, hydroxy, cyano, or halogen; R ４ is H or C １ -C ６ is alkyl, Each R ５ and R ６ However, independently, H, C １ -C ６ Alkyl, 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, or C １ -C ６ alkylene-heterocyclyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 substituents independently selected from deuterium, halogen, and OH; and each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R Ｅ optionally replaced by, or R ５ and R ６ together with the nitrogen to which they are attached form a 3-7 membered heterocycle having 0-2 additional ring heteroatoms selected from O, S, and N, said heterocycle containing 1-4 R Ｅ optionally replaced by Each R ７ and R ８ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ heteroalkyl, hydroxy, cyano, or halogen; １ -C ６ alkyl is optionally substituted with one or more deuterium atoms; Each R ９ and R １０ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ heteroalkyl, hydroxy, cyano, or halogen; or R ９ and R １０ can combine with the carbon to which they are attached to form CO, Each R １１ and R １３ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ heteroalkyl, hydroxy, cyano, or halogen; Each R １２ However, independently, H, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or C １ -C ６ is heteroalkyl, Each R Ｅ are independently halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, NH ２ and OH, R Ｅ is optionally substituted with one or more deuterium atoms, or a pharmaceutically acceptable salt thereof.

5. X is CH(CH ３ ), C.H. ２ 5. The compound of claim 2 or 4, wherein R is 0 or O, or a pharmaceutically acceptable salt thereof.

6. Y is a bond or CH ２ 5. The compound of claim 2 or 4, wherein:

7. R １ is E, and -O-C １ -C ６ 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein: E is selected from alkylene-E.

8. R １ 5. The compound of claim 1, 2, or 4, wherein is E, or a pharmaceutically acceptable salt thereof.

9. E is 1 to 4 R Ｅ C optionally substituted with ３ -C １０ 10. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, which is heterocycloalkyl.

10. E, 【Chemical 324】 and 1 to 3 R are selected from Ｅ 10. The compound of claim 1, 2, or 4, optionally substituted with: or a pharmaceutically acceptable salt thereof.

11. E, 【Hua 325】 and 1 to 3 R Ｅ 10. The compound of claim 1, 2, or 4, optionally substituted with: or a pharmaceutically acceptable salt thereof.

12. Each R Ｅ are independently halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Heteroalkyl, C １ -C ６ Hydroxyalkyl, NH ２ and OH, R Ｅ 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted with 1 to 5 deuterium atoms.

13. Each R Ｅ But independently, Me, CD ３ 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of , Et, F, and OH.

14. R １ but, 【Hua 326-1】 【Hua 326-2】 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, selected from:

15. R １ but, 【Hua 327】 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, selected from:

16. R ２ 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein is selected from H, Me, F, and Cl.

17. R ２ 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein is selected from Me, F, and Cl.

18. R ３ 5. The compound of claim 1, 2, or 4, wherein is H, or a pharmaceutically acceptable salt thereof.

19. R ４ 5. The compound of claim 1, 2, or 4, wherein is H, or a pharmaceutically acceptable salt thereof.

20. R ５ 5. The compound of claim 1, 2, or 4, wherein is H, or a pharmaceutically acceptable salt thereof.

21. R ６ But, Me, and CD ３ 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, selected from:

22. R ７ 5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein is selected from H, F, and Me.

23. R ８ is methyl, and CH ２ 10. The compound of claim 1, 2, or 4, or a pharmaceutically acceptable salt thereof, wherein:

24. Z is C=O, CF ２ , and C.H. ２ 5. The compound of claim 2 or 4, or a pharmaceutically acceptable salt thereof, selected from:

25. Each R １２ 5. The compound of claim 1, 2, or 4, wherein is H, or a pharmaceutically acceptable salt thereof.

26. Each R １１ are independently selected from H, Me, hydroxy, and F, or two R １１ 5. The compound of claim 2 or 4, or a pharmaceutically acceptable salt thereof, wherein: is taken together with the carbon to which they are attached to form a spiro-fused cyclopropyl;

27. Each R １３ is independently H, or a pharmaceutically acceptable salt thereof.

28. A compound of formula (IVa-2), or a pharmaceutically acceptable salt thereof, wherein: 【Hua 328】 X is O or C(R １１ ) ２ and R ２ But H, C １ -C ６ alkyl, and halogen; R ６ But C １ -C ６ Alkyl and C １ -C ６ heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1 to 5 instances of deuterium; R ７ But H, C １ -C ６ Alkyl, C １ -C ６ alkoxy, and halogen, each alkyl optionally substituted with 1 to 5 instances of deuterium; R ８ But C １ -C ６ alkyl, optionally substituted with 1 to 5 deuterium atoms; Each R ９ and R １０ However, independently, H, C １ -C ６ alkyl, or halogen; Each R １１ However, independently, H, C １ -C ６ alkyl, hydroxy, and halogen, or two R １１ together with the carbon to which they are attached to form a spiro-fused C ３ -C ７ forming a cycloalkyl, Each R Ｅ are independently halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ hydroxyalkyl, and OH; R Ｅ is optionally substituted with 1 to 5 deuterium atoms, The compound, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

29. The compound is 【Hua 329-1】 【Hua 329-2】 【Hua 329-3】 【Hua 329-4】 【Hua 329-5】 【Hua 329-6】 【Hua 329-7】 【Hua 329-8】 【Hua 329-9】 30. The compound of any one of claims 1, 2, 4, and 28, or a pharmaceutically acceptable salt thereof, selected from:

30. The compound is 【Hua 330-1】 【Hua 330-2】 【Hua 330-3】 【Hua 330-4】 【Hua 330-5】 【Hua 330-6】 【Hua 330-7】 【Hua 330-8】 【Hua 330-9】 【Hua 330-10】 【Hua 330-11】 【Hua 330-12】 【Hua 330-13】 【Hua 330-14】 【Hua 330-15】 【Hua 330-16】 【Hua 330-17】 【Hua 330-18】 【Hua 330-19】 【Hua 330-20】 【Hua 330-21】 【Hua 330-22】 【Hua 330-23】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

31. 30. A composition comprising a compound of any one of claims 1, 2, 4, and 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32. A composition comprising a compound described in any one of claims 1, 2, 4, and 28, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound described in any one of claims 1, 2, 4, and 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in treating a disease or disorder that can be treated by modulation of EHMT1 or EHMT2.

33. 33. The composition of claim 32, wherein the disease or disorder is selected from the group consisting of cancer, sickle cell disease, and beta thalassemia.

34. 34. The composition of claim 33, wherein the disease or disorder is cancer.

35. 35. The composition of claim 34, wherein the cancer is selected from the group consisting of breast cancer, melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchial cancer, blastoma, carcinoma, chondrosarcoma, oral or pharyngeal cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, liver cancer, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmic cancer, osteosarcoma, ovarian cancer, pancreatic cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small intestine or appendix cancer, small cell lung cancer, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, bladder cancer, uterine or endometrial cancer, and vulvar cancer.

36. 36. The composition of claim 35, 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.

37. 33. The composition of claim 32, wherein the composition is used in combination with at least one additional therapeutic agent.

38. 38. The composition of claim 37, wherein the at least one additional therapeutic agent is chemotherapy or radiation.

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