Inhibitors of the MYST family of lysine acetyltransferases

Abstract

Provided herein is a compound of formula (I). Methods for the preparation of the compound of formula (I) and intermediates useful in the preparation of the compound of formula (I) are described herein. The compound of formula (I) can be useful as an inhibitor of the MYST family of lysine acetyltransferases (KAT) for the treatment and / or prevention of hyperproliferative diseases, disorders or conditions, such as cancer. In particular, the compound of formula (I) is useful for the inhibition of KAT6A and KAT6B, which are enzymes that are frequently mutated, overexpressed, amplified and / or translocated in cancer, altering their normal expression, activity and function. The use of the compound of formula (I) in the manufacture of pharmaceutical compositions or for treating cancer is further described (including for treating cancer in combination with other anti-cancer agents). TIFF2025511122000345.tif22165

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 324,619, filed March 28, 2022, U.S. Provisional Patent Application No. 63 / 324,624, filed March 28, 2022, and U.S. Provisional Patent Application No. 63 / 476,826, filed December 22, 2022. The disclosures of each of the above related applications are incorporated herein by reference in their entirety.

[0002] Provided herein are compounds of formula (I). Processes for preparing compounds of formula (I) and intermediates useful in preparing compounds of formula (I) are described herein. Compounds of formula (I) may be useful as inhibitors of the MYST family of lysine acetyltransferases (KAT) for the treatment and / or prevention of hyperproliferative diseases, disorders, or conditions, such as cancer. In particular, compounds of formula (I) are useful for inhibiting KAT6A and KAT6B, enzymes that are frequently mutated, overexpressed, amplified, and / or translocated in cancer, altering their normal expression, activity, and function. Use of compounds of formula (I) in the manufacture of pharmaceutical compositions or for treating cancer (including in combination with other anticancer agents) is further described. [Background technology]

[0003] Epigenetic regulation is a complex, dynamic process critical to cellular physiology and control of gene expression, cell cycle progression, cell proliferation rate, and stem cell maintenance and differentiation (Allis and Jenuwein, Nature Reviews Genetics 2016, Vol. 17, pp. 487-500). Lysine acetyltransferases (KATs) and histone deacetylases (HDACs) play important roles in epigenetic regulation. KATs are a diverse family of enzymes that acetylate both histones and non-histone proteins. Histones are essential components of the chromatin-DNA complex, and their acetylation state is essential for their function (Vernarecci, et al., Epigentics 2009, Vol. 5, pp. 105-111). KATs catalyze the post-translational modification of histones through acetylation of the epsilon-amino group of lysines on histone proteins. This acetylation confers an open conformation to chromatin, typically promoting gene transcription.

[0004] One important family of KAT enzymes is known as the MYST family, which consists of five members, including KAT6A (also known as MOZ or MYST3), KAT6B (also known as MORF or MYST4), KAT5 (also known as Tip60), KAT7 (also known as HBO1 or MYST2), and Kat8 (also known as MOF or MYST1) (Wiesel-Motiuk and Assaraf, Drug Resistance Updates 2020, Vol 53, 100729; Wapenaar and Dekker, Clinical Epigenetics 2016, 8:59, 1 (DOI 10.1186 / s13148-016-0225-2), “Wapenaar et al., 2016”). The MYST family of KATs is particularly important in the regulation of the cell cycle (Carrozza, et al., Trends in Genetics 2003, Vol. 19, pp. 321-329).

[0005] Dysregulation of KAT6 protein expression supports tumor progression (Trisciuoglio et al., Emerging role of histone acetyltransferase in stem cells and Cancer. Stem Cells Int. Volume 2018, Article ID 8908751 (https: / / doi.org / 10.1155 / 2018 / 8908751)). Dysregulation of KAT6A through gene amplification, overexpression, or mutation has been documented in multiple cancer types, including breast, lung, ovarian, colon, and rectal adenocarcinoma, and cervix (Huang, et al., Molecular and Cellular Biology 2016, Vol. 63, pp. 1900-1907; Zack, et al., Nature Genetics 2013, Vol. 45, pp. 1134-1140). The locus containing the KAT6A gene (8p11-p12 amplicon) has been reported to be the 12th most commonly amplified region of the genome across all cancer types (Zack, et al., 2013). In acute myeloid leukemia (AML), it has been documented that recurrent oncogenic fusions of KAT6A can induce transformation to a malignant state (Sheikh, et al., Blood 2015, Vol. 125, pp. 1910-1921). Translocations of KAT6A and fusions to its partners, such as CBP, p300, TIF2, and NCOA3, are known to result in aggressive forms of AML (Sheikh, et al., 2015).

[0006] A key aspect of the catalytic mechanism of the KAT family of enzymes is the acetylation of lysine residues using the cofactor Ac-CoA as the acetyl donor. One possible catalytic mechanism is the stepwise transfer of an acetyl group from acetyl coenzyme A (Ac-CoA) to transiently form an acetyl-enzyme intermediate. This acetyl-enzyme intermediate is the source of the acetyl group that is subsequently transferred to a substrate, typically a lysine on a histone (Wapenaar et al., 2016). In the MYST family of KATs, there is a conserved cysteine ​​that is transiently acylated as part of the catalytic cycle, as indicated by the arrow below. Amino acid sequence alignment of the vicinity of the Ac-CoA binding site of the MYST family of KATs [ka] In one embodiment, the present disclosure provides compounds that can covalently bind to this conserved cysteine.

[0007] Enzyme inhibitors that covalently interact with conserved cysteines at or near the active site of enzymes are an important therapeutic modality. Therapeutic agents that react covalently and specifically to form covalent adducts with active site cysteines offer potential advantages in efficacy, potentially lower doses, and increased duration of target engagement, resulting in reduced dosing frequency.

[0008] In addition to the role that KATs play in epigenetic regulation, they also acetylate nonhistone proteins (Glozak, et al., 2005; Das and Kundu, 2008). Through modifying the acetylation status of nonhistone proteins, KATs are involved in regulating protein function and stability, protein-protein and protein-DNA interactions, and the control of enzyme activity (Glozak, et al., Gene 2005, Vol. 363, pp. 15-23; Das and Kundu, IUBMB Life 2005, Vol. 57, pp. 137-148).

[0009] Provided herein are compounds of formula (I) that can inhibit the MYST family of lysine acetyltransferases. The compounds described in this disclosure inhibit MYST family members, including KAT6A. In some embodiments, inhibition is via covalent modification of a cysteine ​​residue at the Ac-CoA binding site. The compounds described herein are useful for the treatment of cancers, including breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, uterine / cervical cancer, and leukemia. The compounds of formula I can be used as single agents or in combination with standard of care treatments for specific cancers. Summary of the Invention

[0010] Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in treating conditions, diseases, or disorders by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, including hyperproliferative disorders and cancer.

[0011] In one embodiment, a compound of formula (I): [ka] (In the formula, R 1 can contain one, two, or three R 1a C3-C8-cycloalkyl optionally substituted with: C3-C8-cycloalkyl-C1-C6 alkyl, where C3-C8-cycloalkyl is optionally substituted with 1, 2 or 3 R 1a C-C-cycloalkyl-C-C alkyl optionally substituted with one, two, or three R 1b phenyl optionally substituted with one, two, or three R 1b phenyl-C1-C6 alkyl optionally substituted with one, two, or three R 1b naphthyl optionally substituted with one, two, or three R 1b 5- or 6-membered monocyclic heteroaryl optionally substituted with one, two, or three R 1bis an 8-10 membered bicyclic heteroaryl optionally substituted with Each R 1a are independently selected from hydrogen, halo, C1-C6 alkoxy, and C3-C8-cycloalkyloxy; Each R 1b is hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxyalkyloxy, -O-alkylene-NR 1b1 R 1b4 , -O-alkylene-C(O)OR 1b1 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , [ka] , cyano, -(CH2) 0-2 C(O)-OR 1b1 , -(CH2) 0-2 C(O)NR 1b1 R 1b2 , -(CH2) 0-2 NR 1b1 C(O)R 1b3 , -(CH2) 0-2 OH, and C3-C8-cycloalkyloxy; R 1b1 is hydrogen or C1-C6 alkyl; R 1b2 is hydrogen or C1-C6 alkyl; R 1b3 is hydrogen or C1-C6 alkyl; R 1b4 is hydrogen, [ka] and; R 2 teeth, [ka] selected from the group consisting of: R 2a is hydrogen or C1-C6 alkyl; Each R 2bare independently hydrogen, halo, -(CH2) 0-2 OH, C1-C3 alkyl, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3, or C3-C8 cycloalkyloxy; Each R 2e are independently hydrogen, —OH, halo, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or C3-C8 cycloalkyloxy; [ka] teeth, [ka] and; For rings (a), (b), and (c), One X 1 is CR 3 and other X 1 N and CR 2b are independently selected from; R 2d is hydrogen, halo, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, or C3-C8-cycloalkyloxy; R 3 is -(CH2) 0-2 Y or -(CH2) 0-2 -LY; L is -L 1 -L 2 -L 3 - and L 1 , L 2 and L 3 are each independently a bond, -CRR-, O, or S(O) 0-2 , C(O) or NR, where each R is independently H or alkyl; Y is R Y and R 2e Y is a 5-membered monocyclic heteroaryl optionally substituted with R Yand one or two R 2e Y is a 6-membered monocyclic aryl or heteroaryl optionally substituted with R Y and one or two R 2e Y is an 8-membered bicyclic heteroaryl optionally substituted with R Y and one, two, or three R 2e Y is a 9-membered bicyclic heteroaryl optionally substituted with R Y and one, two, or three R 2e Y is a 10-membered bicyclic heteroaryl optionally substituted with R Y and one or two R 2e Y is an 8- or 9-membered bicyclic heterocycle optionally substituted with R Y and one or two R 2e Y is a 4-9 membered monocyclic or bicyclic heterocycloalkyl optionally substituted with [ka] and Y is -(CH2) 0-3 NR 3b R Y or Y is -(CH2) 0-3 NR 3b C(O)R Y and; R Y is -(CH2) 0-3 NR 3b C(O)R 3a , -(CH2) 0-2 NR 3b S(O)2R 3a , -C(O)R 3a , -S(O)2R 3a , -C(O)NR 3b R 3a , -C(O)R 3a C3-C8 heterocycloalkyl substituted with -(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 C(O)R 3a , -(CH2) 0-3 NR3b (C1-C6 alkylene)NR 3b1 S(O)2R 3a , -(CH2) 0-3 NR 3b C(O)(C1-C6 alkylene)NR 3b1 C(O)R 3a , or -(CH2) 0-3 NR 3b C(O)(C1-C6 alkylene)NR 3b1 S(O)2R 3a and R 3a , R 3b and R 3b1 is selected from (i), (ii) or (iii): (i)R 3a , R 3b and R 3b1 One of the groups is selected from group a): C1-C6 alkyl substituted with 1 or 2 independently selected halo; C1-C6 alkyl substituted with cyano; C1-C6 alkyl substituted with fluoroalkoxy; aryloxy or heteroaryloxy (each of which is selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, Cyano, C 3-8 Cycloalkyl or C 3-8 C1-C6 alkyl substituted with (optionally substituted with 1 to 3 substituents independently selected from heterocycloalkyl); C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 3c R 3d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 3c R 3dCHΞCH-CH2-OH; -CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; chloropyridyl; fluoropyridyl; chloropyrazinyl; fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl, difluorophenyl; and monofluorophenyl; R 3a , R 3b and R 3b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; or (ii)R 3a , R 3b and R 3b1 One of the groups a): hydrogen; C1-C6 alkyl; aryloxy or heteroaryloxy (each of which is C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, Cyano, C 3-8 Cycloalkyl or C 3-8 C1-C6 alkyl substituted with 1 to 3 substituents each independently selected from heterocycloalkyl; C2-C6 alkenyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; spirocycloalkyl; pyridyl; pyrimidinyl; and phenyl; R 3a , R 3b and R 3b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; or (iii)R 3a , R 3b and R 3b1 are each independently hydrogen or C1-C6 alkyl; R 3c is hydrogen or C1-C6 alkyl, and R 3d is hydrogen, or C1-C6 alkyl; or R 3c and R 3d form, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; HET1 is C3-C8 heterocycloalkyl; For ring (d), X 2a is O or S; One X 2 is CR 4 and other X 2 N and CR 2b are independently selected from; R 4 is -(CH2) 0-3 NR 4b C(O)R 4a , -(CH2) 0-2 NR 4b S(O)2R 4a , -C(O)R 4a , -C(O)NR 4b R 4a , -NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a , -(CH2) 0-3 NR 4b C(O)(C1-C6 alkylene)NR 4b1 C(O)R 4a , -C(O)NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a , -C(O)-HET1-C(O)R 4a , -C(O)-HET1-NR 4b C(O)R 4a , -(CH2) 0-3 NR 4b C(O)-HET1-C(O)R 4a , -C(O)R 4a C3-C8 heterocycloalkyl substituted with (preferably, the C3-C8 heterocycloalkyl is bonded to ring (d) through a carbon in the C3-C8 heterocycloalkyl ring); or -(CH2) 0-2 HET2-C(O)R 4a and; R 4a , R 4b and R 4b1 is selected from (i), (ii) and (iii): (i)R 4a , R 4band R 4b1 one of which is selected from group a): alkyl substituted with 1 or 2 independently selected halos; C1-C6 alkyl substituted with cyano; C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 4c R 4d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 4c R 4d CHΞCH-CH2-OH; CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; R 4a , R 4b and R 4b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; (ii)R 4a , R 4b and R 4b1 one of the groups a) is selected from group a): hydrogen; alkyl; C2-C6 alkenyl; C3-C8 cycloalkenyl; —C(O)—C3-C8 cycloalkyl; C2-C6 alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; R 4a , R 4b and R 4b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; or (iii)R 4a , R 4b and R 4b1 are each independently hydrogen or C1-C6 alkyl; R 4c is hydrogen or C1-C6 alkyl, and R 4d is hydrogen, or C1-C6 alkyl; or R 4c and R 4dform, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; HET1 is C3-C8 heterocycloalkyl; HET2 has one or two R 2e an 8-, 9-, or 10-membered bicyclic heterocycle optionally substituted with For rings (e) and (f), R 5 is replaced by Z and R 2e is a 5-membered monocyclic heteroaryl optionally substituted with 5 is replaced by Z and R 2e is a 6-membered monocyclic heteroaryl optionally substituted with R 5 is -C(O)N(R 5b )Z;R 5 is replaced by Z and R 2e heterocycloalkyl optionally substituted with R 5 is -(CH2) 0-2 O-HET1-Z; R 5 is -(CH2) 0-2 OZ; Z is -(CH2) 0-3 NR 5b C(O)R 5a , -(CH2) 0-2 NR 5b S(O)2R 5a , -C(O)R 5a , -S(O)2R 5a , -(CH2) 0-3 -C(O)NR 5b R 5a , -(CH2) 0-3 NR 5b (C1-C6 alkylene)NR 5b1 C(O)R 5a , -NR 5b C(O)R 5a C3-C8 heterocycloalkyl substituted with -S(O)R 5a C3-C8 heterocycloalkyl substituted with, or -C(O)R 5a is a C3-C8 heterocycloalkyl substituted with; R 5a , R5b and R 5b1 is selected from (i), (ii) or (iii): (i)R 5a , R 5b and R 5b1 one of which is selected from group a): C1-C6 alkyl substituted with 1 or 2 independently selected halo; C1-C6 alkyl substituted with cyano; C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 5c R 5d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 5c R 5d CHΞCH-CH2-OH; CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl, and R 5a , R 5b and R 5b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; (ii)R 5a , R 5b and R 5b1 one of the groups a) is selected from group a): hydrogen; C1-C6 alkyl; C2-C6 alkenyl; C3-C8 cycloalkenyl; —C(O)—C3-C8 cycloalkyl; C2-C6 alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; R 5a , R 5b and R 5b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; or (iii)R 5a , R 5b and R 5b1 are each independently hydrogen or C1-C6 alkyl; Each R 5c are independently hydrogen or C1-C6 alkyl, and R 5d is hydrogen, or C1-C6 alkyl; or R 5c and R 5d form, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; HET1 is C3-C8 heterocycloalkyl; For ring (g), Q 1 is CR Q1 and Q 2 is N and Q 3 is O; or Q 1 is CR Q1 and Q 2 is O and Q 3 is N; or Q 1 is S and Q 2 is N and Q 3 is N; or Q 1 is N and Q 2 is N and Q 3 is O; or Q 1 is O and Q 2 is N and Q 3 is N;R Q1 is hydrogen, C(O)C1-C6 alkyl, or Cl; R 6 is replaced by Q and R 2e or R is a 5- or 6-membered monocyclic heteroaryl optionally substituted with 6 is Q; Q is -(CH2) 0-3 NR 6b C(O)R 6a , -(CH2) 0-2 NR 6b S(O)2R 6a , -C(O)R 6a , -C(O)NR 6b R 6a , or -C(O)R 6a is a C3-C8 heterocycloalkyl substituted with; R 6a and R6b is selected from (i), (ii) or (iii): (i)R 6a and R 6b one of which is selected from group a): C1-C6 alkyl substituted with 1 or 2 independently selected halo; C1-C6 alkyl substituted with cyano; C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 6c R 6d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)cycloalkyl;Alkynyl;-CHΞCH-CH2-NR 6c R 6d CHΞCH-CH2-OH; CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; R 6a and R 6b the other of which is selected from group b): hydrogen, and C1-C6 alkyl; (ii)R 6a and R 6b one of the groups a): C1-C6 alkyl; C2-C6 alkenyl; C3-C8 cycloalkenyl; -C(O)cycloalkyl; alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; R 6a and R 6b the other of which is selected from group b): hydrogen, and C1-C6 alkyl; or (iii)R 6a and R 6b are each independently hydrogen and C1-C6 alkyl; R 6c is hydrogen or C1-C6 alkyl, and R 6d is hydrogen, or C1-C6 alkyl; or R 6c and R 6dform, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; Each R 7 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0012] In one embodiment, a compound of formula (I): [ka] (In the formula, R 1 can contain one, two, or three R 1a C3-C8-cycloalkyl optionally substituted with: C3-C8-cycloalkyl-C1-C6 alkyl, where C3-C8-cycloalkyl is optionally substituted with 1, 2 or 3 R 1a C-C-cycloalkyl-C-C alkyl optionally substituted with one, two, or three R 1b phenyl optionally substituted with one, two, or three R 1b phenyl-C1-C6 alkyl optionally substituted with one, two, or three R 1b naphthyl optionally substituted with one, two, or three R 1b a 5- or 6-membered monocyclic heteroaryl optionally substituted with one, two, or three R 1b is an 8-10 membered bicyclic heteroaryl optionally substituted with Each R 1a are independently selected from hydrogen, halo, C1-C6 alkoxy, and C3-C8-cycloalkyloxy; Each R 1b is hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxyalkyloxy, -O-alkylene-NR 1b1 R 1b4 , -O-alkylene-C(O)OR 1b1 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , [ka] , cyano, -(CH2) 0-2 C(O)-OR 1b1 , -(CH2) 0-2 C(O)NR 1b1 R 1b2 , -(CH2) 0-2 NR 1b1 C(O)R 1b3 , -(CH2) 0-2 OH, and C3-C8-cycloalkyloxy; R 1b1 is hydrogen or C1-C6 alkyl; R 1b2 is hydrogen or C1-C6 alkyl; R 1b3 is hydrogen or C1-C6 alkyl; R 1b4 is hydrogen, [ka] and; R 2 teeth, [ka] selected from the group consisting of: R 2a is hydrogen or C1-C6 alkyl; Each R 2b are independently hydrogen, halo, -(CH2) 0-2 OH, C1-C3 alkyl, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3, or C3-C8 cycloalkyloxy; Each R 2e are independently hydrogen, —OH, halo, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or C3-C8 cycloalkyloxy; [ka] teeth, [ka] and; For rings (a), (b), and (c), One X 1 is CR 3 and other X 1 N and CR 2b are independently selected from; R 2d is hydrogen, halo, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, or C3-C8-cycloalkyloxy; R 3 is -(CH2) 0-2 Y; Y is R Y and R 2e Y is a 5-membered monocyclic heteroaryl optionally substituted with R Y and one or two R 2e Y is a 6-membered monocyclic aryl or heteroaryl optionally substituted with R Y and one or two R 2e Y is an 8-membered bicyclic heteroaryl optionally substituted with R Y and one, two, or three R 2e Y is a 9-membered bicyclic heteroaryl optionally substituted with R Y and one, two, or three R 2e Y is a 10-membered bicyclic heteroaryl optionally substituted with R Y and one or two R 2e Y is an 8- or 9-membered bicyclic heterocycle optionally substituted with R Y and one or two R 2e Y is a 4-9 membered monocyclic or bicyclic heterocycloalkyl optionally substituted with [ka] and Y is -(CH2)0-3 NR 3b R Y or Y is -(CH2) 0-3 NR 3b C(O)R Y and; R Y is -(CH2) 0-3 NR 3b C(O)R 3a , -(CH2) 0-2 NR 3b S(O)2R 3a , -C(O)R 3a , -S(O)2R 3a , -C(O)NR 3b R 3a , -C(O)R 3a C3-C8 heterocycloalkyl substituted with -(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 C(O)R 3a , -(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 S(O)2R 3a , -(CH2) 0-3 NR 3b C(O)(C1-C6 alkylene)NR 3b1 C(O)R 3a , or -(CH2) 0-3 NR 3b C(O)(C1-C6 alkylene)NR 3b1 S(O)2R 3a and R 3a , R 3b and R 3b1 One of the groups is selected from group a): C1-C6 alkyl substituted with 1 or 2 independently selected halo; C1-C6 alkyl substituted with cyano; C1-C6 alkyl substituted with fluoroalkoxy; aryloxy or heteroaryloxy (each of which is selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, Cyano, C 3-8 Cycloalkyl or C 3-8C1-C6 alkyl substituted with (optionally substituted with 1 to 3 substituents independently selected from heterocycloalkyl); C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 3c R 3d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 3c R 3d CHΞCH-CH2-OH; -CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; chloropyridyl; fluoropyridyl; chloropyrazinyl; fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl, difluorophenyl; and monofluorophenyl; R 3a , R 3b and R 3b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; R 3c is hydrogen or C1-C6 alkyl, and R 3d is hydrogen, or C1-C6 alkyl; or R 3c and R 3d form, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; HET1 is C3-C8 heterocycloalkyl; For ring (d), X 2a is O or S; One X 2 is CR 4 and other X 2 N and CR 2b are independently selected from; R 4 is -(CH2) 0-3 NR 4b C(O)R 4a , -(CH2) 0-2 NR 4b S(O)2R4a , -C(O)R 4a , -C(O)NR 4b R 4a , -NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a , -(CH2) 0-3 NR 4b C(O)(C1-C6 alkylene)NR 4b1 C(O)R 4a , -C(O)NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a , -C(O)-HET1-C(O)R 4a , -C(O)-HET1-NR 4b C(O)R 4a , -(CH2) 0-3 NR 4b C(O)-HET1-C(O)R 4a , -C(O)R 4a C3-C8 heterocycloalkyl substituted with (preferably, the C3-C8 heterocycloalkyl is bonded to ring (d) through a carbon in the C3-C8 heterocycloalkyl ring); or -(CH2) 0-2 HET2-C(O)R 4a and; R 4a , R 4b and R 4b1 one of which is selected from group a): alkyl substituted with 1 or 2 independently selected halos; C1-C6 alkyl substituted with cyano; C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 4c R 4d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 4c R 4dCHΞCH-CH2-OH; CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; R 4a , R 4b and R 4b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; R 4c is hydrogen or C1-C6 alkyl, and R 4d is hydrogen, or C1-C6 alkyl; or R 4c and R 4d form, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; HET1 is C3-C8 heterocycloalkyl; HET2 has one or two R 2e an 8-, 9-, or 10-membered bicyclic heterocycle optionally substituted with For rings (e) and (f), R 5 is replaced by Z and R 2e is a 5-membered monocyclic heteroaryl optionally substituted with 5 is replaced by Z and R 2e is a 6-membered monocyclic heteroaryl optionally substituted with R 5 is -C(O)N(R 5b )Z;R 5 is replaced by Z and R 2e heterocycloalkyl optionally substituted with R 5 is -(CH2) 0-2 O-HET1-Z; R 5 is -(CH2) 0-2 OZ; Z is -(CH2) 0-3 NR 5b C(O)R 5a , -(CH2) 0-2 NR5b S(O)2R 5a , -C(O)R 5a , -S(O)2R 5a , -(CH2) 0-3 -C(O)NR 5b R 5a , -(CH2) 0-3 NR 5b (C1-C6 alkylene)NR 5b1 C(O)R 5a , -NR 5b C(O)R 5a C3-C8 heterocycloalkyl substituted with -S(O)R 5a C3-C8 heterocycloalkyl substituted with, or -C(O)R 5a is a C3-C8 heterocycloalkyl substituted with; R 5a , R 5b and R 5b1 one of which is selected from group a): C1-C6 alkyl substituted with 1 or 2 independently selected halo; C1-C6 alkyl substituted with cyano; C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 5c R 5d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 5c R 5d CHΞCH-CH2-OH; CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl, R 5a , R 5b and R 5b1 the other of which is selected from group b): hydrogen, and C1-C6 alkyl; Each R 5c are independently hydrogen or C1-C6 alkyl, and R5d is hydrogen, or C1-C6 alkyl; or R 5c and R 5d form, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; HET1 is C3-C8 heterocycloalkyl; For ring (g), Q 1 is CR Q1 and Q 2 is N and Q 3 is O; or Q 1 is CR Q1 and Q 2 is O and Q 3 is N; or Q 1 is S and Q 2 is N and Q 3 is N; or Q 1 is N and Q 2 is N and Q 3 is O; or Q 1 is O and Q 2 is N and Q 3 is N;R Q1 is hydrogen, C(O)C1-C6 alkyl, or Cl; R 6 is replaced by Q and R 2e or R is a 5- or 6-membered monocyclic heteroaryl optionally substituted with 6 is Q; Q is -(CH2) 0-3 NR 6b C(O)R 6a , -(CH2) 0-2 NR 6b S(O)2R 6a , -C(O)R 6a , -C(O)NR 6b R 6a , or -C(O)R 6a is a C3-C8 heterocycloalkyl substituted with; R 6a and R 6bone of which is selected from group a): C1-C6 alkyl substituted with 1 or 2 independently selected halo; C1-C6 alkyl substituted with cyano; C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 6c R 6d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)cycloalkyl;Alkynyl;-CHΞCH-CH2-NR 6c R 6d CHΞCH-CH2-OH; CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; R 6a and R 6b the other of which is selected from group b): hydrogen, and C1-C6 alkyl; R 6c is hydrogen or C1-C6 alkyl, and R 6d is hydrogen, or C1-C6 alkyl; or R 6c and R 6d form, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; Each R 7 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0013] In another aspect, compounds are provided that contain alkenyl- or alkynyl-containing electrophilic groups capable of irreversibly and / or covalently binding to KAT6A or KAT6B, including other electrophilic groups such as nitriles and halomethyl ketones.

[0014] In one embodiment, a compound of formula (I): [ka] (In the formula, R 1 can contain one, two, or three R 1a C3-C8-cycloalkyl optionally substituted with one, two or three R 1a C-C-cycloalkylalkyl optionally substituted with one, two or three R 1b phenyl optionally substituted with one, two, or three R 1b naphthyl optionally substituted with one, two, or three R 1b a 5- or 6-membered monocyclic heteroaryl optionally substituted with 1b is an 8-10 membered bicyclic heteroaryl optionally substituted with Each R 1a are independently selected from H, halo, C1-C6 alkoxy, and C3-C8-cycloalkyloxy; Each R 1b are independently selected from H, halo, C1-C6 alkoxy, cyano, and C3-C8-cycloalkyloxy; R 2 teeth, [ka] selected from the group consisting of: For ring (a), R 2b is hydrogen or C1-C6 alkyl; One X 1 is C(CH2R 2c ) and the other two X 1 N and CR 2e are independently selected from; R 2c is one or two R 2c1 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R2c1 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with R 2c can contain one, two, or three R 2c1 or R 2c can contain one, two, or three R 2c1 is a 10-membered bicyclic heteroaryl optionally substituted with Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, -CN, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -(CH2) 0-1 NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; For ring (b), One X 1 is C(CH2R 2c ) and the other two X 1 N and CR 2e are independently selected from; R 2c is R 2c2 and R 2c3 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c is R 2c2 and R 2c3 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c is R 2c2 and one or two R 2c3is a 6-membered monocyclic heteroaryl optionally substituted with R 2c is R 2c2 and one or two R 2c3 or R 2c can contain one, two, or three R 2c1 is a 10-membered bicyclic heteroaryl optionally substituted with R 2c2 is hydrogen, C1-C6 alkylcarbonyl, -CN, -CH2NH2, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CH2NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; R 2c3 are independently H, halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyloxy; Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -CN, -CH2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CH2NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; For ring (c), One X 1 is C(CH2R 2c ) and the other two X 1 N and CR 2e are independently selected from; [ka] teeth, [ka] and; R 2c is one or two R 2c1 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with R 2c can contain one, two, or three R 2c1 or R 2c can contain one, two, or three R 2c1 is a 10-membered bicyclic heteroaryl optionally substituted with Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, -CN, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -CH2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CH2NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; R 2d is halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8-cycloalkyloxy; Each R 2e are independently hydrogen, halo, C1-C3 alkyl, cyclopropyl, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, or -OCF3); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0015] In another aspect, the present invention provides a compound comprising R 2 NH2 (Formula A) R 2 teeth, [ka] selected from the group consisting of: For ring (a), R 2b is hydrogen or C1-C6 alkyl; One X 1 is C(CH2R 2c ) and the other two X 1 N and CR 2e are independently selected from; R 2c is one or two R 2c1 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with R 2c can contain one, two, or three R 2c1 or R 2c can contain one, two, or three R 2c1 is a 10-membered bicyclic heteroaryl optionally substituted with Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, -CN, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -(CH2) 0-1 NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; For ring (b), One X 1 is C(CH2R 2c ) and the other two X 1 N and CR 2e are independently selected from; R 2c is R 2c2 and R 2c3 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c is R 2c2 and one or two R 2c3 is a 6-membered monocyclic heteroaryl optionally substituted with R 2c is R 2c2 and one or two R 2c3 or R 2c can contain one, two, or three R 2c1 is a 10-membered bicyclic heteroaryl optionally substituted with R 2c2 is C1-C6 alkylcarbonyl, -CN, -(CH2) 0-1 NH2, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; R 2c3are independently H, halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyloxy; Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -CN, -(CH2) 0-1 NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; For ring (c), One X 1 is C(CH2R 2c ) and the other two X 1 N and CR 2e are independently selected from; [ka] teeth, [ka] and; R 2c is one or two R 2c1 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with R 2c can contain one, two, or three R 2c1 or R 2c can contain one, two, or three R 2c1is a 10-membered bicyclic heteroaryl optionally substituted with Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, -CN, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -(CH2) 0-1 NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; R 2d is halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8-cycloalkyloxy; Each R 2e are independently hydrogen, halo, C1-C3 alkyl, cyclopropyl, CHF2, CF3, C1-C4 alkoxy, -OCHF2, or -OCF3); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0016] In another aspect, provided herein are pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating disorders by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, comprising a therapeutically effective amount of a compound provided herein, e.g., a compound of some or any of the embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), and a specific compound, and a pharmaceutically acceptable carrier thereof.

[0017] In another aspect, provided herein are methods for treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, comprising: a) administering to a subject a therapeutically effective amount of a compound provided herein, e.g., a compound of some or any of the embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), and certain compounds or stereoisomers thereof, stereoisomers thereof. or b) administering a therapeutically effective amount of a compound provided herein, e.g., a compound of some or any embodiment, Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), and a composition comprising a particular compound or a stereoisomer, mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0018] In another aspect, provided herein are methods for preparing compounds of formula (I), and particular compounds or stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof, comprising: [ka] or a salt thereof (wherein R 1 can contain one, two, or three R 1a C3-C8-cycloalkyl optionally substituted with: C3-C8-cycloalkyl-C1-C6 alkyl, where C3-C8-cycloalkyl is optionally substituted with 1, 2 or 3 R 1a C-C-cycloalkyl-C-C alkyl optionally substituted with one, two, or three R 1bphenyl optionally substituted with one, two, or three R 1b naphthyl optionally substituted with one, two, or three R 1b 5- or 6-membered monocyclic heteroaryl optionally substituted with one, two, or three R 1b is an 8-10 membered bicyclic heteroaryl optionally substituted with Each R 1a are independently selected from hydrogen, halo, C1-C6 alkoxy, and C3-C8-cycloalkyloxy; Each R 1b is hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxyalkyloxy, -O-alkylene-NR 1b1 R 1b4 , -O-alkylene-C(O)OR 1b1 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , [ka] , cyano, -(CH2) 0-2 C(O)OR 1b1 , -(CH2) 0-2 C(O)NR 1b2 R 1b3 , -(CH2) 0-2 NRc(O)R, -(CH2) 0-2 OH, and C3-C8-cycloalkyloxy; R 1b1 is hydrogen or C1-C6 alkyl; R 1b2 is hydrogen or C1-C6 alkyl; R 1b3 is hydrogen or C1-C6 alkyl; R 1b4 is hydrogen, [ka] and; a)R 2x teeth, [ka] and R 2a is hydrogen or C1-C6 alkyl; Each R 2b are independently hydrogen, halo, C1-C3 alkyl, -(CH2) 0-2 OH, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3, or C3-C8 cycloalkyloxy; Each R 2e are independently hydrogen, —OH, halo, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or C3-C8 cycloalkyloxy; [ka] teeth, [ka] and; One X 1 is CR 3 and other X 1 N and CR 2b are independently selected from; R 2d is hydrogen, halo, C1-C6 alkyl, C 1-6 cycloalkyl, C1-C6 alkoxy, or C3-C8-cycloalkyloxy; R 3 is -(CH2) 0-2 Y x or -(CH2) 0-2 -LY x and; L is -L 1 -L 2 -L 3 - and L 1 , L 2 and L 3 are each independently a bond, -CRR-, O, or S(O) 0-2 , C(O) or NR, where each R is independently H or alkyl; Y x is R 2e is a 5-membered monocyclic heteroaryl optionally substituted with x is one or two R 2e an 8-membered bicyclic heteroaryl optionally substituted with x can contain one, two, or three R 2e is a 9-membered bicyclic heteroaryl optionally substituted with x can contain one, two, or three R 2e is a 10-membered bicyclic heteroaryl optionally substituted with x is one or two R 2e an 8- or 9-membered bicyclic heterocycle optionally substituted with x is one or two R 2e or Y is a 4- to 9-membered monocyclic or bicyclic heterocycloalkyl optionally substituted with x teeth, [ka] and; a1) Y has a substitutable nitrogen included as a ring atom in a 5-membered monocyclic heteroaryl, an 8-membered bicyclic heteroaryl, a 9-membered bicyclic heteroaryl, a 10-membered bicyclic heteroaryl, and an 8- or 9-membered bicyclic heterocycle; or a2) Y is -(CH2) 0-2 -NH2, or -(CH2) 0-2 substituted with -NH-(C1-C6 alkylene)NH2; The group in a1) is of the formula LG-C(O)R 3a or The group in a2) is of the formula LG-C(O)R 3a , LG-S(O)2R 3a ;LG-C(O)(C1-C6 alkylene)NR 3b C(O)R 3a , LG-C(O)(C1-C6 alkylene)NR 3b S(O)2R 3a is treated with an intermediate of LG is a leaving group such as halo or OH that has been activated with a reagent such as HATU, HBTU, T3P, EDCI / HOBt or other agent known to one skilled in the art; R 3a and R 3b one of which is selected from group a): C1-C6 alkyl substituted with 1 or 2 independently selected halo; C1-C6 alkyl substituted with cyano; C1-C6 alkyl substituted with fluoroalkoxy; aryloxy or heteroaryloxy (each of which is selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, Cyano, C 3-8 Cycloalkyl or C 3-8 C1-C6 alkyl substituted with (which may be further substituted with 1 to 3 substituents independently selected from heterocycloalkyl); C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 3c R 3d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 3c R 3d -CHΞCH-CH2-O-C1-C6 alkyl; -CHΞCH-CH2-O-C1-C6 alkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; R 3a and R 3b the other of which is selected from group b): hydrogen, and C1-C6 alkyl; R 3c is hydrogen or C1-C6 alkyl, and R 3d is hydrogen, or C1-C6 alkyl; or R 3c and R 3dform together with the nitrogen to which they are attached a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; or b)R 2x teeth, [ka] and Each R 2b are independently hydrogen, halo, C1-C3 alkyl, -(CH2) 0-2 OH, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3, or C3-C8 cycloalkyloxy; Each R 2e are independently hydrogen, halo, —OH, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or C3-C8 cycloalkyloxy; X 2a is O or S; One X 2 is CR 4x and other X 2 N and CR 2b are independently selected from; b1)R 4x is -(CH2) 0-2 HET2;R 4x is -C(O)-HET1; R 4x is -(CH2) 0-3 NR 4b C(O)-HET1; or R 4x is C3-C8 heterocycloalkyl; HET2 is one or two R 2e an 8-, 9-, or 10-membered bicyclic heterocycle optionally substituted with and having a substitutable nitrogen included as a ring atom, and HET1 is a C3-C8 heterocycloalkyl including a substitutable nitrogen as a ring atom in HET1; b2)R 4x is -(CH2) 0-2 NH2; R 4x is -NR 4b (C1-C6 alkylene)NH2; R4x is -(CH2) 0-3 NR 4b C(O)(C1-C6 alkylene)NH2; R 4x is -C(O)NR 4b (C1-C6 alkylene)NH2; or R 4x is -C(O)-HET1-NH2; The group in b1) is of the formula LG-C(O)R 4a or The group in b2) is of the formula LG-C(O)R 4a or LG-S(O)2R 4a treated with intermediates; LG is a leaving group such as halo or OH that has been activated with a reagent such as HATU, HBTU, T3P, EDCI / HOBt or other agent known to one skilled in the art; R 4a is alkyl substituted with one or two independently selected halo; C1-C6 alkyl substituted with cyano; C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 4c R 4d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 4c R 4d CHΞCH-CH2-OH; CHΞCH-CH2-O-C1-C6 alkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl; R 4b is hydrogen or C1-C6 alkyl; R 4c is hydrogen or C1-C6 alkyl, and R 4d is hydrogen, or C1-C6 alkyl; or R 4c and R 4dform, together with the nitrogen to which they are attached, a 3- to 8-membered saturated ring, the other 2-7 ring members being carbon; c)R 2x teeth, [ka] and; Each R 2b are independently hydrogen, halo, C1-C3 alkyl, -(CH2) 0-2 OH, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3, or C3-C8 cycloalkyloxy; R 5x is Z x and R 2e is a 5-membered monocyclic heteroaryl optionally substituted with 5x is Z x and R 2e is a 6-membered monocyclic heteroaryl optionally substituted with R 5x is -C(O)LG 1 ;R 5x is -(CH2) 0-2 O-HET1; or R 5x is -(CH2) 0-2 O-(CH2) 0-3 NH2;LG 1 is a leaving group such as halo or OH that has been activated with a reagent such as HATU, HBTU, T3P, EDCI / HOBt or other agent known to one of skill in the art; c1)Z x is -(CH2) 0-3 NH2; or Z x is -(CH2) 0-3 NR 5b (C1-C6 alkylene)NH2; c2)Z x is a C3-C8 heterocycloalkyl containing a substitutable nitrogen as a ring atom; In c1) the group is of the formula LG 2 -C(O)R 5a or LG 2 -S(O)2R 5a treated with intermediates; In c2) the group is of the formula LG 2 -C(O)R 5a treated with intermediates; LG 2 is a leaving group such as halo or OH that has been activated with a reagent such as HATU, HBTU, T3P, EDCI / HOBt or other agent known to one of skill in the art; R 5a is C1-C6 alkyl substituted with one or two independently selected halo; C1-C6 alkyl substituted with cyano; C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 5c R 5d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 5c R 5d ;CHΞCH-CH2-OH;CHΞCH-CH2-O-C1-C6 alkyl;chloropyridyl;fluoropyridyl;chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl;tetrafluorophenyl;trifluorophenyl;difluorophenyl;or monofluorophenyl; R 5b is hydrogen or C1-C6 alkyl; Each R 5c are independently hydrogen or C1-C6 alkyl, and R 5d is hydrogen, or C1-C6 alkyl; or R 5c and R 5d form a 3- to 8-membered saturated ring together with the nitrogen to which they are attached, the other 2-7 ring members being carbon) to produce a compound of formula (I) and a specified compound; or a stereoisomer, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, provided herein are methods for preparing compounds of Formula (I), (Ih), (Ii), and (Ij), and specific compounds or stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts thereof, comprising the steps of: 2 NH2 (Formula A) to R 1 and treating with S(O)X, where X is halo, preferably chloro, using coupling conditions described herein or known to those skilled in the art. In some or any embodiments, halo is bromo. [Brief explanation of the drawings]

[0020] [Figure 1] The results of reversibility / irreversibility studies for compounds provided herein are presented (see Biological Example 2). DETAILED DESCRIPTION OF THE INVENTION

[0021] definition When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. If there are multiple definitions for terms herein, those in this section prevail unless otherwise stated. Unless otherwise specified, when a term is defined as unsubstituted or substituted, the groups in the list of substituents are themselves unsubstituted. For example, a substituted alkyl group can be substituted with, for example, a cycloalkyl group, and the cycloalkyl group is not further substituted unless otherwise specified.

[0022] Reference herein to "about" a value or parameter includes (and describes) variations on that value or parameter itself. For example, a reference to "about X" includes the description of "X."

[0023] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in connection with a temperature, dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. Specifically, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified dose, amount, or weight percent.

[0024] The terms "a" or "an" as used herein mean one or more, unless the context clearly indicates otherwise.

[0025] "Alkyl" refers to a linear or branched hydrocarbon group having 1 to 8 carbon atoms. "Lower alkyl" or "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. In some embodiments, lower alkyl includes methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like. A "C0" alkyl (as in "C0-C6-alkyl") is a covalent bond. "C6 alkyl" refers, for example, to n-hexyl, iso-hexyl, and the like.

[0026] "Alkoxy" refers to an -OR group, where R is an alkyl group, as defined herein. In some embodiments, R is C1-C6 alkyl.

[0027] "Alkyloxyalkyl" means an alkyl group, as defined herein, substituted with an alkoxy, as defined herein. In some embodiments, the alkyloxyalkyl is -CH2OCH3.

[0028] "Alkenyl" means a straight-chain or branched hydrocarbon radical having 2 to 8 carbon atoms and at least one double bond, including ethenyl, propen-1-yl, propen-2-yl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl, etc. "Lower alkenyl" means an alkenyl group having 2 to 6 carbon atoms.

[0029] "Alkynyl" means a straight or branched chain hydrocarbon radical having 2 to 8 carbon atoms and at least one triple bond, and includes ethynyl, propynyl, butynyl, pentyn-2-yl, etc. "Lower alkynyl" means an alkynyl group having 2 to 6 carbon atoms.

[0030] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon atoms. Cycloalkyls can be saturated or partially unsaturated, but cannot contain aromatic rings. In some embodiments, cycloalkyls are C3-C8 cycloalkyls. In some embodiments, cycloalkyls are C3-C6 cycloalkyls. In some embodiments, cycloalkyls include fused, bridged, and spiro ring systems. In some embodiments, cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0031] "Cycloalkylalkyl" means an alkyl group substituted with one or two cycloalkyl groups, as defined herein. In some embodiments, cycloalkylalkyl includes cyclopropylmethyl, 2-cyclobutyl-ethyl, and the like.

[0032] "Cyano-substituted spirocycloalkyl" refers to [ka] In some embodiments, the cyano-substituted spirocycloalkyl is [ka] In some embodiments, the cyano-substituted spirocycloalkyl is: [ka] In some embodiments, the cyano-substituted spirocycloalkyl is: [ka] is.

[0033] "Cycloalkyloxy" means an -OR radical where R is cycloalkyl as defined herein.

[0034] "Cycloalkenyl" means a cycloalkyl as defined herein containing at least one double bond, but wherein the ring is not aromatic.

[0035] "Haloalkyl" means an alkyl group, as defined herein, substituted with one or more halogen atoms, e.g., 1, 2, 3, 4, or 5 halo atoms. Representative examples include 2,2-difluoroethyl, trifluoromethyl, 2-chloro-1-fluoroethyl, and the like.

[0036] "Haloalkoxy" refers to an -OR' group where R' is haloalkyl as defined herein, in some embodiments, haloalkoxy is trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

[0037] "Heteroaryl" refers to a monocyclic or bicyclic monovalent aromatic radical of 5 to 10 ring atoms containing one or more heteroatoms independently selected from oxygen, nitrogen, and sulfur, e.g., 1, 2, or 3 ring heteroatoms, with the remaining ring atoms being carbon. Unless otherwise stated, the point of attachment may be at any atom of any ring of the heteroaryl group, valence rules permitting. In some embodiments, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, tetrazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrazolyl, and the like, and N-oxides thereof. When the heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaryl. "Heteroaryl," as used herein, also includes "8- to 10-membered bicyclic heteroaryl."

[0038] "Heterocycloalkyl," as used herein, refers to a saturated or partially unsaturated (but not aromatic) monocyclic radical of 3 to 9 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused bicyclic radical of 5 to 12 ring atoms, in which one or more heteroatoms, e.g., 1, 2, 3, or 4 ring heteroatoms, are selected from the group consisting of -O-, -S(O) ... n -(n is 0, 1, or 2), -N=, -N(R y )-(wherein, R y For example, -C(O)R 4aand similar groups), with the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Fused bicyclic radicals include bridged and spirocyclic ring systems. Unless otherwise stated, the point of attachment of a group may be located on any atom of any ring within the radical, valence rules permitting. In particular, when the point of attachment is located on a nitrogen atom, R y is absent. More specifically, the term heterocycloalkyl includes azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, iridyl, methyl ... Midazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, octahydropyrrolo[3,4-c]pyrrolyl, (3aR,6aS)-hexahydro-1H-5λ 2 -pyrrolo[3,4-c]pyrrolyl, and tetrahydropyranyl, and their N-oxides.

[0039] "Bicyclic heterocyclic," as used herein, unless otherwise specified, refers to a bicyclic ring system containing one non-aromatic ring and one aromatic ring, wherein any one or more (in some or any embodiments, 1, 2, 3, or 4) of the ring atoms in the bicyclic ring system are O, S(O), 0-2, and N, with the remaining ring atoms being carbon, and bicyclic heterocycles refer to those containing 8 to 12 ring atoms (in some embodiments, 8, 9, or 10 ring atoms). The term "bicyclic heterocycle" does not include fully aromatic bicyclic rings, i.e., benzisoxazole, indazole, etc. In some or any embodiments, bicyclic heterocyclic groups have 8 ring atoms. In some or any embodiments, bicyclic heterocyclic groups have 9 ring atoms. In some or any embodiments, bicyclic heterocyclic rings contain 1, 2, or 3 heteroatom(s) independently selected from nitrogen and oxygen. In some or any embodiments, bicyclic heterocyclic rings contain 1 or 2 heteroatom(s) that are oxygen. In some or any embodiments, the bicyclic heterocyclic ring contains one, two, or three heteroatom(s) that are nitrogen (which can be substituted as described in any aspect or embodiment described herein). In some or any embodiments, the bicyclic heterocyclic ring contains one heteroatom in the non-aromatic ring, or one or two heteroatoms in the aromatic ring, or two heteroatoms in the aromatic ring, or two heteroatoms, one in the aromatic ring and the other in the non-aromatic ring, or two heteroatoms in the aromatic ring and one heteroatom in the non-aromatic ring. In some or any embodiments, the bicyclic heterocyclic group can be a bridged or unbridged and / or fused or non-fused bicyclic group. One or more of the nitrogen and sulfur atoms can be optionally oxidized, one or more of the nitrogen atoms can be optionally quaternized, and one or more of the carbon atoms can be optionally substituted. [ka] The bicyclic heterocycle may be attached to the main structure at any heteroatom or carbon atom that results in a stable compound. The bicyclic heterocycle may be attached to the main structure through any of its rings, including any aromatic or non-aromatic ring, regardless of whether the ring contains a heteroatom. In some or any embodiment, the bicyclic heterocycle includes a 5-membered heteroaryl group, preferably pyrazolyl, e.g., 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridinyl, or 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinyl, fused to a non-aromatic ring, preferably containing a nitrogen ring atom; in some or any embodiment, the remainder of the compound of formula (I) is a 5-membered heteroaryl group, preferably fused to a non-aromatic ring, preferably containing a nitrogen ring atom, via the 5-membered heteroaryl moiety. 4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-1-yl, 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-1-yl, 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl, 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-1-yl, or 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl. When the bicyclic heterocycle is substituted, it can be substituted at any ring, i.e., at any aromatic or non-aromatic ring contained in the bicyclic heterocycle.In some or any embodiments, bicyclic heterocycles include, but are not limited to, 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, benzofuranonyl, dihydrobenzofuranyl, benzotetrahydrothienyl, 2,2-dioxo-1,3-dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, indolinyl, 2-oxo-indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isoindolinyl, 1-oxo-isoindolinyl, 1,3-dioxo-isoindolinyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout the specification.

[0040] "Hydroxyalkyl," as used herein, unless otherwise specified, refers to an alkyl group, as defined herein, substituted with one, two, or three hydroxy groups, provided that the multiple hydroxy groups are not on the same carbon. In some embodiments, hydroxyalkyl refers to a hydroxy C 1-6 -alkyl. In some embodiments, the hydroxyalkyl is hydroxyethyl.

[0041] "Hydroxyalkyloxy," as used herein, unless otherwise specified, refers to an --OR group, where R is hydroxylalkyl as defined herein. In some embodiments, the hydroxyalkyloxy is hydroxyethyloxy.

[0042] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17 thed., Mack Publishing Company, Easton, PA, 1985 (incorporated herein by reference) or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 (both of which are incorporated herein by reference). It is also understood that a compound may have one or more pharmaceutically acceptable salts associated therewith.

[0043] Examples of pharmaceutically acceptable acid addition salts include those with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and those with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethoxybenzoic acid, ... Examples of suitable carboxylic acids include those formed from benzenesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid.

[0044] Examples of pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Preferred salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0045] The terms "substantially free" or "substantially absent" of a stereoisomer with respect to a composition refers to a composition that comprises at least 85 or 90% by weight, and in certain embodiments 95%, 98%, 99%, or 100% by weight, of the specified stereoisomer of the compound in the composition. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of a stereoisomer.

[0046] Similarly, the term "isolated" with respect to a composition refers to a composition that contains at least 85, 90%, 95%, 98%, 99% to 100% by weight of the specified compound, with the remainder containing other chemical species or stereoisomers.

[0047] The term "solvate," as used herein, unless otherwise specified, refers to a compound provided herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0048] The term "isotopic composition" as used herein refers to the amount of each isotope present for a given atom, unless otherwise specified, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of compounds described herein are meant to represent any stable isotope of that atom. For example, unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen with its natural isotopic composition.

[0049] The term "isotopic enrichment," as used herein, unless otherwise specified, refers to the percentage of incorporation of a particular isotope at a molecule instead of the natural isotopic abundance of that atom. In certain embodiments, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the naturally occurring distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0050] The term "isotopically enriched," as used herein, unless otherwise specified, refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0051] As used herein, "alkyl," "cycloalkyl," and "heterocycloalkyl" groups optionally contain deuterium at one or more positions where hydrogen atoms are present and the deuterium composition of the atom(s) is other than the natural isotopic composition.

[0052] Additionally, as used herein, "alkyl," "cycloalkyl," and "heterocycloalkyl" groups optionally contain carbon-13 in amounts other than its natural isotopic composition.

[0053] As used herein, unless otherwise specified, the term "IC 50 " refers to the amount, concentration or dosage of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures such response.

[0054] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "subject" refer to animals such as mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys, e.g., cynomolgus monkeys, chimpanzees, and humans), and in certain embodiments, humans. In certain embodiments, the subject is a farm animal (e.g., a horse, cow, pig, etc.) or a pet (e.g., a dog or cat). In certain embodiments, the subject is a human.

[0055] "Administration" and variants thereof (in some embodiments, "administering" a compound) with respect to a compound of the present invention means introducing the compound or a prodrug of the compound into the system of an animal in need of treatment. When a compound of the present invention or a prodrug thereof is provided in combination with one or more other active agents (in some embodiments, such as surgery, radiation, and chemotherapy), "administration" and variants thereof are understood to include simultaneous and sequential introduction of the compound or a prodrug thereof and the other agent, respectively.

[0056] A "therapeutically effective amount" is the amount of a compound or composition that, when administered to a patient, is sufficient to effect such treatment for a condition, disease, or disorder, e.g., to ameliorate the symptoms of the disease. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient being treated, etc. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and this disclosure.

[0057] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent(s) that can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes the compounds provided herein. In certain embodiments, a therapeutic agent is an agent that is known to be useful for, or has been used, or is currently being used to treat or prevent a disorder or one or more symptoms thereof.

[0058] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) preventing the occurrence of the disease, disorder, or syndrome in humans, i.e., preventing the development of clinical symptoms of the disease, disorder, or syndrome in an animal that may be exposed to or susceptible to the disease, disorder, or syndrome, but that has not yet experienced or displayed symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., halting its progression (stable disease); and (iii) alleviating the disease, disorder, or syndrome, e.g., alleviating or reducing the symptoms thereof and / or causing regression of the disease, disorder, or syndrome. As known in the art, adjustments for systemic versus localized delivery, age, weight, general health, sex, diet, time of administration, drug interactions, and severity of the condition, disease, or disorder may be necessary and would be ascertainable by one of ordinary skill in the art using routine experimentation. "Treating" or "treatment" of any condition, disease, or disorder refers, in certain embodiments, to ameliorating the condition, disease, or disorder present in a subject. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter, which may be difficult to discern by the subject. In yet another embodiment, "treating" or "treatment" includes modulating the condition, disease, or disorder either physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" includes delaying the onset of the condition, disease, or disorder.

[0059] The terms "inhibiting" and "reducing," or any variants of these terms, include any measurable decrease or complete inhibition to achieve a desired result. For example, there can be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more of activity compared to normal, or any range of reduction derivable therein.

[0060] As used herein, the terms "prophylactic agent" and "prophylactic agents" refer to any agent that can be used in the prevention of a condition, disease, or disorder, or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" includes a compound provided herein. In certain other embodiments, the term "prophylactic agent" does not refer to a compound provided herein. In certain embodiments, a prophylactic agent can be an agent that is known to be useful, or has been used, or is currently being used, to prevent or inhibit the onset, development, progression, and / or severity of a condition, disease, or disorder.

[0061] As used herein, the phrase "prophylactically effective amount" refers to an amount of a therapy (e.g., a prophylactic agent) sufficient to result in the prevention or reduction of the progression, recurrence, or onset of one or more symptoms associated with a condition, disease, or disorder, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).

[0062] compound The embodiments described herein include the compounds described and their pharmaceutically acceptable salt(s), hydrates, solvates, stereoisomers, tautomers, or mixtures.

[0063] In some or any embodiments, the compound is according to Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1). In some or any embodiments, the pharmaceutical composition comprises a compound according to Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1). In some or any embodiments, the method of treating comprises administering a compound according to Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1).

[0064] Embodiment A: In some or any embodiments, the compound is R 1 is C3-C8-cycloalkyl-C1-C6 alkyl; or one, two, or three R 1b is phenyl optionally substituted with; Each R 1b is hydrogen, alkyl, -C(O)OH, -C(O)O(C 1-3 alkyl), halo, and C1-C6 alkoxy; R 2 teeth, [ka] selected from the group consisting of: R 2a is hydrogen; Each R 2b are independently hydrogen, C1-C3 alkyl, or -(CH2) 0-2 OH; Each R 2e is hydrogen; Regarding rings (a) and (b) One X 1 is CR 3 and other X 1 are CH, respectively; R 2d is C1-C3 alkoxy; R 3 is -(CH2) 0-2 Y or -(CH2) 0-2 -LY; L is -L 1 -L 2 -L 3 - and L 1 , L 2 and L 3 are each independently a bond, -CRR-, O, or S(O) 0-2 , C(O) or NR, where each R is independently H or alkyl; Y is R Y Y is a 5-membered monocyclic heteroaryl substituted with R Y or Y is an 8- or 9-membered bicyclic heterocycle substituted with R Y and one or two R 2e is a 4-9 membered monocyclic or bicyclic heterocycloalkyl optionally substituted with R Y is -(CH2) 0-3 NR 3b C(O)R 3a , -(CH2) 0-2 NR 3b S(O)2R 3a , -C(O)R 3a , -S(O)2R 3a , -C(O)NR 3b R 3a , or -C(O)R 3a is a C3-C8 heterocycloalkyl substituted with; R 3a is C1-C6 alkyl substituted with one or two halo; C1-C6 alkyl substituted with fluoroalkoxy; aryloxy or heteroaryloxy (each of which is substituted with halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6Alkoxy, Cyano, C 3-8 Cycloalkyl or C 3-8 C1-C6 alkyl substituted with (which may be further substituted with 1 to 3 substituents independently selected from heterocycloalkyl); C2-C6 alkenyl; C2-C6 alkenyl substituted with cyano; C2-C6 alkenyl substituted with halo; -CH=CH-CH2-NR 3c R 3d -CH=CH-CH2-O-C1-C6 alkyl; tetrafluorophenyl; trifluorophenyl; C2-C6 alkynyl; or -CHΞCH-CH2-NR 3c R 3d and; R 3b and R 3b1 are each independently hydrogen or C1-C6 alkyl; R 3c is hydrogen or C1-C6 alkyl, and R 3d is hydrogen or C1-C6 alkyl; For ring (d), X 2a is O; One X 2 is CR 4 and other X 2 are CH, respectively; R 4 is -(CH2) 0-3 NR 4b C(O)R 4a , -NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a , -(CH2) 0-3 NR 4b C(O)(C1-C6 alkylene)NR 4b C(O)R 4a , -C(O)NR 4b (C1-C6 alkylene)NR 4b C(O)R 4a , -C(O)-HET1-C(O)R 4a , -C(O)-HET1-NR 4b C(O)R 4a , -(CH2) 0-3 NR 4bC(O)-HET1-C(O)R 4a , -C(O)R 4a C3-C8 heterocycloalkyl substituted with (preferably said C3-C8 heterocycloalkyl is bonded to ring (d) via a carbon in the C3-C8 heterocycloalkyl ring); or -(CH2) 0-2 HET2-C(O)R 4a and; R 4a is C2-C6 alkenyl or C2-C6 alkynyl; R 4b and R 4b1 are hydrogen, respectively; HET1 is a C3-C8 heterocycloalkyl containing at least one nitrogen; HET2 is an 8-, 9-, or 10-membered bicyclic heterocycle containing at least one nitrogen ring atom, -C(O)R 4a is attached to HET2 via at least one nitrogen ring atom in the HET2 ring; For rings (e) and (f), R 5 is a 5-membered monocyclic heteroaryl substituted with Z; or R 5 is a 6-membered monocyclic heteroaryl substituted with Z; Z is -(CH2) 0-3 NR 5b C(O)R 5a , -(CH2) 0-3 NR 5b (C1-C6 alkylene)NR 5b1 C(O)R 5a , -S(O)2R 5a C3-C8 heterocycloalkyl substituted with, or C(O)R 5a is a C3-C8 heterocycloalkyl substituted with; R 5a is C2-C6 alkenyl or C2-C6 alkynyl; R 5b and R 5b1 are hydrogen, respectively; For ring (g), Q 1 is CH and Q 2is N and Q 3 is O; R 6 is a 5-membered monocyclic heteroaryl substituted with Q; or R 6 is Q; Q is -(CH2) 0-3 NR 6b C(O)R 6a and; R 6a is C2-C6 alkenyl; R 6b is hydrogen; Each R 7 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0065] Embodiment 1: R 1 is C3-C8-cycloalkylalkyl, which is selected from the group consisting of 1, 2 or 3 R 1a or one, two or three R 1b and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0066] Embodiment 2: R 1 is C3-C8-cycloalkylalkyl, which is selected from the group consisting of 1, 2 or 3 R 1a and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0067] Embodiment 3: R 1 can contain one, two, or three R 1aand all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0068] Embodiment 4: Each R 1a are independently hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0069] Embodiment 5: R 1 can contain one, two, or three R 1b and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0070] Embodiment 6: R 1 can contain one, two, or three R 1b and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0071] Embodiment 7: R 1 can contain one, two, or three R 1b and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0072] Embodiment 8: R 1 can contain one, two, or three R 1b and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0073] Embodiment 9:R 1 is an 8- to 10-membered bicyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0074] Embodiment 10: Each R 1b is hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxyC 1-6 -Alkyloxy, -O-Alkylene-NR 1b1 R 1b4 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , [ka] , -(CH2) 0-2 C(O)OR 1b1 , -(CH2) 0-2 C(O)NR 1b2 R 1b3 , and -(CH2) 0-2 NR 1b1 C(O)R 1b3 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 10, compounds according to formula (I) (including any one of embodiments 1 and 5-9) are provided, wherein each R 1b is hydrogen, halo, C1-C3 alkyl, C1-C3 alkoxy, hydroxyC 1-4 -Alkyloxy, -C(O)OR 1b1 , -C(O)NHR 1b3 , and -NHC(O)R 1b3 In a subembodiment of embodiment 10, each R 1bis independently selected from hydrogen, fluoro, ethyl, methoxy, hydroxyethyloxy, —C(O)OH, —C(O)OCH3, and —C(O)NHCH3. In a subembodiment of embodiment 10 and subembodiments thereof, one or two R 1b In a subembodiment of embodiment 10 and subembodiments thereof, there is provided a compound of formula (I), wherein: 1b In a subembodiment of embodiment 10 and subembodiments thereof, there is provided a compound according to formula (I), wherein: 1b is provided a compound of formula (I),

[0075] Embodiment 11. Formula (Ia): [ka] (In the formula, R 1 , R 2a , R 2d , and X 1 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments of embodiment 1, R 2a is hydrogen or methyl. In some or any embodiments, the formula (Ia-1): [ka] (In the formula, R 1 , R 2a , R 2d , R 3 , and X 1and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments of embodiment 11, R 2a In some or any of embodiments of embodiment 11, compounds of formula (Ia) or (Ia-1) are provided, wherein R is hydrogen or C1-C3 alkyl. 2a In some or any of embodiments of embodiment 11, compounds of formula (Ia) or (Ia-1) are provided, wherein R is hydrogen or methyl. 2a In some or any of embodiments of embodiment 11, compounds of formula (Ia) or (Ia-1) are provided, wherein R is hydrogen. 2a In some or any of embodiments of embodiment 11, compounds of formula (Ia) or (Ia-1) are provided, wherein R is C-C alkyl. 2a In some or any of embodiments of embodiment 11, compounds of formula (Ia) or (Ia-1) are provided, wherein R is C1-C3 alkyl. 2a is methyl.

[0076] Embodiment 12. Formula (Ib): [ka] (In the formula, R 1 , R 2d , and X 1 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein) are provided compounds of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, there is provided a compound of Formula (Ib-1): [ka] (In the formula, R 1 , R 2d , R 3 , and X 1 and other groups as defined in the Summary of the Invention or in some or any embodiment provided herein) are provided: a compound of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0077] Embodiment 13. Formula (Ic): [ka] (In the formula, R 1 , R 2d , X 1 , [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein), compounds of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, there is provided a compound of Formula (Ic-1): [ka] (In the formula, R 1 , R 2d , R 3 , X 1 , [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein), compounds of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, there is provided a compound of Formula (Ic-2): [ka] (In the formula, R 1 , R 2d , R 3 , X 1 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein), a compound of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s); and / or a stereoisomer or mixture of stereoisomers thereof.

[0078] Embodiment 14.R 2d is hydrogen, halo, C1-C6 alkyl, C 1-6 Compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-13) are provided, wherein R is cycloalkyl, C-C alkoxy, or C-C cycloalkyloxy, and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein. In some or any embodiment, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) are provided wherein R 2d is halo, methyl, methoxy, isopropoxy, or cyclopropyloxy. In some or any embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) are those in which R 2d is C1-C6 alkoxy, C1-C3 alkoxy, or methoxy.

[0079] Embodiment 15. Each R 2b Compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-14) are provided, wherein one R is hydrogen and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. 2b is halo, C1-C3 alkyl, -(CH2) 0-2 OH, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3, or C3-C8 cycloalkyloxy; other R 2b are each hydrogen, and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0080] Embodiment 16: One X 1 is CR 3 (Optionally, R 2d (in meta position to X) 1 is N and other X 1 is CR 2b or one X 1 is CR 3 (Optionally, R 2d (in meta position with respect to other X 1 is CR 2b (optionally CH); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-15) are provided.

[0081] Embodiment 16a. One X 1 is CR 3 (Optionally, R 2d(in meta position to X) 1 is N and other X 1 is CR 2b and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-15) are provided. In some or any embodiments, one X 1 is CR 3 (Optionally, R 2d (in meta position to X) 1 is N and other X 1 is CH.

[0082] Embodiment 16b. One X 1 is CR 3 (Optionally, R 2d (in meta position with respect to other X 1 is CR 2b and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-15) are provided. In some or any embodiments, one X 1 is CR 3 (Optionally, R 2d (in meta position with respect to other X 1 is CH.

[0083] Embodiment 17.R 3 is —(CH)—Y; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-16b) are provided.

[0084] Embodiment 17a.R3 is —(CH)—LY; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-16b) are provided.

[0085] Embodiment 17b.R 3 Provided are compounds of Formula (Ib) or (Ib-1) (including any one of Embodiments 1-16b), wherein: is —(CH)—LY; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0086] Embodiment 17c.R 3 is -(CH2)-LY; L is -L 1 -L 2 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, are provided compounds of Formula (Ib) or (Ib-1) (including any one of Embodiments 1-16b).

[0087] Embodiment 17d.R 3 Provided are compounds of Formula (Ib) or (Ib-1) (including any one of Embodiments 1-16b), wherein: is -(CH)-LY; L is -CH-O- or -O-CH-; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0088] Embodiment 18. Y is R Y and R 2eCompounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided, wherein Y is a 5-membered monocyclic heteroaryl (in some embodiments, pyrazolyl) optionally substituted with R; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Y and one or two R 2e and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided, wherein Y is a 6-membered monocyclic aryl optionally substituted with R Y and one or two R 2e and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided, wherein Y is a 6-membered monocyclic heteroaryl optionally substituted with R Y and one or two R 2e and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided, wherein Y is an 8-membered bicyclic heteroaryl optionally substituted with R Y and one, two, or three R 2eand all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided, wherein Y is a 9-membered bicyclic heteroaryl optionally substituted with R Y and one, two, or three R 2e and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided, wherein Y is a 10-membered bicyclic heteroaryl optionally substituted with R Y and one or two R 2e an 8- or 9-membered bicyclic heterocycle optionally substituted with (in some embodiments, [ka] (In the formula, R Y is -C(O)R 3a and R 3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein, compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided. Y is selected from group a) Y and one or two R 2e an 8- or 9-membered bicyclic heterocycle optionally substituted with (in some embodiments, [ka] (In the formula, R Y is -C(O)R 3a and R 3ais selected from group a); and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein, compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided. Y is selected from group a) Y and one or two R 2e an 8- or 9-membered bicyclic heterocycle optionally substituted with (in some embodiments, [ka] (In the formula, R Y is -C(O)R 3a and R 3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein, compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided. Y is selected from group a) Y and one or two R 2e and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided.

[0089] Embodiment 18a.Y is R Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -S(O)2R 3a or -C(O)R 3a (In the formula, R 3a is selected from group a); or Y is R Y and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided, wherein Y is a 4- to 9-membered monocyclic or bicyclic heterocycloalkyl substituted with R Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -C(O)R 3a (In the formula, R 3a is selected from group a); or Y is R Y and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0090] Embodiment 18b.Y is R Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y or Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -S(O)2R 3a or -C(O)R 3a and R 3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein, compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided, wherein Y is selected from group a); Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y or Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -C(O)R 3a and R 3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided.

[0091] Embodiment 18c.Y is R Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -S(O)2R 3a or -C(O)R 3a and R 3a is selected from group a); or Y is R Y and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided, wherein Y is a 4- to 9-membered monocyclic or bicyclic heterocycloalkyl substituted with R Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -C(O)R 3a and R 3a is selected from group a); or Y is R Y and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0092] Embodiment 18d.Y is R Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y or Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -S(O)2R 3a or -C(O)R 3a and R 3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein, compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided, wherein Y is selected from group a); Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y or Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -C(O)R 3a and R 3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided.

[0093] Embodiment 18e.Y is R Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y or Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -S(O)2R 3a or -C(O)R 3a and R3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein, compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided, wherein Y is selected from group a); Y Y is a 5-membered monocyclic heteroaryl substituted with R Y Y is pyrazolyl substituted with R Y or Y is an 8- or 9-membered bicyclic heterocycle substituted with [ka] and R Y is -C(O)R 3a and R 3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-17) are provided.

[0094] Embodiment 18f.Y is [ka] and R Y is -S(O)2R 3a or -C(O)R 3a and R 3a Compounds of formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of embodiments 1-17) are provided, wherein Y is selected from group a); HET1 is 5- to 7-membered heterocycloalkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. [ka] and R Y is -S(O)2R 3a or -C(O)R 3a and R 3a is selected from group a); HET1 is a 5- to 7-membered heterocycloalkyl containing 1 or 2 nitrogen atoms in the ring; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0095] Embodiment 19.R 3b and R 3b1 are each hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0096] Embodiment 20.R Y is -(CH2) 0-3 NHC(O)R 3a , -(CH2) 0-2 NHS(O)2R 3a , -C(O)R 3a , -S(O)2R 3a , -(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 C(O)R 3a , -(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 S(O)2R 3a , -(CH2) 0-3 NR 3b C(O)(C1-C6 alkylene)NR 3b1 C(O)R 3a , -(CH2) 0-3 NR 3bC(O)(C1-C6 alkylene)NR 3b1 S(O)2R 3a , or -C(O)R 3a is a C3-C8 heterocycloalkyl substituted with R 3a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-19) are provided.

[0097] Embodiment 21.R 3a -CH2(halo);-(CH2) 1-2 CN; -CH2OCH(CF3)2; -CH2O(trifluorophenyl); -CH2O(tetrafluorophenyl); halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, Cyano, C 3-8 Cycloalkyl or C 3-8 -CH2O (isoxazolyl) optionally substituted with 1 to 3 substituents each independently selected from heterocycloalkyl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, Cyano, C 3-8 Cycloalkyl or C 3-8 -CHO (pyrimidinyl) optionally substituted with 1 to 3 substituents independently selected from heterocycloalkyl; halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, Cyano, C 3-8 Cycloalkyl or C 3-8-CHO (pyridyl) optionally substituted with 1 to 3 substituents each independently selected from heterocycloalkyl; C-C alkenyl; C-C alkenyl substituted with cyano (in some embodiments, -C(CN)(=CH)); C-C alkenyl substituted with halo (in some embodiments, C-C alkenyl substituted with fluoro); -CH=CH-CH-NR 3c R 3d -CH=CH-CH2-O-C1-C6 alkyl; trifluorophenyl; tetrafluorophenyl; C2-C6 alkynyl; -CHΞCH-CH2-NR 3c R 3d or —CHΞCH—CH—O—C-C alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-20).

[0098] Embodiment 21a.R 3a is a C1-C6 alkyl substituted with one or two independently selected halo; a C1-C6 alkyl substituted with cyano; a C2-C6 alkenyl substituted with cyano (in some embodiments, —C(CN)(═CH2)); a C2-C6 alkenyl substituted with halo (in some embodiments, a C2-C4 alkenyl substituted with fluoro); —CH═CH—CH2—NR 3c R 3d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 3c R 3dProvided are compounds of Formula (Ib) or (Ib-1) (including any one of Embodiments 1-20), wherein: -CHΞCH-CH2-OH; -CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0099] Embodiment 22.R Y teeth, [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-19) are provided.

[0100] Embodiment 22a.R Y teeth, [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-19) are provided.

[0101] Embodiment 23. One R 2b is fluoro, C1-C3 alkyl, -(CH2) 0-2Compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-22) are provided, wherein each R is OH, cyclopropyl, -CHF, -CF, C-C alkoxy, -OCHF, or -OCF, and the others are hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. 2e is hydrogen or —OH; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) (including any one of Embodiments 1-22).

[0102] Embodiment 24. Formula (Id): [ka] (In the formula, R 1 , X 2a , X 2 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein) are provided compounds of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, there is provided a compound of Formula (Id-1): [ka] (In the formula, R 1 , X 2a , R 4 , and X 2and other groups as defined in the Summary of the Invention or in some or any embodiment provided herein) are provided: a compound of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0103] Embodiment 25. Each R 2b Compounds of formula (I), (Id), or (Id-1) (including any one of embodiments 1-10 and 24) are provided, wherein R is hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. 2b is halo, C1-C3 alkyl, -(CH2) 0-2 OH, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3, or C3-C8 cycloalkyloxy; other R 2b are each hydrogen, and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0104] Embodiment 26: In some or any embodiments, one X 1 is CR 3 (Optionally, R 2d (in meta position to X) 1 is N and other X 1 is CR 2b or one X 1 is CR 3 (Optionally, R 2d (in meta position with respect to other X 1 is CR 2b (optionally CH), and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of embodiments 1-10, 24, and 25). In some or all embodiments, one X 1is CR 3 (Optionally, R 2d (in meta position to X) 1 is N and other X 1 is CR 2b and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of embodiments 1-10, 24, and 25). In some or all embodiments, one X 1 is CR 3 (Optionally, R 2d (in meta position to X) 1 is CR 3 (Optionally, R 2d (in meta position with respect to other X 1 is CR 2b (optionally CH), and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of embodiments 1-10, 24, and 25).

[0105] Embodiment 26. One X 2 is CR 4 and other X 2 is CR 2b and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Id), or (Id-1) (including any one of embodiments 1-10, 24, and 25) are provided. In some or all embodiments, one X 2 is CR 4 and other X 2 is CH.

[0106] Embodiment 27.X 2a Compounds of formula (I), (Id), or (Id-1) (including any one of embodiments 1-10, and 24-26) are provided, wherein X is O; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. 2ais S; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Id), or (Id-1) (including any one of Embodiments 1-10, and 24-26).

[0107] Embodiment 28.R 4b and R 4b1 are each hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Id), or (Id-1) (including any one of Embodiments 1-10, and 24-27) are provided.

[0108] Embodiment 29.R 4 is -(CH2) 0-3 NR 4b C(O)R 4a , -(CH2) 0-2 NR 4b S(O)2R 4a , -C(O)R 4a , -C(O)NR 4b R 4a , -NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a , -(CH2) 0-3 NR 4b C(O)(C1-C6 alkylene)NR 4b1 C(O)R 4a , -C(O)NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a , -C(O)-HET1-C(O)R 4a , -C(O)-HET1-NR 4b C(O)R 4a , -(CH2) 0-3 NR 4b C(O)-HET1-C(O)R 4a , -C(O)R 4aC3-C8 heterocycloalkyl substituted with (preferably said C3-C8 heterocycloalkyl is bonded to ring (d) via a carbon in the C3-C8 heterocycloalkyl ring); or -(CH2) 0-2 HET2-C(O)R 4a and;R 4a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Id), or (Id-1) (including any one of Embodiments 1-10, and 24-28) are provided.

[0109] Embodiment 29a.R 4 teeth, -(CH2) 0-2 NHC(O)R 4a ; -NH(C2-C4-alkylene)NHC(O)R 4a ; Nitrogen ring atom in C3-C8 heterocycloalkyl -C(O)R 4a the C3-C8 heterocycloalkyl substituted with (preferably, the C3-C8 heterocycloalkyl is bonded to ring (d) via a carbon in the C3-C8 heterocycloalkyl ring); -C(O)-HET1-C(O)R 4a (In the formula, -C(O)R 4a is attached to the nitrogen ring atom in HET1); -C(O)-HET1-NHC(O)R 4a (wherein —C(O)— is attached to the nitrogen ring atom in HET1); -C(O)NH(C1-C6 alkylene)NHC(O)R 4a ; -(CH2) 0-2 HET2-C(O)R 4a wherein HET2 is a 5-membered monocyclic heteroaryl or an 8- or 9-membered bicyclic heterocyclic ring; 4a is attached to HET2 via the nitrogen ring atom in HET2); -(CH2) 0-3NHC(O)(C1-C6 alkylene)NHC(O)R 4a ;or -(CH2) 0-3 NHC(O)-HET1-C(O)R 4a ; and R 4a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Id), or (Id-1) (including any one of Embodiments 1-10, and 24-28) are provided.

[0110] Embodiment 30.R 4a -CH2(halo);-(CH2) 1-2 CN; C2-C6 alkenyl; C2-C4 alkenyl substituted with cyano; C2-C4 alkenyl substituted with halo; -CH=CH-CH2-NR 4c R 4d -CH=CH-CH2-O-C1-C6 alkyl; C2-C6 alkynyl; -CHΞCH-CH2-NR 4c R 4d or -CHΞCH-CH2-O-C1-C6 alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Provided are compounds of formula (I), (Id), or (Id-1) (including any one of embodiments 1-10, and 24-29a), wherein:

[0111] Embodiment 30a.R 4a is a C1-C6 alkyl substituted with one or two independently selected halo; a C1-C6 alkyl substituted with cyano; a C2-C6 alkenyl substituted with cyano (in some embodiments, —C(CN)(═CH2)); a C2-C6 alkenyl substituted with halo (in some embodiments, a C2-C4 alkenyl substituted with fluoro); —CH═CH—CH2—NR 4c R 4d ;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;C2-C6 alkynyl;-CHΞCH-CH2-NR4c R 4d Provided are compounds of Formula (I), (Id), or (Id-1) (including any one of embodiments 1-10, and 24-29a), wherein: -CHΞCH-CH2-OH; -CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0112] Embodiment 31 HET1-C(O)R 4a teeth, [ka] HET1-NHC(O)R 4a teeth, [ka] HET2-C(O)R 4a teeth, [ka] and;R 4a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Id), or (Id-1) (including any one of embodiments 1-10, and 24-30) are provided.

[0113] Embodiment 32.R 4 teeth, [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Id), or (Id-1) (including any one of Embodiments 1-10, and 24-28) are provided.

[0114] Embodiment 32a.R 4 teeth, [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Id), or (Id-1) (including any one of Embodiments 1-10, and 24-28) are provided.

[0115] Embodiment 33. Formula (Ie): [ka] (In the formula, R 1 , R 2b , R 5 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein) are provided compounds of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, there is provided a compound of Formula (Ie-1): [ka] (In the formula, R 1 , R 2b , R 5 and other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein) according to Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0116] Embodiment 34. Formula (If): [ka] (In the formula, R 1 , R 2b , R 5 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein) are provided compounds of formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, there is provided a compound of formula (If-1): [ka] (In the formula, R 1 , R 2b , R 5 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein), a compound of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s); and / or a stereoisomer or mixture of stereoisomers thereof.

[0117] Embodiment 35. Each R 2b are independently hydrogen or C-C alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In some or all embodiments, compounds of formula (I), (Ie), (If), (Ie-1), or (If-1) (including any one of embodiments 1-10 and 34) are provided, wherein each R 2b is independently hydrogen or methyl.

[0118] Embodiment 36.R 5 is pyridinyl, pyrazolyl, or imidazolyl; each of which is substituted with Z and R 2eand all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of Embodiments 1-10, 34, and 35).

[0119] Embodiment 36a.R 5 is -C(O)N(R 5b )Z and R 5b is selected from group b); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 36a, compounds of formula (I), (Ie), (If), (Ie-1), or (If-1) (including any one of embodiments 1-10, 34, and 35) are provided, wherein R 5 is —C(O)NHZ; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of formula (I), (Ie), (If), (Ie-1), or (If-1) (including any one of embodiments 1-10, 34, and 35) are provided.

[0120] Embodiment 36b.R 5 is replaced by Z and R 2e and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0121] Embodiment 36c.R 5 is -(CH2) 0-2and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, are provided compounds of formula (I), (Ie), (If), (Ie-1), or (If-1) (including any one of embodiments 1-10, 34, and 35).

[0122] Embodiment 36d.R 5 is -(CH2) 0-2 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of embodiments 1-10, 34, and 35).

[0123] Embodiment 37.R 5a -CH2(halo);-(CH2) 1-2 CN; C2-C6 alkenyl; C2-C4 alkenyl substituted with cyano; C2-C4 alkenyl substituted with halo; -CH=CH-CH2-NR 5c R 5d -CH=CH-CH2-O-C1-C6 alkyl; C2-C6 alkynyl; -CHΞCH-CH2-NR 5c R 5d Provided are compounds of formula (I), (Ie), (If), (Ie-1), or (If-1) (including any one of embodiments 1-10 and 34-36), wherein: -CHΞCH-CH2-OH; -CHΞCH-CH2-O-C1-C6 alkyl; cyano-substituted spirocycloalkyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0124] Embodiment 38. Each R 5b and R 5b1are each hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of Embodiments 1-10, and 34-37).

[0125] Embodiment 39. Z is -(CH2) 0-3 NHC(O)R 5a , -(CH2) 0-2 NHS(O)2R 5a , -C(O)R 5a , -S(O)2R 5a , -(CH2) 0-3 -C(O)NHR 5a , -(CH2) 0-3 NH(C1-C6 alkylene)NHC(O)R 5a , -NHC(O)R 5a C3-C8 heterocycloalkyl substituted with -S(O)R 5a C3-C8 heterocycloalkyl substituted with, or -C(O)R 5a is a C3-C8 heterocycloalkyl substituted with R 5a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ie), (If), (Ie-1), or (If-1) (including any one of Embodiments 1-10 and 34-38) are provided.

[0126] Embodiment 40.Z is [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of formula (I), (Ie), (If), (Ie-1), or (If-1) (including any one of embodiments 1-10, and 34-36) are provided.

[0127] Embodiment 40.Z is [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of formula (I), (Ie), (If), (Ie-1), or (If-1) (including any one of embodiments 1-10, and 34-36) are provided.

[0128] Embodiment 41. Formula (Ig): [ka] (In the formula, R 1 , Q 1 , Q 2 , Q 3 , R 6 , R 7 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein), compounds of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, compounds of Formula (Ig-1): [ka] (In the formula, R 1 , Q 1 , Q 2 , Q 3 , R 6 , R 7 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein), a compound of Formula (I) (including any one of embodiments 1-10); or a pharmaceutically acceptable salt(s); and / or a stereoisomer or mixture of stereoisomers thereof.

[0129] Embodiment 42.Q 1 is CR Q1and Q 2 is O and Q 3 Compounds of formula (I), (Ig), or (Ig-1) (including any one of embodiments 1-10 and 41) are provided, wherein Q is N; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. 1 is S and Q 2 is N and Q 3 Compounds of formula (I), (Ig), or (Ig-1) (including any one of embodiments 1-10 and 41) are provided, wherein Q is N; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. 1 is N and Q 2 is N and Q 3 Compounds of formula (I), (Ig), or (Ig-1) (including any one of embodiments 1-10 and 41) are provided, wherein Q is O; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. 1 is O and Q 2 is N and Q 3 Compounds of formula (I), (Ig), or (Ig-1) (including any one of embodiments 1-10 and 41) are provided, wherein Q is N; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. 1 is CR Q1 (Optionally, R Q1 is hydrogen), and Q 2 is N and Q 3 Compounds of formula (I), (Ig), or (Ig-1) (including any one of embodiments 1-10 and 41) are provided, wherein R is O; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In some or all embodiments, R Q1 is hydrogen, C(O)CH, or Cl. In some or any embodiments, R Q1 is hydrogen.

[0130] Embodiment 43.R 6 is replaced by Q and R 2e or R 6 is -(CH2) 0-3 NHC(O)R 6a and;R 6a is selected from group a); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ig), or (Ig-1) (including any one of Embodiments 1-10 and 42) are provided.

[0131] Embodiment 44.R 6a -CH2(halo);-(CH2) 1-2 CN; C2-C6 alkenyl; C2-C4 alkenyl substituted with cyano; C2-C4 alkenyl substituted with halo; -CH=CH-CH2-NR 3c R 3d -CH=CH-CH2-O-C1-C6 alkyl; tetrafluorophenyl; trifluorophenyl; C2-C6 alkynyl; -CHΞCH-CH2-NR 3c R 3d or —CHΞCH—CH—O—C—C alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Provided are compounds of formula (I), (Ig), or (Ig-1) (including any one of embodiments 1-10 and 43).

[0132] Embodiment 44a.R 6a is a C1-C6 alkyl substituted with one or two independently selected halo; a C1-C6 alkyl substituted with cyano; a C2-C6 alkenyl substituted with cyano (in some embodiments, —C(CN)(═CH2)); a C2-C6 alkenyl substituted with halo (in some embodiments, a C2-C4 alkenyl substituted with fluoro); —CH═CH—CH2—NR 6c R 6d;-CH=CH-CH2-O-C1-C6 alkyl;C3-C8 cycloalkenyl;-C(O)-C3-C8 cycloalkyl;Tetrafluorophenyl;Trifluorophenyl;C2-C6 alkynyl;-CHΞCH-CH2-NR 6c R 6d Provided are compounds of formula (I), (Ig), or (Ig-1) (including any one of embodiments 1-10, and 43), wherein: -CHΞCH-CH2-OH; -CHΞCH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0133] Embodiment 45.R 6b is hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of Formula (I), (Ig), or (Ig-1) (including any one of Embodiments 1-10 and 42) are provided.

[0134] Embodiment 46. One R 7 is C-C alkyl, C-C alkoxy, or C-C cycloalkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0135] Embodiment 47.R 3c , R 3d , R 4c , R 4d , R 5c , R 5d , R 6c , and R 6d are each independently hydrogen or C1-C3 alkyl; or R 3c and R 3d , R 4c and R 4d , R 5c and R 5d , and R 6cand R 6d together with the nitrogen to which they are attached form a pyrrolidinyl or piperidinyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0136] Embodiment 47a.R 3a , R 4a , R 5a , and R 6a -CH2(halo);-(CH2) 1-2 CN; C2-C6 alkenyl; C2-C4 alkenyl substituted with cyano; C2-C4 alkenyl substituted with halo; -CH=CH-CH2-NR 3c R 3d -CH=CH-CH2-O-C1-C6 alkyl; tetrafluorophenyl; trifluorophenyl; C2-C6 alkynyl; -CHΞCH-CH2-NR 3c R 3d or -CHΞCH-CH2-O-C1-C6 alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. Provided are compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1) (including any one of the preceding embodiments),

[0137] Embodiment 47b. R Y teeth, [ka] and; R 4 teeth, [ka] and; Z is [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1) (including any one of the preceding embodiments) are provided.

[0138] Embodiment 47c. R Y teeth, [ka] and; R 4 teeth, [ka] and; Z is [ka] and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1) (including any one of the preceding embodiments) are provided.

[0139] Embodiment 48: Compounds are provided in which the 8- or 9-membered bicyclic heterocycle (optionally substituted as provided herein) is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forming an 8-membered bicyclic heterocycle optionally substituted as provided herein. In an embodiment of embodiment 48, compounds are provided in which the 8- or 9-membered bicyclic heterocycle (optionally substituted as provided herein) is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forming an 8-membered bicyclic heterocycle optionally substituted as provided herein; the remainder of the molecule is bonded to the 5-membered heteroaryl group fused to the non-aromatic cyclic group via the 5-membered heteroaryl moiety. In an embodiment of embodiment 48, compounds are provided in which the non-aromatic portion of the 8- or 9-membered bicyclic heterocycle (optionally substituted as provided herein) contains a heteroatom, preferably nitrogen, in the ring.

[0140] Embodiment 49: Provided is a pharmaceutical composition comprising the compound of any one of embodiments 1-48, or a stereoisomer, mixture of stereoisomers, and / or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0141] Embodiment 50: Provided is a method for treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-48 or a stereoisomer, mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the composition of embodiment 4.

[0142] Embodiment 51: The method of embodiment 50 is provided, wherein the condition, disease, or disorder is a hyperproliferative disease, e.g., cancer. In some or any of the embodiments, the cancer is a specific type selected from lymphoma, melanoma, carcinoma (e.g., adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma), astrocytoma, glioma, medulloblastoma, myeloma, meningioma, neuroblastoma, and sarcoma (e.g., angiosarcoma, chondrosarcoma, osteosarcoma). In some or any of the embodiments, the cancer may be a cancer that overexpresses MYST; the cancer may overexpress MYST protein compared to non-cancerous tissue; the cancer may overproduce MYST mRNA compared to non-cancerous tissue; the cancer may be a cancer that overexpresses MYST, and the overexpressed MYST protein or MYST mRNA may be any one of the KATs of the MYST family, e.g., KAT6A. In some or any embodiments, the cancer is selected from the group consisting of: leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, ductal carcinoma, colon and rectal cancer, colon cancer, squamous cell carcinoma, stomach cancer, adrenocortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain cancer, cancer of the female reproductive system, cancer of the male reproductive system (including testicular cancer and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, and / or Wilms' tumor.In some or any embodiments, the cancer is breast cancer, including ER-positive breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, or blood cancer (including leukemia or lymphoma).

[0143] Embodiment B: In one embodiment, R 1 is the unsubstituted C 3-8 cycloalkylalkyl, preferably cyclohexylmethyl, or phenyl, wherein the phenyl is halo, preferably fluoro, and C 1-3 optionally substituted with 1 or 2 groups independently selected from alkoxy, preferably methoxy; R 2 is ring (a) or ring (b); one X 1 is C(CH2R 2c ) and the other two X 1 are each CH; preferably, 2c ) is R 2d in meta position with respect to R 2b is hydrogen or C1-C6 alkyl, preferably hydrogen or methyl; R 2c is a 5-membered heteroaryl, preferably pyrazol-1-yl, optionally substituted with cyano or —CHNHC(O)CH; or R 2c is C 1-6 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl optionally substituted with alkylcarbonyl; or R 2c is a 6-membered heteroaryl, preferably pyridin-2-yl; R 2d is C 1-3 is an alkoxy, Provided is a compound of formula (I): or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0144] Embodiment 52. Formula (Ih): [ka] (In the formula, R 1 , R 2b , R 2d , and X 1 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments of embodiment 52, R 2b is hydrogen or methyl.

[0145] Embodiment 53. Formula (Ii): [ka] (In the formula, R 1 , R 2d , and X 1 and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0146] Embodiment 54. Formula (Ij): [ka] (In the formula, R 1 , R 2d , X 1 , and X 2 and all other groups are as defined in the Summary of the Invention or in some or any embodiment provided herein; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0147] Embodiment 55:R 1is C3-C8-cycloalkylalkyl, wherein said C3-C8-cycloalkylalkyl is selected from the group consisting of 1, 2 or 3 R 1a or one, two or three R 1b and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0148] Embodiment 56:R 1 is C3-C8-cycloalkylalkyl, wherein said C3-C8-cycloalkylalkyl is selected from the group consisting of 1, 2 or 3 R 1a and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0149] Embodiment 57: Each R 1a are independently H; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0150] Embodiment 58:R 1 can contain one, two, or three R 1b and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0151] Embodiment 59:R 1can contain one, two, or three R 1b and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0152] Embodiment 60:R 1 can contain one, two, or three R 1b and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0153] Embodiment 60a:R 1 is an 8- to 10-membered bicyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0154] Embodiment 61: Each R 1b are provided compounds according to Formula (I), (Ih), (Ii), or (Ij) (including any one of embodiments 52-55 and 58-60), wherein each R is independently selected from H, halo, and C-C alkoxy; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 61, each R 1b In a subembodiment of embodiment 61, compounds of formula (I), (Ih), (Ii), or (Ij) are provided wherein each R is independently selected from H, halo, and C-C alkoxy. 1bIn a subembodiment of embodiment 61 and its subembodiments, one or two R 1b In a subembodiment of embodiment 61 and its subembodiments, there is provided a compound of formula (I), (Ih), (Ii), or (Ij), wherein: 1b In a subembodiment of embodiment 61 and subembodiments thereof, there is provided a compound of formula (I), (Ih), (Ii), or (Ij), wherein: 1b is provided a compound of formula (I), (Ih), (Ii), or (Ij), wherein:

[0155] Embodiment 62:R 2d Compounds according to Formula (I), (Ih), (Ii), or (Ij) (including any one of embodiments 52-61) are provided, wherein R is halo, C-C alkyl, C-C alkoxy, or C-cycloalkyloxy; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 62, R 2d Compounds of Formula (I), (Ih), (Ii), or (Ij) are provided wherein R is C1-C6 alkoxy, preferably C1-C3 alkoxy, preferably methoxy. In a subembodiment of embodiment 62, R 2d is methoxy, isopropoxy, or cyclopropyloxy.

[0156] Embodiment 63: Each R 2e are independently hydrogen, fluoro, C-C alkyl, cyclopropyl, -CHF, -CF, C-C alkoxy, -OCHF, or -OCF; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 63, compounds according to formula (I), (Ih), (Ii), or (Ij) (including any one of embodiments 52-61) are provided, wherein each R2e is hydrogen.

[0157] Embodiment 64: R 2c is one or two R 2c1 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, -CN, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -(CH2) 0-1 NH2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , —NH(C1-C6 alkyl), —N(C1-C6 alkyl) 2-, 5-, or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; Compounds according to Formula (I) or (Ih) (including any one of embodiments 55-63) are provided, wherein all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 64, R 2c is one or two R 2c1 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8-membered bicyclic heterocycle optionally substituted with R 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with

[0158] Embodiment 64a: In an embodiment of embodiment 64, each R 2c1 is hydrogen (i.e., R 2c is unsubstituted); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 64, compounds are provided (including any one of embodiments 55-63) in which one R 2c1 is hydrogen, and other R 2c1 is C1-C6 alkylcarbonyl, -CN, -(CH2) 0-1 NH2 and -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f Selected from; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 64, compounds are provided (including any one of embodiments 55-63) in which one R 2c1 is hydrogen, and other R 2c1 is —CN; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of embodiments 55-63).

[0159] Embodiment 64b: In a subembodiment of embodiment 64 or 64a, R 2c is pyrazolyl, pyridinyl, or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is selected from the group consisting of one or two R 2c1 In a subembodiment of embodiment 64 or 64a, R 2c is one or two R 2c1 In a subembodiment of embodiment 64 or 64a, R is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R2c1 In a subembodiment of embodiment 64 or 64a, R is an 8-membered bicyclic heterocycle optionally substituted with 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with

[0160] Embodiment 64c: In an embodiment of embodiment 64, R 2c is pyrazolyl, preferably pyrazol-2-yl, and is unsubstituted (i.e., both R 2c1 is hydrogen), or one R is preferably cyano 2c1 (i.e., other R 2c1 is hydrogen); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In an embodiment of embodiment 64, compounds are provided (including any one of embodiments 55-63), wherein R 2c is pyridinyl, preferably pyridin-2-yl, and is unsubstituted (i.e., both R 2c1 is hydrogen), or one R is cyano 2c1 (i.e., other R 2c1 is hydrogen); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In an embodiment of embodiment 64, compounds are provided (including any one of embodiments 55-63), wherein R 2c is 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, and is unsubstituted (i.e., both R 2c1 is hydrogen) or one R 2c1 (i.e., other R 2c1 is hydrogen), and one R 2c1is alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of embodiments 55-63).

[0161] Embodiment 64d: In any embodiment of embodiment 64 or 64a, R 2c is one or two R 2c1 and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0162] Embodiment 64d-1: In a subembodiment of embodiment 64d, the 8- or 9-membered bicyclic heterocycle (wherein one or two R 2c1 is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, and preferably contains one or two R 2c1 Compounds are provided in which the compound forms an optionally substituted 8-membered bicyclic heterocycle.

[0163] Embodiment 64d-2: In a subembodiment of embodiment 64d, the 8- or 9-membered bicyclic heterocycle (wherein one or two R 2c1 is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, and preferably contains one or two R 2c1 and the remainder of the molecule is attached to said 5-membered heteroaryl group fused to said non-aromatic cyclic group via a 5-membered heteroaryl moiety.

[0164] In a subembodiment of any one of embodiment 64d, 64d-1, and 64d-2, the 8- or 9-membered bicyclic heterocycle (one or two R 2c1Compounds are provided wherein the non-aromatic portion of (optionally substituted with) contains a heteroatom, preferably nitrogen, in the ring.

[0165] Embodiment 64d-4: In a subembodiment of any one of embodiments 64d, 64d-1, 64d-2, and 64d-3, the 8- or 9-membered bicyclic heterocycle has one R that is hydrogen. 2c1 and a second R selected from hydrogen and C1-C6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl. 2c1 Compounds are provided in which the compound is substituted with

[0166] Embodiment 65: R 2c is R 2c2 and R 2c3 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c is R 2c2 and R 2c3 an 8- or 9-membered bicyclic heterocycle optionally substituted with R 2c is R 2c2 and one or two R 2c3 is a 6-membered monocyclic heteroaryl optionally substituted with R 2c2 is C1-C6 alkylcarbonyl, -CN, -(CH2) 0-1 NH2, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; R 2c3are independently H, halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyloxy; Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -CN, -(CH2) 0-1 NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; Compounds according to Formula (I) or (Ii) (including any one of embodiments 55-63) are provided, wherein all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 65, R 2c is R 2c2 and R 2c3 5-membered monocyclic heteroaryl optionally substituted with one or two R 2c1 an 8-membered bicyclic heterocycle optionally substituted with R 2c is R 2c2 and R 2c3 an 8-membered bicyclic heterocycle optionally substituted with R 2c is R 2c2 and one or two R 2c3 is a 6-membered monocyclic heteroaryl optionally substituted with

[0167] Embodiment 65a: In an embodiment of embodiment 65, each R 2c1 is hydrogen (i.e., R 2cis unsubstituted); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 65, compounds are provided (including any one of embodiments 55-63) in which one R 2c1 is hydrogen, and other R 2c1 is C1-C6 alkylcarbonyl, -CN, -(CH2) 0-1 NH2 and -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f Selected from; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 65, compounds are provided (including any one of embodiments 55-63) in which one R 2c1 is hydrogen, and other R 2c1 is —CN; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of embodiments 55-63).

[0168] Embodiment 65b: In an embodiment of embodiment 65, R 2c2 is C1-C6 alkylcarbonyl, -CN, -(CH2) 0-1 NH2, or -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f and;R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0169] Embodiment 65c: In any embodiment of embodiment 65 or 65b, each R 2c3 is hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, including any one of embodiments 55-63.

[0170] Embodiment 65d: In a subembodiment of embodiment 65, 65b, or 65c, R 2c is pyrazolyl, pyridinyl, or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is R 2c2 and R 2c3 and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 65, 65b, or 65c, compounds are provided in which R 2c is R 2c2 and R 2c3 In a subembodiment of embodiment 65, 65b, or 65c, R is a 5-membered monocyclic heteroaryl optionally substituted with 2c is R 2c2 and R 2c3 In a subembodiment of embodiment 65, 65b, or 65c, R is an 8-membered bicyclic heterocycle optionally substituted with 2c is R 2c2 and R 2c3 is a 6-membered monocyclic heteroaryl optionally substituted with

[0171] In an embodiment of embodiment 65, R 2c is cyanoR 2c2 pyrazolyl, preferably pyrazol-2-yl, substituted with R 2c3is hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In an embodiment of embodiment 65, compounds are provided (including any one of embodiments 55-63) in which R 2c is cyanoR 2c2 pyridinyl, preferably pyridin-2-yl, substituted with R 2c3 is hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In an embodiment of embodiment 65, compounds are provided (including any one of embodiments 55-63) in which R 2c is R 2c2 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl substituted with, preferably 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, and R 2c2 is alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl, and R 2c3 is hydrogen; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein, including any one of embodiments 55-63.

[0172] Embodiment 65f: In an embodiment of embodiment 65, R 2c is one or two R 2c1 and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0173] Embodiment 65f-1: In a subembodiment of embodiment 65f, the 8- or 9-membered bicyclic heterocycle (wherein one or two R 2c1 is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, and preferably contains one or two R 2c1 Compounds are provided in which the compound forms an optionally substituted 8-membered bicyclic heterocycle.

[0174] Embodiment 65f-2: In a subembodiment of embodiment 65f, the 8- or 9-membered bicyclic heterocycle (wherein one or two R 2c1 is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, and preferably contains one or two R 2c1 and the remainder of the molecule is attached to said 5-membered heteroaryl group fused to said non-aromatic cyclic group via a 5-membered heteroaryl moiety.

[0175] Embodiment 65f-3: In a subembodiment of any one of embodiments 65f, 65f-1, and 65f-2, the 8- or 9-membered bicyclic heterocycle (one or two R 2c1 Compounds are provided wherein the non-aromatic portion of (optionally substituted with) contains a heteroatom, preferably nitrogen, in the ring.

[0176] Embodiment 65f-4: In a subembodiment of any one of embodiments 65f, 65f-1, 65f-2, and 65f-3, the 8- or 9-membered bicyclic heterocycle has one R that is hydrogen. 2c1 and a second R selected from hydrogen and C1-C6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl. 2c1 Compounds are provided in which the compound is substituted with

[0177] Embodiment 65g: In an embodiment of embodiment 65, R 2c is R 2c2 and R 2c3 and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0178] Embodiment 65g-1: In a subembodiment of embodiment 65g, the 8- or 9-membered bicyclic heterocyclic (R 2c2and R 2c3 (optionally substituted with) is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably R 2c2 and R 2c3 Compounds are provided in which the compound forms an optionally substituted 8-membered bicyclic heterocycle.

[0179] Embodiment 65g-2: In a subembodiment of embodiment 65g, the 8- or 9-membered bicyclic heterocycle (R 2c2 and R 2c3 (optionally substituted with) is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably R 2c2 and R 2c3 and the remainder of the molecule is attached to said 5-membered heteroaryl group fused to said non-aromatic cyclic group via a 5-membered heteroaryl moiety.

[0180] Embodiment 65g-3: In a subembodiment of any one of embodiments 65g, 65g-1, and 65g-2, the 8- or 9-membered bicyclic heterocycle (R 2c2 and R 2c3 Compounds are provided wherein the non-aromatic portion of (optionally substituted with) contains a heteroatom, preferably nitrogen, in the ring.

[0181] Embodiment 65g-4: In a subembodiment of any one of embodiments 65g, 65g-1, 65g-2, and 65g-3, the 8- or 9-membered bicyclic heterocycle is substituted with C1-C6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl, and R 2c3 is hydrogen.

[0182] Embodiment 66: R 2c is one or two R 2c1 5-membered monocyclic heteroaryl optionally substituted with one or two R 2c1an 8- or 9-membered bicyclic heterocycle optionally substituted with 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, -CN, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -(CH2) 0-1 NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; Compounds according to Formula (I) or (Ij) (including any one of embodiments 55-63) are provided, wherein all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 66, R 2c is one or two R 2c1 is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 an 8-membered bicyclic heterocycle optionally substituted with R 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with

[0183] Embodiment 66a: In an embodiment of embodiment 66, each R 2c1 is hydrogen (i.e., R 2c is unsubstituted); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 66, compounds are provided (including any one of embodiments 55-63) in which one R 2c1 is hydrogen, and other R 2c1is C1-C6 alkylcarbonyl, -CN, -(CH2) 0-1 NH2 and -(CH2) 0-1 NHC(O)R 2f , -(CH2) 0-1 NHC(O)OR 2f Selected from; R 2f is C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkylC1-C3 alkyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment of embodiment 66, compounds are provided (including any one of embodiments 55-63) in which one R 2c1 is hydrogen, and other R 2c1 is —CN; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein (including any one of embodiments 55-63).

[0184] Embodiment 66b: In a subembodiment of embodiment 66 or 66a, R 2c is pyrazolyl, pyridinyl, or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is selected from the group consisting of one or two R 2c1 In a subembodiment of embodiment 66 or 66a, R 2c is one or two R 2c1 In a subembodiment of embodiment 66 or 66a, R is a 5-membered monocyclic heteroaryl optionally substituted with 2c is one or two R 2c1 In a subembodiment of embodiment 66 or 66a, R is an 8-membered bicyclic heterocycle optionally substituted with 2c can contain one, two, or three R 2c1 is a 6-membered monocyclic heteroaryl optionally substituted with

[0185] Embodiment 66c: In an embodiment of embodiment 66, R 2cis pyrazolyl, preferably pyrazol-2-yl, and is unsubstituted (i.e., both R 2c1 is hydrogen), or one R is preferably cyano 2c1 (i.e., other R 2c1 is hydrogen); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In an embodiment of embodiment 66, compounds are provided (including any one of embodiments 55-63) in which R 2c is pyridinyl, preferably pyridin-2-yl, and is unsubstituted (i.e., both R 2c1 is hydrogen), or one R is cyano 2c1 (i.e., other R 2c1 is hydrogen); and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In an embodiment of embodiment 66, compounds are provided (including any one of embodiments 55-63) in which R 2c is 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, and is unsubstituted (i.e., both R 2c1 is hydrogen) or one R 2c1 (i.e., other R 2c1 is hydrogen), and one R 2c1 is alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl; and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein.

[0186] Embodiment 66d: In any of embodiments 66 or 66a, R 2c is one or two R 2c1and all other groups are as defined in the Summary of the Invention or in any or any embodiment provided herein.

[0187] Embodiment 66d-1: In a subembodiment of embodiment 66d, the 8- or 9-membered bicyclic heterocycle (wherein one or two R 2c1 is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, and preferably contains one or two R 2c1 Compounds are provided in which the compound forms an optionally substituted 8-membered bicyclic heterocycle.

[0188] Embodiment 66d-2: In a subembodiment of embodiment 66d, the 8- or 9-membered bicyclic heterocycle (wherein one or two R 2c1 is a 5-membered heteroaryl group, preferably pyrazolyl, fused to a non-aromatic cyclic group, and preferably contains one or two R 2c1 and the remainder of the molecule is attached to said 5-membered heteroaryl group fused to said non-aromatic cyclic group via a 5-membered heteroaryl moiety.

[0189] Embodiment 66d-3: In a subembodiment of any one of embodiments 66d, 66d-1, and 66d-2, the 8- or 9-membered bicyclic heterocycle (wherein one or two R 2c1 Compounds are provided wherein the non-aromatic portion of (optionally substituted with) contains a heteroatom, preferably nitrogen, in the ring.

[0190] Embodiment 66d-4: In a subembodiment of any one of embodiments 66d, 66d-1, 66d-2, and 66d-3, the 8- or 9-membered bicyclic heterocycle has one R that is hydrogen. 2c1 and a second R selected from hydrogen and C1-C6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl. 2c1Compounds are provided in which the compound is substituted with

[0191] Embodiment 67: One X 1 is C(CH2R 2c ) and the other two X 1 are CR 2e and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment, compounds according to Formula (I), (Ih), (Ii), or (Ij) (including any one of embodiments 52-66d-4) are provided, wherein each CR 2e is CH. In a subembodiment, C(CHR 2c ) is R 2d It is in a meta position relative to .

[0192] Embodiment 68: One X 1 is C(CH2R 2c ) and the second X 1 is N and the third X 1 is CR 2e and all other groups are as defined in the Summary of the Invention or in any or all embodiments provided herein. In a subembodiment, compounds according to Formula (I), (Ih), (Ii), or (Ij) (including any one of embodiments 52-66d-4) are provided, wherein CR 2e is CH. In a subembodiment, C(CHR 2c ) is R 2d It is in a meta position relative to .

[0193] Embodiment 69: One X 1 is C(CH2R 2c ) and the other two X 1 are provided compounds according to Formula (I), (Ih), (Ii), or (Ij) (including any one of embodiments 52-66d-4), wherein each C(CHR 2c ) is R 2dIt is in a meta position relative to .

[0194] Embodiment 70: Provided is a pharmaceutical composition comprising the compound of any one of embodiments 52-69 or a stereoisomer, mixture of stereoisomers, and / or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0195] Embodiment 71: Provided is a method for treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including Kat6a and Kat6b, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 52-69 or a stereoisomer, mixture of stereoisomers thereof, and / or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a composition according to embodiment 70.

[0196] Embodiment 72: The method of embodiment 71 is provided, wherein the condition, disease, or disorder is a hyperproliferative disease, e.g., cancer. In some or any of the embodiments, the cancer is a specific type selected from lymphoma, melanoma, carcinoma (e.g., adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma), astrocytoma, glioma, medulloblastoma, myeloma, meningioma, neuroblastoma, and sarcoma (e.g., angiosarcoma, chondrosarcoma, osteosarcoma). In some or any of the embodiments, the cancer may be a cancer that overexpresses MYST; the cancer may overexpress MYST protein compared to non-cancerous tissue; the cancer may overproduce MYST mRNA compared to non-cancerous tissue; the cancer may be a cancer that overexpresses MYST, and the overexpressed MYST protein or MYST mRNA may be any one of the KATs of the MYST family, e.g., KAT6A. In some or any embodiments, the cancer is selected from the group consisting of: leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, ductal carcinoma, colon and rectal cancer, colon cancer, squamous cell carcinoma, stomach cancer, adrenocortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain cancer, cancer of the female reproductive system, cancer of the male reproductive system (including testicular cancer and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, and / or Wilms' tumor.In some or any embodiments, the cancer is breast cancer, including ER-positive breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, or blood cancer (including leukemia or lymphoma).

[0197] In some embodiments, the present invention provides: (a) compounds described herein, e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), embodiments A, B, and 1-72, and pharmaceutically acceptable salts and compositions thereof; (b) compounds described herein, e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), embodiments A, B, and 1-72, and pharmaceutically acceptable salts and compositions thereof, for use in treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B; (c) processes for the preparation of compounds described herein, e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B, and 1-72, as described in more detail elsewhere herein; (d) a pharmaceutical formulation comprising a compound described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B, and 1-72, or a stereoisomer, mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier; (e) a method for treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, in a subject, comprising administering an effective therapeutic amount of a compound described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B, and 1-72, a pharmaceutically acceptable salt, or a composition thereof; (f) a pharmaceutical formulation comprising a compound described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), embodiments A, B, and 1-72, or a stereoisomer, mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof, together with one or more other active agents for treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, optionally in a pharmaceutically acceptable carrier; or (g) A method for the treatment of a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, in a subject, comprising the administration of an effective therapeutic amount of a compound described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B, and 1-72, a pharmaceutically acceptable salt, or a composition thereof, in combination and / or alternation with one or more agents for the treatment of a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B. is provided.

[0198] Optically active compounds It is understood that the compounds provided herein have several chiral centers and can exist in and be isolated in optically active and racemic forms. It is understood that any racemic, optically active, diastereomeric, tautomeric, or stereoisomeric form of the compounds provided herein, or mixtures thereof, that possess the useful properties described herein, are within the scope of the present invention. Methods for preparing optically active forms (in certain embodiments, by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases) are well known in the art.

[0199] In some or any embodiments, the term "stereoisomer" includes diastereomers, enantiomers, rotamers, atropisomers, positional isomers, and geometric isomers; and mixtures thereof.

[0200] In certain embodiments, methods for obtaining optically active materials are known in the art and include at least the following: i) Physical separation of crystals - a technique in which macroscopic crystals of individual stereoisomers are manually separated. This technique can be used when crystals of separate stereoisomers are present, i.e., when the material is a conglomerate and the crystals are visually distinct; ii) simultaneous crystallization - a technique in which individual stereoisomers are crystallized separately from a solution of the racemate, which is only possible if the latter is a conglomerate in the solid state; iii) Enzymatic resolution - a technique that involves partial or complete separation of the racemate due to different reaction rates with enzymes for the stereoisomers; iv) enzymatic asymmetric synthesis - a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain a stereomerically pure or enriched synthetic precursor of a desired stereoisomer; v) chemical asymmetric synthesis - a synthetic technique in which a desired stereoisomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomeric separation - a technique in which a racemate is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their now more distinguishable structural differences, and the chiral auxiliary is later removed to yield the desired enantiomer; vii) Primary and secondary asymmetric transformations - techniques that disrupt the equilibrium of diastereomers from the racemate to obtain a predominance in solution of the diastereomer from the desired enantiomer, or preferential crystallization of the diastereomer from the desired enantiomer, so that ultimately, in principle, all material is converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then released from the diastereomer; viii) Kinetic resolution - this technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by the unequal reaction rates of stereoisomers using chiral non-racemic reagents or catalysts under kinetic conditions; ix) stereospecific synthesis from non-racemic precursors - a synthetic technique in which the desired stereoisomer is obtained from non-chiral starting materials and the stereochemical integrity is not or only minimally compromised throughout the course of the synthesis; x) Chiral liquid chromatography - a technique in which stereoisomers of a racemate are separated in a liquid mobile phase due to their different interactions with a stationary phase. The stationary phase may be composed of a chiral substance or the mobile phase may contain additional chiral substances to induce the different interactions; xi) Chiral gas chromatography - a technique in which the racemate is evaporated and the stereoisomers are separated by their different interactions with the gaseous mobile phase and a column containing a fixed non-racemic chiral adsorbent phase; xii) Extraction with chiral solvents - a technique in which stereoisomers are separated by preferential dissolution of one stereoisomer in a particular chiral solvent; xiii) Transport through chiral membranes—a technique in which a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids (one containing the racemate), and a driving force, e.g., concentration or pressure difference, causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one stereoisomer of the racemate to pass through.

[0201] Isotopically enriched compounds Also provided herein are isotopically enriched compounds, including, but not limited to, isotopically enriched disubstituted pyrazoles.

[0202] Isotopic enrichment (in certain embodiments, deuteration) of pharmaceuticals to improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles has been demonstrated for several classes of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol., 20:393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et al., Mutation Res. 308:33 (1994); Gordon et al., Drug Metab. Dispos., 15:589 (1987); Zello et al., Metabolism, 43:487 (1994); Gately et al., J. Nucl. Med., 27:388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

[0203] Isotopic enrichment of drugs can be used, in certain embodiments, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses required to achieve a desired effect, (4) decrease the amount of doses required to achieve a desired effect, (5) increase the formation of active metabolites (if any are formed), and / or (6) decrease the production of harmful metabolites in specific tissues and / or to generate more effective and / or safer drugs for combination therapy (whether combination therapy is intended or not).

[0204] The substitution of an atom for one of its isotopes will often result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the kinetic isotope effect ("KIE"). For example, if a C-H bond is broken in the rate-determining step in a chemical reaction (i.e., the step with the highest transition state energy), the substitution of deuterium for that hydrogen will cause a decrease in the reaction rate, and the process will slow down. This phenomenon is known as the deuterium kinetic isotope effect ("DKIE"). See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999).

[0205] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken and the same reaction in which deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to extremely large numbers, such as 50 or more (meaning that the reaction may be 50 times slower or more than when deuterium is substituted for hydrogen). High DKIE values ​​can be partially attributed to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is attributed to the small mass of hydrogen atoms because transition states involving protons can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it is statistically much less likely to undergo this phenomenon.

[0206] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with two neutrons in its nucleus and an atomic weight close to three. It occurs naturally in the environment in extremely low concentrations and is most commonly found as TO. Tritium decays slowly (half-life = 12.3 years) and emits low-energy beta particles that cannot penetrate the outer layer of human skin. Internal exposure is the primary hazard associated with this isotope, but it must be ingested in large amounts to pose a significant health risk. Compared to deuterium, smaller amounts of tritium must be consumed before hazardous levels are reached. Substitution of tritium ("T") for hydrogen also results in stronger binding than deuterium, providing a numerically greater isotope effect. Similarly, for carbon, 13 C or 14 C. Regarding sulfur 33 S, 34 S, or 36 S, for nitrogen 15 N and oxygen 17 O or 18 Isotopic substitution for other elements, including but not limited to O, may result in similar kinetic isotope effects.

[0207] For example, DKIEs have been used to reduce the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can result in metabolic switching. The concept of metabolic switching states that when a xenogen is sequestered by a phase I enzyme, it binds transiently and rebinds in diverse conformations before chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively wide size of the binding pockets in many phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially result in different ratios of known and entirely new metabolites. This new metabolic profile may confer higher or lower toxicity.

[0208] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulatory system. In certain embodiments, such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases to react with or convert these foreign substances into more polar intermediates or metabolites for renal excretion. Some of the more common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (CH) bond to either a carbon-oxygen (CO) or a carbon-carbon (CC) π bond. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles compared to the parent compound. For many drugs, such oxidation is rapid. As a result, these drugs often require the administration of multiple or high daily doses.

[0209] As such, isotopic enrichment at a given position in the compounds provided herein will produce a detectable KIE that will affect the pharmacokinetic, pharmacological, and / or toxicological profile of the compounds provided herein compared to a similar compound with natural isotopic composition.

[0210] Pharmaceutical Compositions and Methods of Administration The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the compounds disclosed herein can be provided in a suitable pharmaceutical composition and administered by a suitable route of administration.

[0211] The methods provided herein include administering a pharmaceutical composition containing at least one compound described herein, including compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B, and 1-72, in salt form, as appropriate, used either alone or with one or more compatible and pharmaceutically acceptable carriers, e.g., diluents or adjuvants, or in combination with another agent for the treatment of a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B.

[0212] In some embodiments, the second drug may be formulated or packaged together with the compound provided herein.The second drug will be formulated together with the compound provided herein only if, according to the judgment of one skilled in the art, such co-formulation will not interfere with the activity of either the drug or the administration method.In some embodiments, the compound provided herein and the second drug are formulated separately.They may be packaged together or separately for the convenience of one skilled in the art.

[0213] In clinical practice, the active agents provided herein can be administered by any conventional route, particularly orally, parenterally, rectally, or by inhalation (e.g., in the form of an aerosol). In certain embodiments, the compounds provided herein are administered orally.

[0214] It can be used as a solid composition for oral administration in the form of tablets, pills, hard gelatin capsules, powders or granules.In these compositions, the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.

[0215] These compositions may contain substances other than diluents, for example, lubricants such as magnesium stearate, or coatings intended for controlled release.

[0216] As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups, and elixirs containing inert diluents such as water or liquid paraffin may be used. These compositions may also contain substances other than diluents, such as, in certain embodiments, wetting, sweetening, or flavoring products.

[0217] Compositions for parenteral administration may be emulsions or sterile solutions. As solvents or vehicles, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters, in certain embodiments, ethyl oleate, may be used. These compositions may also contain adjuvants, especially wetting, isotonicizing, emulsifying, dispersing, and stabilizing agents. Sterilization may be achieved by several methods, in certain embodiments, using a bacterial filter, by irradiation, or by heat. They may also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or any other injectable sterile medium at the time of use.

[0218] Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

[0219] Composition can be aerosol.For use in the form of liquid aerosol, composition can be a stable sterile solution or solid composition that is dissolved in non-pyrogenic sterile water, physiological saline or any other pharmaceutically acceptable vehicle when used.For use in the form of dry aerosol that is intended to be directly inhaled, active ingredient is finely divided and combined with water-soluble solid diluent or vehicle, in some embodiments, dextran, mannitol or lactose.

[0220] In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein or other prophylactic or therapeutic agent), and typically one or more pharmaceutically acceptable carriers. In certain embodiments, and in this context, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. For any embodiment described under "excipient," such a pharmaceutical carrier can be a sterile liquid, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When a pharmaceutical composition is administered intravenously, water can be used as a carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0221] Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and in certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form. The composition or single-unit dosage form may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

[0222] The lactose-free compositions provided herein may contain excipients that are well known in the art and, in certain embodiments, are listed in the United States Pharmacopoeia (USP36-NF31 S2). Typically, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. An exemplary lactose-free dosage form contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0223] Because water can facilitate the decomposition of some compounds, anhydrous pharmaceutical compositions and dosage forms containing active ingredients are also encompassed herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a means of simulating long-term storage to determine characteristics such as shelf life or stability of a formulation over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Therefore, because moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, transportation, and use of formulations, the effect of water on a formulation can be very significant.

[0224] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that include at least one active ingredient that includes lactose and a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0225] Anhydrous pharmaceutical compositions should be prepared and stored such that their anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. In certain embodiments, suitable packaging includes, but is not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0226] Pharmaceutical compositions and dosage forms are further provided that comprise one or more compounds that reduce the rate at which the active ingredient decomposes. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants, such as ascorbic acid, pH buffers, or salt buffers.

[0227] Pharmaceutical compositions and single unit dosage forms may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral formulations may include standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such compositions and dosage forms contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier to provide the form for proper administration to a subject; the formulation should be compatible with the mode of administration. In certain embodiments, the pharmaceutical composition or single unit dosage form is sterile and in suitable form for administration to a subject, in certain embodiments, an animal subject, e.g., a mammalian subject, and in certain embodiments, a human subject.

[0228] A pharmaceutical composition is formulated to be compatible with its intended route of administration. In certain embodiments, routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, intrasynovial, and rectal administration. In certain embodiments, the composition is formulated according to customary procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In one embodiment, the pharmaceutical composition is formulated according to customary procedures for subcutaneous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizing agent and a local anesthetic, such as lignocamne, to relieve pain at the site of injection.

[0229] In certain embodiments, dosage forms include, but are not limited to, tablets; caplets; capsules, e.g., soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; poultices (compresses); pastes; powders; bandages; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

[0230] The composition, shape, and type of the dosage forms provided herein typically vary depending on their use. In certain embodiments, a dosage form used in the initial treatment of a viral infection may contain a greater amount of one or more of its active ingredients than a dosage form used in the maintenance treatment of the same infection. Similarly, a parenteral dosage form may contain a smaller amount of one or more of its active ingredients than an oral dosage form used to treat the same disease or disorder. These and other ways in which the specific dosage forms encompassed herein vary from one another will be readily apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0231] Typically, the components of the composition are supplied separately, or mixed together in unit dosage form, in a sealed container such as an ampoule or sachet indicating the quantity of active ingredient, as a lyophilized powder or a water-free concentrate.When the composition is administered by injection, it can be dispensed in an infusion bottle containing sterile pharmaceutical grade water or saline.When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed before administration.

[0232] Typical dosage forms include about 0.1 mg to about 1000 mg of a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, per day, given as a single, once-daily dose in the morning or as divided doses throughout the day taken with food. Particular dosage forms may have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, or 1000 mg of active compound.

[0233] Oral Dosage Forms Pharmaceutical compositions suitable for oral administration can be provided in individual dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of active ingredient and can be prepared by methods of pharmacy well known to those skilled in the art. See generally Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0234] In certain embodiments, the oral dosage form is solid and is prepared under anhydrous conditions using anhydrous ingredients as described in detail herein. However, the scope of the compositions provided herein extends beyond anhydrous solid oral dosage forms. Thus, additional forms are described herein.

[0235] Typical oral dosage forms are prepared by combining the active ingredient(s) intimately with at least one excipient according to conventional pharmaceutical compounding techniques. The excipients can take a variety of forms depending on the form of preparation desired for administration. In certain embodiments, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. In certain embodiments, excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0236] Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit forms when solid excipients are used.If desired, tablets can be coated by standard aqueous or non-aqueous techniques.Such dosage forms can be prepared by any of the methods of pharmacy.In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation.

[0237] In some embodiments, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, for example, powder or granules, optionally mixed with an excipient, in a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0238] In certain embodiments, excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0239] In certain embodiments, fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in a pharmaceutical composition is typically present in about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0240] In certain embodiments, suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL PH101, AVICEL PH103, AVICEL RC581, AVICEL PH105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients or additives include AVICEL PH103™ and Starch 1500 LM.

[0241] Disintegrants are used in compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while those containing too little may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant, neither too much nor too little, should be used to form a solid oral dosage form so as not to adversely alter the release of the active ingredient. The amount of disintegrant used varies based on the type of formulation and is readily discernible to those skilled in the art. Typical pharmaceutical compositions contain about 0.5 to about 15 weight percent disintegrant, particularly about 1 to about 5 weight percent disintegrant.

[0242] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0243] Lubricants that may be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, in certain embodiments, syloid silica gel (AEROSIL 200 manufactured by W.R. Grace Co. of Baltimore, MD), coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

[0244] Delayed-Release Dosage Forms Active ingredients, e.g., compounds provided herein, can be administered by controlled release means or by delivery devices well known to those skilled in the art. In certain embodiments, the active ingredients ... and 6,699,500 (each of which is incorporated herein by reference in its entirety). Such dosage forms may, in certain embodiments, be used to provide slowed or controlled release of one or more active ingredients using hydropropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide desired release profiles of varying rates. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Thus, included herein are single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps, and caplets, adapted for controlled release.

[0245] All controlled-release pharmaceutical products share a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of optimally designed controlled-release preparations in medical treatment is characterized by the minimum amount of drug substance used to cure or control a condition, disease, or disorder in the shortest amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosing frequency, and increased subject compliance. Controlled-release formulations can also be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus the occurrence of secondary (e.g., adverse) effects.

[0246] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that rapidly produces the desired therapeutic effect and gradually and continuously release another amount of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of this drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug being metabolized and excreted from the body. Controlled-release of the active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0247] In certain embodiments, drugs can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In certain embodiments, pumps can be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, polymeric materials can be used. In yet other embodiments, controlled release systems can be placed within a subject at appropriate sites determined by those skilled in the art, thereby requiring only a fraction of the systemic dose (e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in a review by Langer (Science 249:1527-1533 (1990)).The active ingredient may be dispersed in a solid inner matrix, e.g., hydrophilic polymers such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and partially hydrolyzed cross-linked polyvinyl acetate, which is insoluble in body fluids. The active ingredient is then surrounded by an outer polymer membrane, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylic acid copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer.The active ingredient then diffuses through the outer polymer membrane in a release rate-controlling process.The percentage of active ingredient in such parenteral compositions is highly dependent on its specific characteristics and the needs of the patient.

[0248] Parenteral Dosage Forms In certain embodiments, parenteral dosage forms are provided. Parenteral dosage forms can be administered to a subject by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses the subject's natural defenses against contaminants, parenteral dosage forms are typically sterile or can be sterilized before administration to a subject. In certain embodiments, parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0249] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.In some embodiments, suitable vehicles include but are not limited to: water for injection USP; aqueous vehicles, such as but not limited to sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles, such as but not limited to ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, such as but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0250] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms.

[0251] Transdermal, topical and mucosal dosage forms Also provided are transdermal, topical, and mucosal dosage forms. Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues in the oral cavity can be formulated as mouthwashes or oral gels. Additionally, transdermal dosage forms include "reservoir type" or "matrix type" patches, which can be applied to the skin and worn for a specific period of time to allow the desired amount of active ingredient to penetrate.

[0252] Suitable excipients (e.g., carriers and diluents) and other substances that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts and depend on the specific tissue to which a given pharmaceutical composition or dosage form is to be applied. With that in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form toxic, pharmaceutically acceptable lotions, tinctures, creams, emulsions, gels, or ointments. Moisturizers or moisture-retaining agents may also be applied to pharmaceutical compositions and dosage forms, if desired. Examples of such additional ingredients are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0253] Depending on the specific tissue to be treated, additional components may be used before, together with, or after treatment with the provided active ingredient. In certain embodiments, permeation enhancers may be used to assist in delivering the active ingredient to the tissue. Suitable permeation enhancers include, but are not limited to, acetone; various alcohols, such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides, such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones, such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters, such as Tween 80 (Polysorbate 80) and Span 60 (sorbitan monostearate).

[0254] The pH of pharmaceutical compositions or dosage forms, or the tissue to which pharmaceutical compositions or dosage forms are applied, can also be adjusted to improve the delivery of one or more active ingredients.Similarly, the polarity of solvent carriers, their ionic strength, or tonicity can be adjusted to improve delivery.Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously modify the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery.In this regard, stearates can function as lipid vehicles for formulation, as emulsifiers or surfactants, and as delivery enhancers or penetration enhancers.Different salts, hydrates, or solvates of active ingredients can be used to further adjust the properties of the resulting composition.

[0255] Dosage and Unit Dosage Form For human therapeutics, a physician will determine the posology deemed most appropriate according to prophylactic or curative treatment and according to age, weight, stage of infection, and other factors specific to the subject being treated. In certain embodiments, the dose is about 1 to about 1000 mg per day for an adult, or about 5 to about 250 mg per day for an adult, or about 10 to 50 mg per day for an adult. In certain embodiments, the dose is about 5 to about 400 mg per day for an adult, or 25 to 200 mg per day for an adult. In certain embodiments, dose rates of about 50 to about 500 mg per day are also contemplated.

[0256] In a further aspect, methods are provided for treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, in a subject in need thereof by administering an effective amount of a compound provided herein, or a stereoisomer, mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof to the subject. The amount of the compound or composition effective in treating a disorder or one or more symptoms thereof will vary depending on the nature and severity of the condition, disease, or disorder, and the route by which the active ingredient is administered. Frequency and dosage will also vary according to subject-specific factors, depending on the particular therapy (e.g., therapeutic or prophylactic agent) administered, the severity of the disorder, disease, or condition, the route of administration, and the subject's age, physical condition, weight, response, and medical history. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0257] In certain embodiments, exemplary doses of the compositions include milligram or microgram amounts of active compound per kilogram of subject or sample weight (e.g., from about 10 micrograms per kilogram to about 50 milligrams per kilogram, from about 100 micrograms per kilogram to about 25 milligrams per kilogram, or from about 100 micrograms per kilogram to about 10 milligrams per kilogram). For the compositions provided herein, in certain embodiments, the dosage administered to a subject is 0.140 mg / kg to 3 mg / kg of the subject's body weight, based on the weight of the active compound. In certain embodiments, the dosage administered to a subject is 0.20 mg / kg to 2.00 mg / kg, or 0.30 mg / kg to 1.50 mg / kg of the subject's body weight.

[0258] In certain embodiments, the recommended daily dose range of the compositions provided herein for the conditions, diseases, or disorders described herein is within the range of about 0.1 mg to about 1000 mg per day, given as a single, once-daily dose or as divided doses throughout the day. In certain embodiments, the daily dose is administered twice daily in equally divided doses. In certain embodiments, the daily dose range should be about 10 mg to about 200 mg per day, in other embodiments about 10 mg to about 150 mg per day, in further embodiments about 25 to about 100 mg per day, and in further embodiments about 100 to about 300 mg per day. In some cases, it may be necessary to use dosages of the active ingredients outside the ranges disclosed herein, as will be apparent to those skilled in the art. It is further noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with the subject's response.

[0259] Different therapeutically effective amounts may be applicable for different conditions, diseases, or disorders, as will be readily apparent to those skilled in the art. Similarly, amounts sufficient to prevent, manage, treat, or ameliorate such disorders, but insufficient to cause or reduce adverse effects associated with the compositions provided herein, are also encompassed by the dosage and dose frequency schedules described herein. Furthermore, when a subject is administered multiple doses of the compositions provided herein, not all of the doses need to be the same. In certain embodiments, the dosage administered to a subject may be increased to improve the preventive or therapeutic effect of the composition, or may be decreased to reduce one or more side effects experienced by a particular subject.

[0260] In certain embodiments, the daily dosage of the compositions provided herein, by weight of the active compound, administered to prevent, treat, manage, or ameliorate a condition, disorder, disease, or one or more symptoms thereof in a subject, is about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 120 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 180 mg / kg, about 190 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, about 250 mg / kg, about 260 mg / kg, about 270 mg / kg, about 280 mg / kg, about 290 mg / kg, about 300 mg / kg, about 350 mg / kg, about 360 mg / kg, about 370 mg / kg, about 380 mg / kg, about 390 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 850 mg / kg, about 860 mg / kg, about 870 mg / kg, about 880 mg / kg, about 890 mg / kg, about 900 mg / kg, about 910 mg / kg, about 920 mg / kg, about 930 mg / kg, about 940 mg / kg, g / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 225 mg / kg, about 250 mg / kg, about 275 mg / kg, about 300 mg / kg, about 325 mg / kg, about 350 mg / kg, about 375 mg / kg, about 400 mg / kg, about 425 mg / kg, about 450 mg / kg, about 475 mg / kg, about 500 mg / kg, or about 600 mg / kg. In certain embodiments, the daily dosage of the compositions provided herein by weight of the active compound administered to prevent, treat, manage, or ameliorate a condition, disorder, disease, or one or more symptoms thereof in a subject is about 1-10 mg / kg, about 10 mg / kg, about 25-50 mg / kg, about 50-100 mg / kg, about 50-150 mg / kg, about 100-150 mg / kg, about 100-200 mg / kg, about 150-200 mg / kg, about 150-250 mg / kg, about 250-300 mg / kg, about 300-350 mg / kg, about 300-400 mg / kg, about 200-400 mg / kg, about 100-300 mg / kg, or about 400-500 mg / kg, inclusive.

[0261] In certain embodiments, a twice-daily dosage of the compositions provided herein by weight of the active compound administered to prevent, treat, manage, or ameliorate a condition, disorder, disease, or one or more symptoms thereof in a subject is about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 225 mg / kg, about 250 mg / kg, about 275 mg / kg, or about 300 mg / kg. In certain embodiments, the twice-daily dosage of the compositions provided herein by weight of the active compound administered to prevent, treat, manage, or ameliorate a condition, disorder, disease, or one or more symptoms thereof in a subject is about 1-10 mg / kg, about 10 mg / kg, about 25-50 mg / kg, about 50-100 mg / kg, about 50-150 mg / kg, about 100-150 mg / kg, about 100-200 mg / kg, about 150-200 mg / kg, or about 150-250 mg / kg, inclusive.

[0262] In certain embodiments, repeated administrations of the same composition may be administered, and the administrations may be separated by at least 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, repeated administrations of the same prophylactic or therapeutic agent may be administered, and the administrations may be separated by at least 4 hours, 6 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0263] In certain aspects, provided herein are unit dosages comprising a compound, or a stereoisomer, mixture of stereoisomers, and / or pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail herein. In certain embodiments, the unit dosage contains 1-1000 mg, 5-250 mg, or 10-50 mg of the active ingredient. In particular embodiments, the unit dosage contains about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of the active ingredient. Such unit dosages can be prepared according to techniques well known to those skilled in the art.

[0264] In certain embodiments, dosages of the second agent used in the combination therapy are provided herein. In certain embodiments, lower dosages are used in the combination therapy provided herein than those that have been or are currently used to treat conditions, diseases, or disorders by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B. Recommended dosages of the second agent can be obtained from the knowledge of one of ordinary skill in the art. For those second agents approved for clinical use, recommended dosages can be found, for example, in Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis of Therapeutics 9 th Ed,Mc-Graw-Hill,New York;Physician's Desk Reference(PDR)57 th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in their entireties.

[0265] In various embodiments, the therapies (e.g., a compound provided herein and a second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 to about 10 hours apart, about 12 to about 14 hours apart, about 16 to about 18 hours apart, about 18 to about 20 hours apart, about 19 to about 22 hours apart, about 23 to about 24 hours apart, about 24 to about 26 hours apart, about 25 to about 28 hours apart, about 26 to about 28 hours apart, about 27 to about 29 hours apart, about 30 to about 30 hours apart, about 31 to about 32 hours apart, about 32 to about 34 hours apart, about 33 to about 35 hours apart, about 34 to about 36 hours apart, about 35 to about 37 hours apart, about 36 to about 38 hours apart, about 37 to about 39 hours apart, about 38 to about 40 hours apart, about 39 to about 42 ... The therapies may be administered about 10 hours apart, about 10 to about 11 hours apart, about 11 to about 12 hours apart, about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 84 to 96 hours apart, or 96 to 120 hours apart. In various embodiments, the therapies are administered 24 hours or less apart or 48 hours or less apart. In certain embodiments, two or more therapies are administered within the same patient visit. In other embodiments, a compound provided herein and a second agent are administered simultaneously.

[0266] In other embodiments, a compound provided herein and the second agent are administered about 2-4 days apart, about 4-6 days apart, about 1 week apart, about 1-2 weeks apart, or more than 2 weeks apart.

[0267] In certain embodiments, repeated administrations of the same agent may be administered, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, repeated administrations of the same agent may be administered, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0268] In certain embodiments, the compound provided herein and the second active agent are administered to a patient, in certain embodiments, a mammal, e.g., a human, in an order and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit when administered separately. In certain embodiments, the second active agent can be administered sequentially in any order at the same time or at different times; however, if not administered simultaneously, they should be administered sufficiently close in time to provide the desired therapeutic or prophylactic effect. In certain embodiments, the compound provided herein and the second active agent exert their effects at overlapping times. Each second active agent can be administered separately in any appropriate form and by any suitable route. In other embodiments, the compound provided herein is administered before, simultaneously with, or after the administration of the second active agent.

[0269] In certain embodiments, a compound provided herein and a second agent are cyclically administered to a patient. Cycling therapy involves administering a first agent (e.g., a first prophylactic or therapeutic agent) within a period of time, followed by administration of a second agent and / or a third agent (e.g., a second and / or third prophylactic or therapeutic agent) within a period of time, and repeating this sequential administration. Cycling therapy may reduce the development of resistance to one or more of the therapies, avoid or reduce side effects of one of the therapies, and / or improve the efficacy of treatment.

[0270] In some embodiments, the compound provided herein and the second active agent are administered about once every two weeks, about once every 10 days, or about once every week, within a cycle of less than about three weeks. A cycle can include administration of the compound provided herein and the second agent by infusion over about 90 minutes per cycle, about 1 hour per cycle, or about 45 minutes per cycle. Each cycle can include at least one week of rest, at least two weeks of rest, or at least three weeks of rest. The number of cycles administered is about 1 to about 12 cycles, more typically about 2 to about 10 cycles, and more typically about 2 to about 8 cycles.

[0271] In other embodiments, the treatment course is administered to the patient simultaneously, i.e., the individual doses of the second agent are administered separately, but within a time interval such that the compound provided herein can act together with the second active agent. In some embodiments, one component can be administered once per week in combination with the other component, which can be administered once every two weeks or once every three weeks. That is, the dosing regimen can be carried out simultaneously, even if the therapeutic agents are not administered at the same time or within the same day.

[0272] The second agent may act additively or synergistically with the compound provided herein. In certain embodiments, the compound provided herein is administered simultaneously with one or more second agents in the same pharmaceutical composition. In another embodiment, the compound provided herein is administered simultaneously with one or more second agents in separate pharmaceutical compositions. In yet another embodiment, the compound provided herein is administered before or after administration of the second agent. Administration of the compound provided herein and the second agent by the same or different routes of administration, e.g., oral and parenteral, is contemplated. In certain embodiments, when the compound provided herein is administered simultaneously with a second agent that potentially produces adverse side effects, including but not limited to toxicity, the second active agent may be advantageously administered at a dose below the threshold at which adverse side effects are induced.

[0273] kit Also provided are kits for use in methods for treating conditions, diseases, or disorders by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B. The kits may include instructions providing a healthcare provider with information about the use of the compounds or compositions provided herein, a second agent or composition, and the use of the second agent or composition to treat conditions, diseases, or disorders by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B. The instructions may be provided in printed or electronic form, such as a floppy disk, CD, or DVD, or a website address from which such instructions can be obtained. A unit dose of the compounds or compositions provided herein, or the second agent or composition, may include a dosage such that, when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the subject for at least one day. In some embodiments, the compounds or compositions may be included as a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0274] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes solid matrices or materials that are customarily used in systems and can hold the compounds provided herein and / or second agents suitable for administration to a subject within a fixed limit. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes, etc. When electron beam sterilization technology is used, the packaging should have a sufficiently low density to allow sterilization of the contents.

[0275] How to use Inhibitors of post-translational lysine acetylation mediated by MYST family KATs are considered promising anti-neoplastic agents and may therefore be useful therapeutic agents for use in, for example, the treatment of cancer. Such agents may also be useful therapeutic agents for the treatment of cancers that exhibit overexpression of MYST proteins.

[0276] Provided herein are methods for treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, such as a single enantiomer, a mixture of enantiomeric pairs, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers, an individual geometric isomer, a mixture of geometric isomers, or a combination thereof. or a pharmaceutically acceptable salt, solvate, prodrug, phosphate, or active metabolite thereof.

[0277] In certain embodiments, provided herein are methods for treating a condition, disease, or disorder in a subject by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B. In certain embodiments, the method includes administering to a subject in need thereof an amount of a compound effective for treating the condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, in combination with a second agent. The compound can be any compound described herein, and the second agent can be any second agent described in the art or herein. In certain embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.

[0278] Diseases that may be treated with a compound according to any of the formulae described herein, including those in embodiments A, B, and 1-72, include leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, ductal carcinoma, colon and rectal cancer, colon cancer, squamous cell carcinoma, stomach cancer, adrenocortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain cancer, cancer of the female reproductive system, cancer of the male reproductive system (including testicular and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, head cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, cancer of the nervous system, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary tumors, plasma cell neoplasms, primary CNS lymphoma, rectal cancer, respiratory system, retinoblastoma, salivary gland cancer, skin cancer, biliary tract cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thyroid cancer, urinary system cancer, uterine cancer, uterine sarcoma, vaginal cancer, endocrine, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, glioblastoma, brain stem glioma, pituitary adenoma, vasculature, Waldenstrom's macroglobulinemia, and / or Wilms' tumor.

[0279] Assay Method Compounds can be assayed for effectiveness in treating a condition, disease, or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, according to any assay known to one of skill in the art. Exemplary assay methods are provided elsewhere herein.

[0280] Second therapeutic agent In certain embodiments, the compounds and compositions provided herein are useful in methods for treating conditions, diseases, or disorders by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, further comprising administering a second agent. The second agent can be any agent known to those of skill in the art to be effective for treating conditions, diseases, or disorders by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, including those currently approved by the U.S. Food and Drug Administration or other similar agency abroad.

[0281] In some embodiments, the disease is cancer and the second agent is a cancer treatment. In some embodiments, the disease is cancer and the second agent is a standard of care treatment for the particular cancer being treated. In some embodiments, the disease is cancer and the second agent is a chemotherapeutic agent.In some embodiments, the second agent is an alkylating agent (e.g., cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine (DTIC), nitrosoureas, temozolomide (oral dacarbazine); anthracyclines (e.g., daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin); cytoskeletal disrupting agents (taxanes, e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel); epothilones; histone deacetylase inhibitors (e.g., inhibitors of topoisomerase I (e.g., irinotecan and topotecan); inhibitors of topoisomerase II (e.g., etoposide, teniposide, and tafluposide); kinase inhibitors (e.g., sorafenib, cobimetinib, cabozantanib, lapatinib, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and vismodegib); nucleotide analogs and precursor analogs (e.g., azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gefitinib ... mucitabine, hydroxyurea, mercaptopurine, methotrexate, and thioguanine; peptide antibiotics (e.g., bleomycin and actinomycin); platinum agents (e.g., carboplatin, cisplatin, and oxaliplatin); retinoids (e.g., tretinoin, alitretinoin, and bexarotene); vinca alkaloids or derivatives (e.g., capecitabine, vinblastine, vincristine, vindesine, and vinorelbine); eribulin; ixabepilone; radiation; bevacizumab; olaparib; aromatase inhibitors (e.g., , letrozole, anastrozole, and exemestane); rituximab; ibritumomab; prednisone; kinase inhibitors, such as sorafenib, cobimetinib, cabozantinib, lapatinib, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and vismodegib; CDK1, 4, and / or 6 inhibitors, such as palbociclib, Kisqali, or Verzenio; immunotherapy, such as checkpoint inhibitors (e.g., pembrolizumab, nivolumab, and atezolizumab); and enzalutamide.

[0282] In some embodiments, the disease is cancer and the second agent is an inhibitor of CDK1, 4, and / or 6. In some embodiments, the disease is cancer and the second agent is palbociclib, ribociclib, or abemaciclib.

[0283] In some embodiments, the disease is cancer and the second agent is an immunotherapy, e.g., a checkpoint inhibitor (e.g., pembrolizumab, nivolumab, and atezolizumab).

[0284] In some embodiments, the disease is breast cancer and the second agent is fulvestrant.

[0285] In some embodiments, the disease is breast cancer (e.g., postmenopausal breast cancer) and the second agent is radiation, docetaxel, paclitaxel, platinum agents (cisplatin, carboplatin), vinorelbine, capecitabine, liposomal doxorubicin, gemcitabine, mitoxantrone, ixabepilone, albumin-bound paclitaxel, eribulin, trastuzumab, pertuzimab, ado-trastuzumab, lapatinib, bevacizumab, olaparib, radiation, an aromatase inhibitor (e.g., letrozole, anastrozole, and exemestane), or tamoxifen.

[0286] In some embodiments, the disease is liver cancer (eg, hepatocellular carcinoma, hepatocellular carcinoma not amenable to surgery or locoregional therapy) and the second agent is sorafenib.

[0287] In some embodiments, the disease is prostate cancer and the second agent is radiation, abiraterone, or enzalutamide.

[0288] In some embodiments, the disease is pancreatic adenocarcinoma and the second agent is radiation.

[0289] In some embodiments, the disease is ovarian cancer and the second agent is bevacizumab, olaparib, radiation, an aromatase inhibitor (e.g., letrozole, anastrozole, and exemestane), or tamoxifen.

[0290] In some embodiments, the disease is B-cell lymphoma and the second agent is rituximab, radiation, ibritumomab, cyclophosphamide, doxorubicin, vincristine, or prednisone.

[0291] In some embodiments, the compounds provided herein are administered in combination with one second agent. In further embodiments, the compounds provided herein are administered in combination with two second agents. In yet further embodiments, the compounds provided herein are administered in combination with two or more second agents.

[0292] As used herein, the term "in combination" includes the use of more than one therapies (e.g., one or more prophylactic and / or therapeutic agents). The use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disorder. A first therapy (e.g., a prophylactic or therapeutic agent, e.g., a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.

[0293] As used herein, the term "synergistic" includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) that has been or is currently being used to prevent, manage, or treat a disorder, which is more effective than the additive effect of the therapy. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) allows for the use of lower dosages of one or more of the therapies and / or less frequent administration of the therapy to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and / or administer the therapy less frequently reduces the toxicity associated with administering the therapy to a subject without reducing the efficacy of the therapy in preventing or treating the disorder. A synergistic effect may also result in improved efficacy of the agents in preventing or treating a disorder. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either of the therapies alone.

[0294] The active compounds provided herein may be administered in combination or alternation with other therapeutic agents, particularly those effective in treating conditions, diseases, or disorders by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B. In combination therapy, effective dosages of two or more agents are administered together, while in alternating or sequential step therapy, effective dosages of each agent are administered sequentially or sequentially. The dosage administered will depend on the absorption, inactivation, and excretion rates of the drug and other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the condition, disease, or disorder being treated. It should be further understood that for any particular subject, specific dosing regimens and schedules may be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0295] Preparation of compounds The compounds provided herein can be prepared, isolated, or obtained by any method apparent to one skilled in the art. The compounds provided herein can be prepared according to the exemplary preparation schemes provided below. Reaction conditions, steps, and reactants not provided in the exemplary preparation schemes will be apparent and known to those skilled in the art.

[0296] Additional steps and reagents not provided in the exemplary preparation schemes will be known to those skilled in the art. Exemplary preparation methods are described in detail in the Examples herein.

[0297] General Scheme 1 General Scheme 1A illustrates the synthesis of compounds of formula (I), where R 2 is a ring (b); one X 1 is CR 3 and the other two are CH; all other groups are as defined in the Summary of the Invention or any embodiment described herein. General Scheme 1B describes the preparation of compounds of formula (I), where R 2 is a ring (b); one X 1 is CR 3 and the other two are CH; R 3 is —(CH)Y; Y is [ka] and all other groups are as defined in the Summary of the Invention or any embodiment described herein.

[0298] General Scheme 1 describes the preparation of compounds of formula (I). [ka] Scheme (A) describes a method for preparing appropriately substituted benzo[d]isoxazole compounds, in which in step 1, 2-fluorobenzonitrile can be converted to the benzo[d]isoxazol-3-amine scaffold by reaction with N-hydroxyacetamide in the presence of a base such as potassium t-butoxide. In step 2, the free amine can be converted to the benzo[d]isoxazol-3-amine scaffold by reaction with N-hydroxyacetamide in the presence of a base such as triethylamine, pyridine, or sodium hydride. 1 It can be reacted with S(O)2Cl.

[0299] Scheme (B) shows a method for preparing a compound (wherein R 3 describes the synthesis of -(CH)Y, where Y is an appropriately substituted 5-membered heteroaryl, such as pyrazole. This synthesis can be extended to other heteroaryls, including C-linked heteroaryls, by one skilled in the art.

[0300] The synthesis of benzo[d]isoxazole compounds can be initiated from an appropriately substituted 2-fluoro-4-(hydroxymethyl)benzonitrile. The hydroxy group can be converted to a compound of formula Ms-X, where Ms-X is: [ka] The fluorobenzonitrile can be converted to a substituted pyrazole moiety by reaction with N-hydroxyacetamide in the presence of a base such as potassium t-butoxide (Step 2 above). In the next step (Step 3), the free amine can be converted to a benzo[d]isoxazol-3-amine skeleton by its reaction with N-hydroxyacetamide in the presence of a base such as potassium t-butoxide (Step 2 above). In the next step (Step 3), the free amine can be converted to a substituted pyrazole moiety by reaction with N-hydroxyacetamide in the presence of a base such as triethylamine, pyridine, or sodium hydride (Step 3). 1 The final step is amine deprotection (step 4), followed by amide formation in step 5 (using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt, or other agents known to those skilled in the art, R 3a C(O)Cl (where R 3ais selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R 3a S(O)2Cl (where R 3a may involve sulfonamide formation in a group selected from a).

[0301] General Scheme 2 General Scheme 2 illustrates the synthesis of compounds of formula (I), where R 2 is a ring(c); [ka] teeth, [ka] and;R 3 is —(CH)Y, where Y is pyrazolyl or pyridinyl, each of which is R Y and all other groups are as defined in the Summary of the Invention or any embodiment described herein). [ka] [1,2,4]Triazolo[4,3-a]pyridine compounds can be prepared by starting with an appropriately substituted methyl-2-chloroisonicotinate. In Scheme (A) above, the ester can be reduced to an alcohol using a reducing agent such as LiBH4 (Step 1 above). The hydroxy group can be converted to a substituted pyrazole moiety by reacting with 1-(methylsulfonyl)-1H-pyrazole of formula X in the presence of a base, such as CsCO3, as shown in Step 2 above. The resulting 2-chloropyridine can be converted to the corresponding 2-hydrazinopyridine by heating in the presence of hydrazine hydrate (Step 3). In Step 4, reaction with cyanogen bromide can result in the assembly of the [1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold. Reaction with R in the presence of a base, such as triethylamine, pyridine, or sodium hydride, can then be carried out. 1 Reaction with S(O)Cl can provide N-linked pyrazole-substituted compounds. The final step is amine deprotection (step 4), followed by amide formation in step 6 (using a coupling agent, e.g., HATU, HBTU, T3P, EDCI / HOBt, or other agents known to those skilled in the art, R 3a C(O)Cl (where R 3a is selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R 3a S(O)2Cl (where R 3a may involve sulfonamide formation in a group selected from a).

[0302] For C-linked heteroaryl-substituted final compounds, a slightly modified Scheme (B) can be used. In this case, the main difference is that hydroxymethylpyridine can be converted to a bromomethyl group using phosphorus tribromide (Step 2). Finally, this bromomethyl group can be subjected to Negishi coupling conditions using a 2-bromoheteroaryl compound (2-bromopyridine in Scheme (B)) via the mediation of zinc dust followed by a palladium catalyst, such as tetrakis(triphenylphosphine)palladium. Such methods can be applied to other heteroaryl analogs as well.

[0303] General Scheme 3 General Scheme 3 illustrates the synthesis of compounds of formula (I), where R 2 is a ring(c); [ka] teeth, [ka] and;R 3 is -(CH2)Y, and Y is R Y and R 2e The present invention describes the preparation of pyrazolyl optionally substituted with ; all other groups are as defined in the Summary of the Invention or any embodiment described herein. [ka] [1,2,3]Triazolo[1,5-a]pyridine compounds can be synthesized using substituted 2-cyanopyridine compounds. Introduction of the N-linked pyrazole moiety (Steps 1 and 2) can be performed using the procedures described above for [1,2,4]triazolo[4,3-a]pyridine compounds. Assembly of the core scaffold is described above in Steps 3 and 4. 2-Cyanopyridines can be converted to 1-amino 2-cyanopyridines by reaction with sulfonylated hydroxylamines (Step 3), followed by cyclization in the presence of hydroxylamine and acetic anhydride. In the final step (Step 5), the free amine can be converted to R 1 S(O)Cl. In this scheme, R Y can be a group bearing an amine with an appropriate protecting group. After scaffold assembly in step 5, the final step is deprotection of the amine followed by amide formation (using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art), R 3a C(O)Cl (where R 3a is selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R 3a S(O)2Cl (where R 3a may involve sulfonamide formation in a group selected from a).

[0304] General Scheme 4 General Scheme 4 illustrates the synthesis of compounds of formula (I), where R 2 is ring (a), and R 3 is —(CH 2 )Y; all other groups are as defined in the Summary of the Invention or any embodiment described herein. [ka] Benzopyrazole compounds can be synthesized by using an appropriately substituted 2-fluorobenzonitrile as the starting material. Steps 1, 2, and 3 can be carried out as previously described in General Schemes 2 and 3 above. The fluorobenzonitrile intermediate can be converted to N-methylbenzopyrazole (Step 4, using methylhydrazine) or unsubstituted benzopyrazole (Step 5, using hydrazine) as shown above. In Step 6, the free amine is converted to R 2 in the presence of a base, such as triethylamine, pyridine, or sodium hydride. 1 In this scheme, Y is a substituent R bearing an amine with a suitable protecting group. Y After scaffold assembly in step 6, the final step is amine deprotection followed by amide formation (using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art, R 3a C(O)Cl (where R 3a is selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R 3a S(O)2Cl (where R 3a may involve sulfonamide formation in a group selected from a).

[0305] General Scheme 5 General Scheme 5 illustrates the synthesis of compounds of formula (I), where R 2 is a ring(c); [ka] teeth, [ka] and;R 3is —(CH 2 )Y; all other groups are as defined in the Summary of the Invention or any embodiment described herein. [ka] Starting with an appropriately substituted 2-cyano-4-formylpyridine, step (s) 1 comprises the reduction of the aldehyde to the alcohol with NaBH4, followed by displacement with a leaving group, e.g., methylsulfonyl or halide, and can be carried out as previously described in steps 2 and 3 of General Scheme 4. The reduction in step 2 can be achieved by treating picolinonitrile with LAH in THF. Treatment of the 2-aminomethylpyridine intermediate with cyanogen bromide in toluene (step 3) can provide the imidazo[1,5-a]pyridin-3-amine intermediate, which can be converted to R as shown in step 2 and as described in General Scheme 1(A). 1 S(O)Cl and a base such as pyridine, triethylamine, or sodium hydride can be used to convert to the desired compound of formula I. In this scheme, Y is a substituent R bearing an amine with a suitable protecting group. Y After scaffold assembly in step 4, the final step is amine deprotection followed by amide formation (using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art, R 3a C(O)Cl (where R 3a is selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R 3a S(O)2Cl (where R 3a may involve sulfonamide formation in a group selected from a).

[0306] General Scheme 6 General Scheme 6 illustrates the synthesis of compounds of formula (I), where R 2is a ring(c); [ka] teeth, [ka] and;R 3 is —(CH 2 )Y; all other groups are as defined in the Summary of the Invention or any embodiment described herein. [ka] An appropriately substituted 2-cyano-5-formylpyridine can be subjected to steps 1 and 2 according to the method described in Scheme 5 above. Steps 3 and 4 involve N-formylation followed by reflux in phosphorous oxychloride to construct the imidazo[1,5-a]pyridine ring. Nitration and reduction with reagents in step 5 can provide the substituted imidazo[1,5-a]pyridin-1-amine. The final sulfonamide product can be prepared by converting this amine to R as shown in step 6 and as described in General Scheme 1. 1 S(O)Cl and a base such as pyridine, triethylamine, or sodium hydride. In this scheme, Y is a substituent R bearing an amine with a suitable protecting group. Y After scaffold assembly in step 6, the final step is amine deprotection followed by amide formation (using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art, R 3a C(O)Cl (where R 3a is selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R 3a S(O)2Cl (where R 3amay involve sulfonamide formation in a group selected from a).

[0307] General Scheme 7 General Scheme 7 illustrates the synthesis of compounds of formula (I), where R 2 is a ring (d); X 2a is O; one X 2 is CR 4 and other X 2 where each is CH; all other groups are as defined in the Summary of the Invention or any embodiment described herein. [ka] The synthesis of benzofuran compounds can begin with an appropriately substituted 2-hydroxybenzaldehyde compound. Cyclization to the benzofuran compound (Step 1) occurs by heating with ethyl bromoacetate in the presence of a base, such as KCO. The resulting acid can be converted to the corresponding primary amide (Step 2) using ammonium chloride and an amide coupling agent, such as HATU, HBTU, T3P, EDCI / HOBt, or other agents known to those skilled in the art, in the presence of a base. Synthesis of acylsulfonamides in Step 3 can be achieved by deprotonating the primary amide with a base such as NaH, followed by reaction with an appropriately substituted sulfonyl chloride. Step 4 constitutes the deprotection of the amine protecting group, followed by Step 5, in which the amine is coupled with an appropriately substituted acid using a coupling agent, such as HBTU, or with an appropriately substituted acid chloride or sulfonyl chloride in the presence of a base, such as triethylamine. In this scheme, R 4 can be an amine-bearing linker with an appropriate protecting group. After scaffold assembly in step 3, the final step is amine deprotection followed by amide formation (using a coupling agent, e.g., HATU, HBTU, T3P, EDCI / HOBt, or other agents known to those skilled in the art). 3a C(O)Cl (where R 3ais selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R 3a S(O)2Cl (where R 3a may involve sulfonamide formation in a group selected from a).

[0308] General Scheme 8 General Scheme 8 illustrates the synthesis of compounds of formula (I), where R 2 is ring (e) or ring (f); all other groups are as defined in the Summary of the Invention or any embodiment described herein). The synthesis of N'-benzoylsulfonylhydrazide compounds of formula (I) can begin with the Suzuki coupling of an appropriately substituted 2-bromoheteroaryl or the Chan-Lam coupling of an appropriately substituted pyrazole (for example) with methyl or ethyl 3-carboxyphenylboronic acid / ester (Step 1). In Step 2, the ester can be converted to the corresponding hydrazide by reaction with hydrazine hydrate under heating. The hydrazide can be converted to the sulfonylhydrazide by reaction with an appropriately substituted sulfonyl chloride in the presence of a base such as pyridine. In this general scheme, R 5 is replaced by Z and R 2e It may be a 5- or 6-membered monocyclic heteroaryl optionally substituted with [ka]

[0309] Z carries an amine with a suitable protecting group. After scaffold assembly in step 3, the final step is deprotection of the amine followed by amide formation (using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art), followed by R 3a C(O)Cl (where R 3ais selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R 3a S(O)2Cl (where R 3a may involve sulfonamide formation in a group selected from a).

[0310] General Scheme 9 General Scheme 9 illustrates the synthesis of compounds of formula (I), where R 2 is a ring(g), and Q 1 and Q 2 are N and Q respectively. 3 is O; or Q 2 and Q 3 are N and Q respectively. 1 is S or O; or Q 1 is CH and Q 2 is N and Q 3 This article describes the preparation of (wherein is O). Ring (g) can be prepared by reacting an appropriately substituted phenyl-heteroarylamine with R in the presence of a base, such as triethylamine, pyridine, or sodium hydride. 1 In ring (g), R 6 is replaced by Q and R 2e or R 6 is Q. Q initially bears an amine with a suitable protecting group. After scaffold assembly in step 1, the final step is deprotection of the amine followed by amide formation (using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art), R 3a C(O)Cl (where R 3a is selected from group a) or R 3a C(O)OH (wherein, R 3a is selected from group a)) or via activation of a sulfonyl chloride (R3a S(O)2Cl (where R 3a may involve sulfonamide formation in a group selected from a). [ka]

[0311] Assembly of the key intermediate (phenyl-heteroarylamine) shown in Step 1(A) can be accomplished via a variety of means, as known to those skilled in the art. Some examples are illustrated in Scheme 9(B). In row (1), an appropriately substituted benzoic acid can be activated using a coupling agent, such as HATU, HBTU, T3P, EDCI / HOBt, or other agents known to those skilled in the art, followed by reaction with guanidine. Cyclization to the aminoheteroaryl intermediate can be achieved via iodobenzene diacetate mediation. In row (2), an appropriately substituted benzaldehyde can be condensed with semicarbazide / thiosemicarbazide in the presence of, but not limited to, NaOAc. Oxidative cyclization to the key aminoheteroaryl intermediate can be achieved in the presence of iodine and a base, such as K2CO3 or Cs2CO3. In another example (column 3), an appropriately substituted methyl benzoate ester can be converted to the corresponding 3-oxo-3-phenylpropanenitrile using a base, such as LDA, and reacting with acetonitrile. Cyclization to the aminoisoxazole compound occurs in the presence of hydroxylamine. Column 4 shows another general method for assembling this key intermediate. The protected 2-amino 5-bromo-substituted heteroaryl compound can undergo Suzuki coupling (or other coupling conditions known to those skilled in the art) with an appropriately substituted phenylboronic acid (or boronic ester). Subsequent deprotection of the amine can provide the desired key intermediate.

[0312] General Scheme 10 General Scheme 10 illustrates the preparation of compounds of formula (I), where R 2 is a ring (b); one X 1 is C(CH2R 2c) and the other two X 1 is CR 2e and;R 2c are two R 2c1 and all other groups are as defined in the Summary of the Invention or any embodiment described herein). [ka]

[0313] The synthesis of benzo[d]isoxazole compounds can begin with an appropriately substituted 2-fluoro-4-(hydroxymethyl)benzonitrile. The hydroxy group can be converted to a substituted pyrazole moiety by reaction with 1-(methylsulfonyl)-1H-pyrazole of formula X in the presence of a base, e.g., CsCO3, as shown in step 1 above. The fluorobenzonitrile can be converted to the benzo[d]isoxazol-3-amine skeleton by its reaction with N-hydroxyacetamide in the presence of a base such as potassium t-butoxide (step 2 above). In the final step (step 3), the free amine can be converted to the benzo[d]isoxazol-3-amine skeleton by reaction with N-hydroxyacetamide in the presence of a base, e.g., triethylamine, pyridine, or sodium hydride. 1 It can be reacted with S(O)2Cl.

[0314] General Scheme 11 General Scheme 11 illustrates the preparation of compounds of formula (I), where R 2 is a ring(c); [ka] teeth, [ka] and one X 1 is C(CH2R 2c ) and the other two X 1 is CR 2e and;R 2c are two R 2c1and all other groups are as defined in the Summary of the Invention or any embodiment described herein). [ka]

[0315] [1,2,4]Triazolo[4,3-a]pyridine compounds can be prepared by starting with an appropriately substituted methyl-2-chloroisonicotinate. In Scheme (A) above, the ester can be reduced to an alcohol using a reducing agent such as LiBH4 (Step 1 above). The hydroxy group can be converted to a substituted pyrazole moiety by reacting with 1-(methylsulfonyl)-1H-pyrazole of formula X in the presence of a base, such as CsCO3, as shown in Step 2 above. The resulting 2-chloropyridine can be converted to the corresponding 2-hydrazinopyridine by heating in the presence of hydrazine hydrate (Step 3). In Step 4, reaction with cyanogen bromide can result in the assembly of the [1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold. Reaction with R in the presence of a base, such as triethylamine, pyridine, or sodium hydride, can then be carried out. 1 Reaction with S(O)2Cl can provide the N-linked pyrazole substituted final compound.

[0316] For C-linked heteroaryl-substituted final compounds, a slightly modified scheme (B) can be used. In this case, the main difference is that hydroxymethylpyridine can be converted to a bromomethyl group using phosphorus tribromide (Step 2). Finally, this bromomethyl group can be subjected to Negishi coupling conditions via zinc dust followed by a palladium catalyst, such as tetrakis(triphenylphosphine)palladium. Such methods can be applied to other heteroaryl analogs as well.

[0317] General Scheme 12 General Scheme 12 illustrates the preparation of compounds of formula (I), where R 2 is a ring(c); [ka] teeth, [ka] and one X 1 is C(CH2R 2c ) and the other two X 1 is CR 2e and;R 2c are two R 2c1 and all other groups are as defined in the Summary of the Invention or any embodiment described herein). [ka]

[0318] [1,2,3]Triazolo[1,5-a]pyridine compounds can be synthesized using substituted 2-cyanopyridine compounds. Introduction of the N-linked pyrazole moiety (Steps 1 and 2) can be performed using the procedures described above for [1,2,4]triazolo[4,3-a]pyridine compounds. Assembly of the core scaffold is described above in Steps 3 and 4. 2-Cyanopyridines can be converted to 1-amino 2-cyanopyridines by reaction with sulfonylated hydroxylamines (Step 3), followed by cyclization in the presence of hydroxylamine and acetic anhydride. In the final step (Step 5), the free amine can be converted to R 1 It can be reacted with S(O)2Cl.

[0319] General Scheme 13 General Scheme 13 illustrates the synthesis of compounds of formula (I), where R 2 is a ring (a); one X 1 is C(CH2R 2c ) and the other two X 1 is CR 2e and;R 2care two R 2c1 and all other groups are as defined in the Summary of the Invention or any embodiment described herein). [ka]

[0320] Benzopyrazole compounds can be synthesized by using an appropriately substituted 2-fluorobenzonitrile as the starting material. Steps 1, 2, and 3 can be carried out as previously described in the synthesis of [1,2,4]triazolo[4,3-a]pyridine compounds (general schemes 2 and 3 above). The fluorobenzonitrile intermediate can be converted to N-methylbenzopyrazole (step 4, using methylhydrazine) or unsubstituted benzopyrazole (step 5, using hydrazine) as shown above. In the final step (step 6), the free amine can be converted to R 2 -methylbenzopyrazole in the presence of a base, such as triethylamine, pyridine, or sodium hydride. 1 It can be reacted with S(O)2Cl.

[0321] General Scheme 14 General Scheme 14 illustrates the preparation of compounds of formula (I), where R 2 is a ring(c); [ka] teeth, [ka] and all other groups are as defined in the Summary of the Invention or any embodiment described herein), which may be prepared as shown below: [ka]

[0322] Starting with an appropriately substituted 2-cyano-4-formylpyridine, step (s) 1 involves the reduction of the aldehyde to the alcohol with NaBH4, followed by the reaction of R 2c -LG (in the formula, R 2c is as defined in any aspect or embodiment provided herein, and LG is a leaving group, e.g., methylsulfonyl or a halide), and may be carried out as previously described in steps 2 and 3 of General Scheme 13. The reduction in step 2 may be achieved by treating picolinonitrile with LAH in THF. Treatment of the 2-aminomethylpyridine intermediate with cyanogen bromide in toluene (step 3) may provide the imidazo[1,5-a]pyridin-3-amine intermediate, which may be converted to R as shown in step 4 and described in General Scheme 10. 1 It can be converted to the desired compound of formula II with S(O)2Cl and a base such as pyridine, triethylamine or sodium hydride.

[0323] General Scheme 15 General Scheme 15 illustrates the synthesis of compounds of formula (I), where R 2 is a ring(c); [ka] teeth, [ka] and all other groups are as defined in the Summary of the Invention or any embodiment described herein), which may be prepared as shown below: [ka]

[0324] An appropriately substituted 2-cyano-5-formylpyridine can be subjected to steps 1 and 2 according to the method described in Scheme A above. Steps 3 and 4 involve N-formylation followed by reflux in phosphorous oxychloride to construct the imidazo[1,5-a]pyridine ring. Nitration and reduction with reagents in step 5 can provide the substituted imidazo[1,5-a]pyridin-1-amine. The final sulfonamide product can be prepared by converting this amine to R as shown in step 6 and as described in general Scheme 10. 1 It can be generated by reaction with S(O)2Cl and a base such as pyridine, triethylamine or sodium hydride. [Example]

[0325] As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in modern scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. Specifically, but not exclusively, the following abbreviations may be used in the examples and throughout this specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (molar); μM (millimolar); Hz (Hertz); MHz (megahertz); mmol (millimol); h, hr, or hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); rt (room temperature); Rf (retention factor); TLC (thin layer chromatography); LCMS (liquid chromatography-mass spectrometry); HPLC (high performance liquid chromatography); AcOH (acetic acid); n-BuLi (n-butyllithium); tBuOK (potassium tert-butoxide); CDCl3 (chloroform-d); CH3CN (acetonitrile); Cs2CO3 (cesium carbonate); DMF (N,N-dimethylformamide); DCM (dichloromethane); DEA (diethylamine); DIPEA (diisopropylethylamine); DMSO (dimethyl sulfoxide); DMSO-d6 (dimethyl sulfoxide-d6); EtOAc or EA (ethyl acetate); Et3N (triethylamine); EtOH (ethanol); HCl (hydrochloric acid); H2SO4 (sulfuric acid); K2CO3 (potassium carbonate); LiOH (lithium hydroxide); MsCl (methanesulfonyl chloride); MeI (methyl iodide) );MeOH (methanol);MeOH-d4 (methanol-d4);NaBH4 (sodium borohydride);NaH (sodium hydride);NaHCO3 (sodium bicarbonate);NaNO2 (sodium nitrite);NaOH (sodium hydroxide);NaOMe (sodium methoxide);Na2SO4 (sodium sulfate);Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0));SO2 (sulfur dioxide);SO2Cl2 (sulfuryl chloride);T3P (propanephosphonic anhydride);THF (tetrahydrofuran);TMEDA (1,2-bis(dimethylamino)ethane);Zn (zinc);ZnCN2 (zinc cyanide).

[0326] For all of the following examples, standard work-up and purification methods known to those skilled in the art may be utilized. Unless otherwise indicated, all temperatures are in degrees Celsius (°C). All reactions are carried out at room temperature unless otherwise noted. The synthetic methodologies described herein are intended to illustrate applicable chemistry through the use of specific examples and do not represent the scope of the present disclosure.

[0327] Synthetic Intermediate Examples Scheme 1: Synthesis of cyclohexylmethanesulfonyl chloride (3) [ka]

[0328] Step 1: Synthesis of S-(cyclohexylmethyl)ethanethioate (2)

[0329] To a stirred solution of compound 1 (2 g, 11.3 mmol) in DMF (20 mL) was added potassium thioacetate (1.93 g, 17 mmol) in portions at room temperature. The reaction mixture was stirred at 50° C. for 1 hour. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to provide the title compound 2 (1.8 g, 92.61%) as a dark brown liquid. TLC: Heptane (R f :0.7) 1 H NMR (400 MHz, CDCl3): δ 2.79 (d, J = 6.8 Hz, 2H), 2.33 (s, 3H), 1.79-1.61 (m, 5H), 1.49-1.38 (m, 1H), 1.27-1.12 (m, 3H), 1.05-0.89 (m, 2H).

[0330] Step 2: Synthesis of cyclohexylmethanesulfonyl chloride (3):

[0331] To a stirred solution of N-chlorosuccinimide (2.7 g, 20.3 mmol) in 2N HCl (1.7 mL) at 0 °C was added a predissolved solution of compound 2 (1 g, 0.58 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was concentrated, and the residue was extracted with diethyl ether. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by silica gel (100-200 mesh) column chromatography using a gradient method of 0-5% EtOAc / heptane to provide the title compound 3 (0.81 g, 71%) as a yellow liquid. TLC: 10% EtOAc / heptane (R f :0.25) 1H NMR (400 MHz, CDCl3): δ 3.63 (d, J = 6.4 Hz, 2H), 2.24-2.18 (m, 1H), 2.01-1.96 (m, 2H), 1.80-1.66 (m, 3H), 1.40-1.29 (m, 2H), 1.25-1.11 (m, 3H).

[0332] Scheme 2: Synthesis of 2,6-dimethoxybenzenesulfonyl chloride (5) [ka]

[0333] To a stirred solution of 1,3-dimethoxybenzene 4 (2 g, 14.4 mmol) and TMEDA (2.4 mL, 15.9 mmol) in THF (20 mL) at 0 °C under a nitrogen atmosphere n BuLi [2.5 M solution in hexane] (6.3 mL, 15.9 mmol) was added portionwise while maintaining an internal reaction temperature below 5 °C. The contents were stirred at the same temperature for 30 min, then cooled to −78 °C, and SO gas was bubbled through for 30 min. The reaction mixture was then gradually warmed to 10 °C, and the resulting precipitate was collected by filtration and washed with dry diethyl ether. The solid was suspended in hexane (20 mL), cooled to 0 °C, and a solution of SO Cl (2.2 mL, 28.8 mmol) in hexane (20 mL) was added dropwise while maintaining an internal temperature below 3 °C. The reaction mixture was then stirred at 0 °C for 1 h, and the solid was collected by filtration and washed with cold hexane. The solid was partitioned between diethyl ether and water, the layers were separated, and the aqueous layer was further extracted with diethyl ether. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound 5 (1 g, 29.23%) as a white solid. TLC: 10% EtOAc / heptane (R f :0.3) 1 H NMR (400 MHz, DMSO-d6): δ 7.27 (t, J = 8.0 Hz, 1H), 6.64 (d, J = 8.8 Hz, 2H), 3.72 (s, 6H).

[0334] Scheme 3: Synthesis of tert-butyl ((1-(methylsulfonyl)-1H-pyrazol-4-yl)methyl)-carbamate (7) [ka]

[0335] To a stirred solution of compound 6 (0.1 g, 0.5 mmol) in DMF (2 mL) at -40 °C, NaHMDS (0.5 mL, 0.5 mmol) was added, followed by methanesulfonyl chloride (0.04 mL, 0.55 mmol), and the resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound 7 (0.06 g, 42.98%) as a white gummy solid. TLC: 50% EtOAc / heptane (R f :0.4). 1 H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.84 (s, 1H), 7.29 (broad s, 1H), 4.02 (broad s, 2H), 3.50 (s, 3H), 1.39 (s, 9H). 10 H 17 LCMS calculated for N3O4S: 275.32; Found: 299.90 (M+23).

[0336] Scheme 4: Synthesis of tert-butyl ((1-(methylsulfonyl)-1H-pyrazol-3-yl)methyl)-carbamate (10) [ka]

[0337] Step 1: Synthesis of tert-butyl ((1H-pyrazol-3-yl)methyl)carbamate (9)

[0338] To a stirred solution of compound 8 (1 g, 10.30 mmol) in DCM (50 mL) at 0 °C, (Boc)2O (2.12 mL, 9.27 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with DCM. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the title compound 9 (1.7 g, 83.7%) as a white solid. TLC: 70% EtOAc / heptane (R f :0.3). C9H 15 LCMS calculated for N3O2: 197.24; Found: 198.2 (M+1).

[0339] Step 2: Synthesis of tert-butyl ((1-(methylsulfonyl)-1H-pyrazol-3-yl)methyl)carbamate (10) and tert-butyl ((1-(methylsulfonyl)-1H-pyrazol-5-yl)methyl)carbamate (10A)

[0340] To a stirred solution of compound 9 (1.7 g, 8.62 mmol) in DMF (25 mL) at -40 °C, NaHMDS (8.6 mL, 8.62 mmol) was added, followed by methanesulfonyl chloride (0.72 mL, 9.40 mmol), and the resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the title compound 10 (0.9 g, 38.1%) as a white gummy solid. TLC: 50% EtOAc / heptane (R f :0.4). 1 H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J = 2.4 Hz, 1H), 7.41 (t, J = 6.0 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 4.15 (d, J = 6.4 Hz, 2H), 3.50 (s, 3H), 1.40 (s, 9H). 1 H NMR shows 10 as the major isomer. 10 H17 LCMS calculated for N3O4S: 275.32; found: 273.95 (M-1). 10A was found to be the minor isomer and less pure and was discarded.

[0341] Scheme 5: Synthesis of tert-butyl 2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (7) [ka]

[0342] To a stirred solution of compound 11 (2.0 g, 9.56 mmol) in DMF (20 mL) at 0 °C, NaHMDS (9.5 mL, 9.56 mmol) was added, followed by methanesulfonyl chloride (0.85 mL, 10.51 mmol), and the resulting reaction mixture was stirred at -40 °C for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was collected, washed with saturated NaHCO3 solution, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the title compound 12 (1.2 g, 43.69%) as a pale yellow liquid. TLC: 50% EtOAc / heptane (R f :0.4). 1 H NMR (400 MHz, DMSO-d): δ 8.00-8.10 (m, 1H), 4.50-4.52 (m, 2H), 4.33-4.31 (m, 2H), 3.53 (s, 3H), 1.45 (s, 9H). VT NMR at 80 °C shows a 1:1 mixture of rotamers.

[0343] Synthesis of Compounds of Formula (I) Synthesis Examples 1 to 3 Scheme 6: Scheme for the synthesis of N-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide, 1-cyclohexyl-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)methanesulfonamide and 1-cyclohexyl-N-(6-((5-(4-(dimethylamino)but-2-ynoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide [ka]

[0344] (Note that although only one regioisomer of the compounds for 16, 17, 18, and 18a is shown in the above scheme and throughout Examples 1-3, both are present in the reaction mixture.) [ka]

[0345] Synthesis of 2,6-difluoro-4-(hydroxymethyl)benzonitrile (14)

[0346] To a stirred solution of compound 13 (5 g, 29.00 mmol) in THF (50 mL) at 0 °C, NaBH (1.6 g, 44.00 mmol) was added, and the resulting reaction mixture was stirred at the same temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to provide the title compound 14 (4.5 g, 88.93%) as a yellow solid. TLC: 30% EtOAc / heptane (R f :0.35). 1H NMR (400 MHz, DMSO-d6): δ 7.35-7.32 (m, 2H), 5.69 (t, J = 6.0 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H).

[0347] Synthesis of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (15)

[0348] To a stirred solution of compound 14 (4 g, 23.12 mmol) in MeOH (60 mL) at -40 °C, NaOMe (5.1 g, 94.00 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the solvent was concentrated under high vacuum. Water was added to the residue, and it was extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the title compound 15 (3.5 g, 81.69%) as a yellow solid. TLC: 50% EtOAc / heptane (R f :0.25). 1 H NMR (400 MHz, CDCl): δ 6.81-6.78 (m, 2H), 4.75 (s, 2H), 3.96 (s, 3H). No OH protons were observed.

[0349] Synthesis of tert-butyl 2-(4-cyano-3-fluoro-5-methoxybenzyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (16) [ka]

[0350] To a stirred solution of compound 15 (1.0 g, 5.5 mmol) in acetonitrile (5 mL) was added CsCO (3.22 g, 9.90 mmol), followed by compound 12 (1.74 g, 6.07 mmol), and the resulting reaction mixture was heated at 70 °C for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel (100-200 mesh) column chromatography using a gradient method of 0-50% EtOAc / heptane to provide the title compound 16 (1.0 g, 48.65%, isolated as an inseparable mixture of regioisomers) as a yellow solid. TLC: 80% EtOAc / heptane (R f :0.45). C 19 H 21 LCMS calculated for FN4O3: 372.40; Found: 373.85 (M+1). 1 The H NMR is complex, indicating a mixture of isomers, which was used as a mixture for the synthesis of the final compound from which a single regioisomer was isolated.

[0351] Synthesis of tert-butyl 2-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (17) [ka]

[0352] To a stirred solution of compound 16 (0.50 g, 1.34 mmol) in DMF (7 mL) was added acetohydroxamic acid (0.31 g, 4.02 mmol), followed by tBuOK (0.45 g, 4.02 mmol) was added, and the reaction mixture was stirred at 65 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude compound was purified by silica gel (100-200 mesh) column chromatography using a gradient method of 0-50% EtOAc / heptane to provide the title compound 17 (0.20 g, 38.64%, isolated as an inseparable mixture of regioisomers) as an off-white solid. TLC: 70% EtOAc / heptane (R f :0.40). C 19 H 23 LCMS calculated for N5O4: 385.42; Found: 386.00 (M+1). 1 The H NMR is complex and indicates a mixture of regioisomers.

[0353] Synthesis of tert-butyl 2-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (18) [ka]

[0354] To a stirred solution of compound 17 (0.160 g, 0.42 mmol) in DCM (3 mL) was added EtN (0.15 mL, 1.14 mmol) followed by cyclohexylmethanesulfonyl chloride (3, 0.11 g, 0.58 mmol) at 0 °C, and the resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled back to room temperature, diluted with DCM, and extracted. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by silica gel (100-200 mesh) column chromatography using a gradient method of 0-60% EtOAc / heptane to provide the title compound 18 (0.18 g, 79.60%, isolated as an inseparable mixture of regioisomers) as an off-white solid. TLC: 80% EtOAc / heptane (R f :0.35). C 26 H 35 LCMS calculated for N5O6S: 545.66; Found: 544.40 (M-1). 1 The H NMR is complex and indicates a mixture of regioisomers.

[0355] Synthesis of 1-cyclohexyl-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide [ka]

[0356] To a stirred solution of compound 18 (180 mg, 0.33 mmol) in DCM (3 mL) was added TFA (0.13 mL, 1.73 mmol) at 0 °C, and the reaction was stirred at room temperature for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled back to room temperature, basified with saturated NaHCO3 solution, and extracted with DCM. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude residue, which was triturated with diethyl ether / pentane to provide the title compound (100 mg, 67.10%, isolated as an inseparable mixture of regioisomers) as a white solid, which was used in the next reaction without further purification. C 21 H 27 LCMS calculated for N5O4S: 445.54; Found: 446.50 (M+1). 1 The H NMR is complex and indicates a mixture of regioisomers.

[0357] Synthesis Example 1 Synthesis of N-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide and a mixture of its positional isomers [ka]

[0358] To a stirred solution of 18a (0.050 g, 0.11 mmol) in DCM (3 mL) at 0 °C, EtN (0.045 mL, 0.63 mmol) was added, followed by acryloyl chloride (0.01 g, 0.11 mmol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with 5% MeOH / DCM. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by reverse-phase HPLC to provide the title compound (7 mg, 9.9%, isolated as an inseparable mixture of regioisomers) as an off-white solid. TLC: 5% MeOH / DCM (Rf :0.5). (See analytical data in Table 1).

[0359] Synthesis Example 2 Synthesis of 1-cyclohexyl-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)methanesulfonamide and a mixture of its positional isomers [ka]

[0360] To a stirred solution of 18a (0.050 g, 0.11 mmol) in DMF (2 mL) at 0 °C was added DIPEA (0.06 mL, 0.39 mmol), followed by T3P (0.06 mL, 0.22 mmol). The reaction was stirred at room temperature for 20 min. A pre-dissolved solution of propiolic acid (8 mg, 0.12 mmol) in DMF (0.5 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. After completion (monitored by TLC), the solvent was concentrated under high vacuum. The residue was quenched with water and extracted with DCM. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by reverse-phase HPLC to provide the title compound (6.1 mg, 11%, isolated as an inseparable mixture of regioisomers) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5). (See analytical data in Table 1).

[0361] Synthesis of 4-(dimethylamino)but-2-ynoic acid (20)

[0362] To a stirred solution of compound 19 (2.0 g, 0.24 mmol) in THF (20 mL) at −78° C. under an inert atmosphere was added n-BuLi (15 mL, 0.24 mmol, 1.6 M in hexane). The mixture was stirred at −78° C. for 1 h and then added to another flask containing crushed CO (11.5 g, 0.241 mmol), and the resulting reaction mixture was stirred at the same temperature for 30 min. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was poured into ice water and washed with ethyl acetate. The aqueous layer was collected and concentrated under reduced pressure to provide a residue, which was diluted with MeOH and filtered. The filtrate was concentrated under reduced pressure to give the title compound 20 (1.4 g, 45.74%) as a light brown solid. TLC: 10% MeOH / DCM (R f :0.3). 1 H NMR (400 MHz, DMSO-d): δ 3.15 (s, 2H), 2.14 (s, 6H). LCMS calculated for C6H9NO2: 127.14; found: 128.2 (M+1).

[0363] Synthesis Example 3 Synthesis of 1-cyclohexyl-N-(6-((5-(4-(dimethylamino)but-2-ynoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide [ka]

[0364] To a stirred solution of compound 18a (70 mg, 0.16 mmol) in DMF (1 mL) at 0 °C, DIPEA (0.09 mL, 0.51 mmol) was added, followed by 20 (18 mg, 0.14 mmol). The resulting mixture was stirred at 0 °C for 5 min. T3P (0.06 mL, 0.19 mmol) was then added, and the reaction was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction was quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by using prep. HPLC to provide the title compound (7 mg, 8%) as a mixture of regioisomers as an off-white solid. TLC: 10% MeOH / DCM (R f :0.5). (See analytical data in Table 1).

[0365] Synthesis Examples 4 to 6 Scheme 7: Scheme for the synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide, N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acrylamide, N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide and N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)ethenesulfonamide [ka]

[0366] Synthesis of tert-butyl ((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazol-4-yl)methyl)carbamate (21)

[0367] To a stirred solution of compound 15 (0.5 g, 2.76 mmol) in acetonitrile (10 mL) at room temperature, Cs2CO3 (2.7 g, 8.28 mmol) was added, followed by compound 7 (1.13 g, 4.14 mmol), and the resulting reaction mixture was heated at 70 °C for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by combi-flash chromatography using a gradient method of 40 to 70% EtOAc / heptane to provide the title compound 21 (0.400 g, 40.22%) as a brown semi-solid. TLC: 80% EtOAc / heptane (R f :0.45). 1 H NMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H), 7.39 (s, 1H), 7.18-7.12 (m, 1H), 7.00 (s, 1H), 6.69 (d, J = 9.6 Hz, 1H), 5.37 (s, 2H), 3.96 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 1.37 (s, 9H). C 18 H 21 LCMS calculated for FN4O3: 360.39; Found: 361.00 (M+1).

[0368] Synthesis of tert-butyl ((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (22)

[0369] To a stirred solution of compound 21 (0.2 g, 0.55 mmol) in a 6:1 mixture of DMF:HO (7 mL) at room temperature, acetohydroxamic acid (0.112 g, 1.50 mmol) was added, followed by KCO (0.414 g, 3.0 mmol). The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, ice water was added, and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by Combiflash chromatography using a gradient method of 40-60% EtOAc / heptane to provide the title compound 22 (0.1 g, 48.25%) as a brown semi-solid. TLC: 80% EtOAc / heptane (R f :0.40). 1 H NMR (400 MHz, DMSO-d6): δ 7.67 (s, 1H), 7.35 (s, 1H), 7.18-7.12 (m, 1H), 6.69 (s, 1H), 6.63 (s, 1H), 5.93 (s, 2H), 5.34 (s, 2H), 3.95 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 1.36 (s, 9H). C 18 H 23 LCMS calculated for N5O4: 373.41; Found: 374.05 (M+1).

[0370] Synthesis of tert-butyl ((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (23)

[0371] To a stirred solution of compound 22 (0.1 g, 0.26 mmol) in DCM (3 mL) at 0 °C, EtN (0.11 mL, 0.80 mmol) was added, followed by cyclohexylmethanesulfonyl chloride (3, 0.057 g, 0.29 mmol), and the reaction was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, water was added, and extracted. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by CombiFlash column chromatography using a gradient method of 40-60% EtOAc / heptane to provide the title compound 23 (0.070 g, 48.98%) as an off-white solid. TLC: 80% EtOAc / heptane (R f :0.35). C 25 H 35 LCMS calculated for N5O6S: 533.64; Found: 532.43 (M-1).

[0372] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide

[0373] To a stirred solution of compound 23 (70 mg, 0.13 mmol) in DCM (2 mL) at 0 °C, TFA (0.1 mL, 1.31 mmol) was added and the reaction was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), it was concentrated under reduced pressure and the crude compound was purified by reverse-phase HPLC to provide the title compound (4 mg, 7%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5). 1H NMR (400 MHz, DMSO-d6): δ 10.41 (broad s, 1H), 7.95 (broad s, 2H), 7.91 (s, 1H), 7.58 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.91 (integrated s, 5H), 3.37 (integrated d, J = 5.6 Hz, 2H), 2.04-1.91 (m, 1H), 1.86 (d, J = 12.4 Hz, 2H), 1.61 (d, J = 12.4 Hz, 2H), 1.59-1.51 (m, 1H), 1.29-1.04 (m, 5H);C 20 H 27 LCMS calculated for N5O4S: 433.53; Found: 434.15 (M+1).

[0374] Synthesis Example 4 Synthesis of N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acrylamide

[0375] To a stirred solution of compound 23a (60 mg, 0.13 mmol) in DCM (5 mL) at 0 °C, EtN (0.09 mL, 0.65 mmol) was added, followed by acryloyl chloride (0.008 mL, 0.11 mmol), and the reaction was stirred at the same temperature for 20 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, water was added, and extracted with 5% MeOH / DCM. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by prep HPLC to provide the title compound (2.5 mg, 7.9%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5). (See Table 1 for analytical data).

[0376] Synthesis Example 5 Synthesis of N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide

[0377] To a stirred solution of compound 23a (60 mg, 0.13 mmol) in DMF (1 mL) at 0 °C was added DIPEA (0.07 mL, 0.41 mmol), followed by T3P (0.08 mL, 0.27 mmol). The reaction was stirred at room temperature for 20 minutes. Then, a pre-dissolved solution of propionic acid (11 mg, 0.16 mmol) in DMF (0.5 mL) was added dropwise, and the reaction was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by prep. HPLC to provide the title compound (6.5 mg, 10%) as an off-white solid. TLC: 100% EtOAc (R f :0.5). (See Table 1 for analytical data).

[0378] Synthesis Example 6 Synthesis of N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)ethenesulfonamide

[0379] To a stirred solution of compound 23a (70 mg, 0.16 mmol) in THF (1 mL) was added NaH [60% dispersion in mineral oil] (12.8 mg, 0.32 mmol) at 0° C., followed by ethenesulfonyl chloride (22 mg, 0.17 mmol), and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), it was diluted with ethyl acetate and extracted. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by prep HPLC to provide the title compound (3.5 mg, 4.0%) as an off-white solid. TLC: 80% EtOAc / heptane (R f :0.35). (See Table 1 for analytical data).

[0380] Synthesis Examples 7 to 9 Scheme 8: Synthesis of N-(6-((3-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide, N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)acrylamide, N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)propiolamide, and N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)propionamide [ka]

[0381] Note that for the final compounds (Synthetic Examples 7-9), the other regioisomer was removed by purification to give the as-recovered isomer.

[0382] Synthesis of tert-butyl ((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazol-3-yl)methyl)carbamate (24 and its positional isomers)

[0383] To a stirred solution of compound 15 (0.2 g, 1.10 mmol) in acetonitrile (5 mL) at room temperature, Cs2CO3 (1.07 g, 3.30 mmol) was added, followed by compound 10 (0.440 g, 1.60 mmol), and the resulting reaction mixture was heated at 70 °C for 6 h. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by combi-flash chromatography using a 40-70% EtOAc / heptane gradient method to provide the title compound 24 (0.180 g, 45.4%, isolated as an inseparable mixture) as a brown semi-solid. TLC: 80% EtOAc / heptane (R f :0.45). 1 H NMR (400 MHz, DMSO-d6): δ 7.78 (s, 1H), 7.24-7.18 (m, 1H), 6.97 (s, 1H), 6.71 (d, J = 9.6 Hz, 1H), 6.15 (d, J = 2.0 Hz, 1H), 5.35 (s, 2H), 4.05 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 1.37 (s, 9H). 1 H NMR also indicates the presence of minor positional isomers; C 18 H 21 LCMS calculated for FN4O3: 360.39; Found: 359.0 (M-1).

[0384] Synthesis of tert-butyl ((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)carbamate (25 and its positional isomers)

[0385] To a stirred solution of compound 24 (0.18 g, 0.5 mmol) in a 6:1 mixture of DMF:HO (7 mL) at room temperature, N-hydroxyacetamide (0.112 g, 1.50 mmol) was added, followed by KCO (0.414 g, 3.0 mmol). The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, ice water was added, and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by Combiflash chromatography using a 40-60% EtOAc / heptane gradient method to provide the title compound 25 (0.130 g, 69.7%, isolated as an inseparable mixture) as a brown semi-solid. TLC: 80% EtOAc / heptane (R f :0.40). 1 H NMR (400 MHz, DMSO-d6): δ 7.78 (broad s, 1H), 7.24-7.18 (m, 1H), 6.97 (s, 1H), 6.71 (d, J = 10 Hz, 1H), 6.16 (s, 1H), 5.35 (s, 2H), 4.05 (d, J = 5.6 Hz, 2H), 3.94 (s, 3H), 1.37 (s, 9H). 1 H NMR also showed the presence of a minor regioisomer; the NH proton was not observed; C 18 H 23 LCMS calculated for N5O4: 373.41; Found: 374.02 (M+1).

[0386] Synthesis of tert-butyl ((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)carbamate (26 and its positional isomers)

[0387] To a stirred solution of compound 25 (0.130 g, 0.34 mmol) in DCM (3 mL) at 0 °C, EtN (0.14 mL, 1.00 mmol) was added, followed by cyclohexylmethanesulfonyl chloride (3, 0.081 g, 0.41 mmol), and the reaction was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the mixture was diluted with DCM, water was added, and extracted. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by CombiFlash column chromatography using a gradient method of 40–60% EtOAc / heptane to provide the title compound 26 (0.065 g, 34.99%, isolated as an inseparable mixture) as a brown gummy solid. TLC: 80% EtOAc / heptane (R f :0.35). C 25 H 35 LCMS calculated for N5O6S: 533.64; Found: 532.03 (M-1). 1 The H NMR is complex, indicating the presence of a minor regioisomer as a mixture with the desired product.

[0388] Synthesis of N-(6-((3-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide

[0389] To a stirred solution of compound 26 (65 mg, 0.12 mmol) in DCM (2 mL) at 0 °C, TFA (0.1 mL, 1.2 mmol) was added and the reaction was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), it was concentrated under reduced pressure and the crude compound was purified by reverse-phase HPLC to provide the title compound (6 mg, 11.36%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (broad s, 2H), 7.92 (d, J = 2.0 Hz, 1H), 6.66 (s, 1H), 6.54 (s, 1H), 6.37 (d, J = 2.4 Hz, 1H), 5.37 (s, 2H), 4.01 (s, 2H), 3.79 (s, 3H), 2.94 (d, J = 6.0 Hz, 2H), 1.86 (d, J = 12.4 Hz, 2H), 1.79-1.76 (m, 1H), 1.61-1.53 ​​(m, 3H), 1.24-1.05 (m, 3H), 0.94 (q, J = 11.2 Hz, 2H). C 20 H 27 LCMS calculated for N5O4S: 433.53; Found: 434.55 (M+1).

[0390] Synthesis Example 7 Synthesis of N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)acrylamide and a mixture of its positional isomers [ka]

[0391] To a stirred solution of 26a (60 mg, 0.13 mmol) in DCM (5 mL) at 0 °C, EtN (0.09 mL, 0.65 mmol) was added, followed by acryloyl chloride (0.008 mL, 0.11 mmol), and the reaction was stirred at the same temperature for 20 min. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, water was added, and extracted with 5% MeOH / DCM. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by prep HPLC to provide the title compound (5 mg, 7.4%, isolated as an inseparable regioisomeric mixture, approximately 75% regioisomers as removed) as an off-white solid. TLC: 5% MeOH / DCM (R f:0.5). (See analytical data in Table 1).

[0392] Synthesis Example 8 Synthesis of N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)propiolamide

[0393] To a stirred solution of compound 26a (80 mg, 0.18 mmol) in DMF (2.5 mL) at 0 °C was added DIPEA (0.12 mL, 0.72 mmol), followed by T3P (0.17 mL, 0.27 mmol). The reaction was stirred at room temperature for 20 min. Then, a predissolved solution of propiolic acid (12 mg, 0.18 mmol) in DMF (0.5 mL) was added dropwise, and the reaction was stirred at room temperature for 16 h. After completion (monitored by TLC), the solvent was concentrated under high vacuum. The residue was quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the crude compound, which was purified by prep-HPLC to give an inseparable mixture of isomers. The isomers were further separated by chiral HPLC (Method: Chiral-Met-B 30% 1.0 ml.1 cm; Mobile phase: A: 0.1% DEA in n-hexane; B: DCM:MeOH (50:50) A:B, 70:30; Injection volume: 10 μL; Flow rate: 1.0 mL / min; Column: CHIRAL PAK IG (250*4.6 mm, 5 μm); Duration maximum 25 min) to provide the title compound (27 mg, 31%) as a white solid. TLC: 100% EtOAc (R f :0.5). (See Table 1 for analytical data.) The minor isomer was not isolated in sufficient quantity due to an integrated impurity.

[0394] Synthesis Example 9 Synthesis of N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)propionamide

[0395] To a stirred solution of compound 26a (80 mg, 0.18 mmol) in DMF (2.5 mL) at 0 °C was added DIPEA (0.12 mL, 0.72 mmol), followed by T3P (0.17 mL, 0.27 mmol). The reaction was stirred at room temperature for 20 min. Then, a predissolved solution of propionic acid (13 mg, 0.18 mmol) in DMF (0.5 mL) was added dropwise, and the reaction was stirred at room temperature for 16 h. After completion (monitored by TLC), the solvent was concentrated under high vacuum. The residue was quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the crude compound, which was purified by prep-HPLC to give an inseparable mixture of isomers. The isomers were further separated by chiral HPLC (Method: Chiral-Met-B 30% 1.0 ml. 1 cm; Mobile phase: A: 0.1% DEA in n-hexane; B: DCM:MEOH (50:50) A:B, 70:30; Injection volume: 5 μL; Flow rate: 1.0 mL / min; Column: CHIRAL PAK IG (250*4.6 mm, 5 μm); Duration maximum 25 min) to provide the title compound (18 mg, 20%) as an off-white solid. TLC: 100% EtOAc (R f :0.5). (See Table 1 for analytical data.) The minor isomer was not isolated in sufficient quantity due to an integrated impurity.

[0396] Synthesis Examples 10-11 Scheme 9: Synthesis of 6-(acrylamidomethyl)-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide and N-((2-fluorophenyl)sulfonyl)-6-(propiolamidomethyl)benzofuran-2-carboxamide [ka]

[0397] Synthesis of 6-bromobenzofuran-2-carboxylic acid (28)

[0398] To a stirred solution of compound 27 (10 g, 49.75 mmol) in DMF (100 mL) was added K2CO3 (20.6 g, 149.250 mmol), followed by ethyl 2-bromoacetate (11 mL, 99.50 mmol). The reaction mixture was stirred at 160°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, acidified with 1N HCl (to pH 4-5), and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound 28 (5.2 g, 43.33%) as a brown solid. This compound was used in the next step without further purification. TLC: 80% EtOAc / heptane (R f :0.5). 1 H NMR (400 MHz, DMSO-d): δ 13.5 (broad s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.4, 1.2 Hz, 1H). LCMS calculated for C9H5BrO3: 241.04; found: 239.12 (M-2).

[0399] Synthesis of 6-bromobenzofuran-2-carboxamide (29)

[0400] To a stirred solution of compound 28 (1.5 g, 6.22 mmol) in DMF (15 mL) was added DIPEA (3.25 mL, 18.66 mmol), followed by HBTU (2.83 g, 7.46 mmol) and NH4Cl (1 g, 18.66 mmol). The reaction was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion, water was added and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound 29 (0.654 g, 43.78%) as a brown solid. This compound was used in the next step without further purification. TLC: 80% EtOAc / heptane (R f :0.6); 1H NMR (400 MHz, DMSO-d): 8.15 (broad s, 1H), 7.93 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.50 (dd, J = 8.8, 1.6 Hz, 1H). LCMS calculated for CHBrNO: 240.06; found: 241.75 (M+1).

[0401] Synthesis of 6-bromo-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide (30)

[0402] To a stirred solution of compound 29 (1.5 g, 6.30 mmol) in THF (20 mL) at 0 °C, NaH [60% dispersion in mineral oil] (0.378 g, 9.45 mmol) was added, and the contents were stirred for 15 min. 2-Fluorobenzenesulfonyl chloride (1.34 g, 6.93 mmol) was added, and the reaction was stirred at room temperature for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0 °C, quenched with ice water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel [100-200 mesh] column chromatography to provide the title compound 30 (2.01 g, 80.72%) as a white solid. TLC: 5% MeOH / DCM (R f. 0.2); 1 H NMR (400 MHz, DMSO-d): δ 7.89 (s, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.46 (q, J = 5.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.27-7.11 (m, 3H). No NH protons were observed; C 15 LCMS calculated for H9BrFNO4S: 398.20; Found: 400.15 (M+2).

[0403] Synthesis of 6-cyano-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide (31)

[0404] To an argon-purged solution of 30 (200 mg, 50 mmol) in DMF (5 mL) was added Zn(CN) (73 mg, 0.63 mmol), followed by Zn dust (32 mg, 50 mmol), and the mixture was purged with argon again for 15 min. Pd(dba) (23 mg, 2.5 mmol) and dppf (37 mg, 5 mmol) were added to the resulting mixture. The reaction was stirred at 130 °C for 16 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was filtered through a pad of Celite, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude compound was purified by prep-HPLC to provide the title compound 31 (0.348 g, 80.18%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.4); 1 H NMR (400 MHz, DMSO-d): δ 8.34 (s, 1H), 8.05-7.96 (m, 3H), 7.78-7.72 (m, 2H), 7.48-7.41 (m, 2H). No NH protons were observed; C 16 LCMS calculated for H9FN2O4S: 344.32; Found: 345.05 (M+1).

[0405] Synthesis of 6-(aminomethyl)-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide (32)

[0406] An autoclave was charged with a solution of 31 (400 mg, 1.16 mmol) in MeOH (10 mL), and the mixture was purged with nitrogen for 5 minutes. A predissolved solution of Raney Ni (w / w of SM) in 7N NH3 / MeOH (5 mL) was added under a nitrogen atmosphere. The reaction mixture was then purged with hydrogen and stirred at room temperature under a hydrogen atmosphere (100 psi) for 4 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered through a pad of Celite, which was washed with MeOH. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by Combiflash chromatography (using a gradient method of 5% MeOH / DCM) to provide the desired title compound 32 (0.314 g, 78.5%) as a yellow solid. TLC: 5% MeOH / DCM (R f :0.5); 1 H NMR (400 MHz, DMSO-d6): δ 8.14 (broad s, 3H), 7.84 (t, J = 7.2 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J = 2.8 Hz, 1H), 7.51-7.42 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.27-7.14 (m, 3H), 4.16 (d, J = 3.6 Hz, 2H). C 16 H 13 LCMS calculated for FN2O4S: 348.35; Found: 347.10 (M-1).

[0407] Synthesis Example 10 Synthesis of 6-(acrylamidomethyl)-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide

[0408] To a stirred solution of 32 (100 mg, 0.28 mmol) in DCM (5 mL) at 0 °C, EtN (0.12 mL, 0.84 mmol) was added, followed by acryloyl chloride (22.6 mg, 0.28 mmol), and the reaction was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, water was added, and extracted with 5% MeOH / DCM. The organic layer was collected, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by reverse-phase HPLC to provide the title compound (5 mg, 4.3%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.5). (See analytical data in Table 1).

[0409] Synthesis Example 11 Synthesis of N-((2-fluorophenyl)sulfonyl)-6-(propiolamidomethyl)benzofuran-2-carboxamide

[0410] To a stirred solution of 32 (150 mg, 0.43 mmol) in DMF (2 mL) at 0 °C was added DIPEA (0.22 mL, 1.29 mmol), followed by T3P (205 μL, 0.64 mmol). The reaction was stirred at room temperature for 20 min. Then, a pre-dissolved solution of propiolic acid (30 mg, 0.43 mmol) in DMF (0.5 mL) was added dropwise, and the reaction was stirred at room temperature for 2 h. After completion (monitored by TLC), the solvent was concentrated under high vacuum. The residue was quenched with water and extracted with DCM. The organic layer was collected, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by reverse-phase HPLC to provide the title compound (7 mg, 4%) as an off-white solid. TLC: 10% MeOH / DCM (R f :0.5). (See analytical data in Table 1).

[0411] Synthesis Examples 12-13 Scheme 10: Synthesis of N-((2-(3-(2-((2-fluorophenyl)sulfonyl)hydrazine-1-carbonyl)-5-methoxyphenyl)pyridin-4-yl)methyl)acrylamide and N-((2-(3-(2-((2-fluorophenyl)sulfonyl)hydrazine-1-carb...

Claims

1. Compound of formula (I): 【Chemistry 1】 R １ is C optionally substituted with 1, 2 or 3 R １ａ -C ３ -cycloalkyl; C ８ -C ３ -C ８ -cycloalkyl-C １ -C ６ alkyl, wherein said C ３ -C ８ -cycloalkyl is optionally substituted with 1, 2 or 3 R １ａ ; said C ３ -C ８ -cycloalkyl-C １ -C ６ alkyl; phenyl optionally substituted with 1, 2 or 3 R １ｂ ; phenyl-C １ｂ -C １ -C ６ alkyl optionally substituted with 1, 2 or 3 R １ｂ ; naphthyl optionally substituted with 1, 2 or 3 R １ｂ ; 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2 or 3 R １ｂ ; or 8- to 10-membered bicyclic heteroaryl optionally substituted with 1, 2 or 3 R; Each R １ａ is hydrogen, halo, C １ -C ６ Alkoxy and C ３ -C ８ - Selected independently from cycloalkyloxy; Each R １ｂ is hydrogen, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, hydroxyalkyloxy, -O-alkylene-NR １ｂ１ R １ｂ４ , -O-alkylene-C(O)OR １ｂ１ , -O-alkylene-O-alkylene-NR １ｂ１ R １ｂ４ , 【Chemistry 2】 , cyano, - (CH ２ ) ０－２ C(O)-OR １ｂ１ ,-(CH ２ ) ０－２ C(O)NR １ｂ１ R １ｂ２ ,-(CH ２ ) ０－２ NR １ｂ１ C(O)R １ｂ３ ,-(CH ２ ) ０－２ OH and C ３ -C ８ - Selected independently from cycloalkyloxy; R １ｂ１ is hydrogen or C １ -C ６ It is alkyl; R １ｂ２ is hydrogen or C １ -C ６ It is alkyl; R １ｂ３ is hydrogen or C １ -C ６ It is alkyl; R １ｂ４ is hydrogen, 【Transformation 3】 And; R ２ teeth, 【Chemistry 4】 Selected from the group consisting of; R ２ａ is hydrogen or C １ -C ６ It is alkyl; Each R ２ｂ These are independently hydrogen, halo, and -(CH ２ ) ０－２ OH, C １ -C ３ Alkyl, cyclopropyl, cyano, -CHF ２ , -CF ３ , C １ -C ４ Alkoxy, -OCHF ２ , -OCF ３ , or C ３ -C ８ It is a cycloalkyloxy; Each R ２ｅ is, independently, hydrogen, -OH, halo, C １ -C ６ alkyl, halo-C １ -C ６ alkyl, C ３ -C ８ cycloalkyl, C １ -C ６ alkoxy, halo-C １ -C ６ alkoxy, or C ３ -C ８ cycloalkyloxy; 【Transformation 5】 teeth, 【Transformation 6】 And; Regarding rings (a), (b), and (c), R ２ｄ X in the meta position relative to １ is CR ３ and the other X １ are independently selected from N and CR ２ｂ ; R ２ｄ is hydrogen, halo, C １ -C ６ Alkyl, C １ -C ６ Cycloalkyl, C １ -C ６ Alkoxy, or C ３ -C ８ -It is a cycloalkyloxy; R ３ is, -(CH ２ ) ０－２ Y or - (CH ２ ) ０－２ -L-Y; L is -L １ -L ２ -L ３ - and L １ , L ２ and L ３ These are, independently, bonded, -CRR-, O, S(O) ０－２ , C(O) or NR, where each R is independently H or alkyl; Y is R Ｙ Replaced with R ２ｅ It is a five-membered monocyclic heteroaryl with arbitrary substitutions; Y is R Ｙ Replaced by and one or two R ２ｅ A six-membered monocyclic aryl or heteroaryl is optionally substituted with; Y is R Ｙ Replaced by and one or two R ２ｅ It is an 8-membered bicyclic heteroaryl with arbitrary substitutions; Y is R Ｙ Substituted with and 1, 2, or 3 R ２ｅ It is a 9-membered bicyclic heteroaryl with arbitrary substitutions; Y is R Ｙ Substituted with and 1, 2, or 3 R ２ｅ It is a 10-membered bicyclic heteroaryl with arbitrary substitutions; Y is R Ｙ Replaced by and one or two R ２ｅ It is an 8 or 9-membered biring complex ring in which R is arbitrarily substituted; Y is R Ｙ Replaced by and one or two R ２ｅ It is a 4- to 9-membered monocyclic or bicyclic heterocycloalkyl compound that is optionally substituted with; Y is 【Transformation 7】 And; Y is - (CH ２ ) ０－３ NR ３ｂ R Ｙ And; or Y is - (CH ２ ) ０－３ NR ３ｂ C(O)R Ｙ And; R Ｙ is, -(CH ２ ) ０－３ NR ３ｂ C(O)R ３ａ ,-(CH ２ ) ０－２ NR ３ｂ S(O) ２ R ３ａ , -C(O)R ３ａ , -S(O) ２ R ３ａ , -C(O)NR ３ｂ R ３ａ , -C(O)R ３ａ C replaced by ３ -C ８ Heterocycloalkyl; -(CH ２ ) ０－３ NR ３ｂ (C １ -C ６ Alkylene) NR ３ｂ１ C(O)R ３ａ ,-(CH ２ ) ０－３ NR ３ｂ (C １ -C ６ Alkylene) NR ３ｂ１ S(O) ２ R ３ａ ,-(CH ２ ) ０－３ NR ３ｂ C(O)(C １ -C ６ Alkylene) NR ３ｂ１ C(O)R ３ａ , or - (CH ２ ) ０－３ NR ３ｂ C(O)(C １ -C ６ Alkylene) NR ３ｂ１ S(O) ２ R ３ａ And, R ３ａ , R ３ｂ and R ３ｂ１ is selected from (i), (ii), or (iii): (i) R ３ａ , R ３ｂ and R ３ｂ１ One of these is group a): C replaced by one or two independently selected halos. １ -C ６ Alkyl; cyano-substituted C １ -C ６ Alkyl; fluoroalkoxy-substituted C １ -C ６ Alkyl; aryloxy or heteroaryloxy (each of these is a halo, C) １－６ Alkyl, C ２－６ Alkenil, C １－６ Alkoxy, cyano, C ３－８ Cycloalkyl or C ３－８ C (substituted with 1 to 3 substituents, each independently selected from heterocycloalkyl groups) １ -C ６ Alkyl; C ２ -C ６ Alkenyl; C substituted with cyano ２ -C ６ Alkenyl; C substituted with halo ２ -C ６ Alkenyl; -CH=CH-CH ２ -NR ３ｃ R ３ｄ ;-CH=CH-CH ２ -O-C １ -C ６ Alkyl; C ３ -C ８ Cycloalkenyl; -C(O)-C ３ -C ８ Cycloalkyl; C ２ -C ６ Alkinyl; -CHΞCH-CH ２ -NR ３ｃ R ３ｄ ; CHΞCH-CH ２ -OH;-CHΞCH-CH ２ -O-C １ -C ６ Selected from alkyl; cyano-substituted spirocycloalkyl; chloropyridyl; fluoropyridyl; chloropyradinyl; fluoropyradinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl, difluorophenyl; and monofluorophenyl; R ３ａ , R ３ｂ and R ３ｂ１ The others among them are: group b): hydrogen, and C １ -C ６ Selected from alkyl groups; or (ii) R ３ａ , R ３ｂ and R ３ｂ１ One of them is group a): hydrogen; C １ -C ６ Alkyl; aryloxy or heteroaryloxy (each of these is C １－６ Alkyl, C ２－６ Alkenil, C １－６ Alkoxy, cyano, C ３－８ Cycloalkyl or C ３－８ C (substituted with 1 to 3 substituents, each independently selected from heterocycloalkyl groups) １ -C ６ Alkyl; C ２ -C ６ Alkenil; C ３ -C ８ Cycloalkenyl; -C(O)-C ３ -C ８ Cycloalkyl; C ２ -C ６ Selected from alkynyl; spirocycloalkyl; pyridyl; pyrimidinyl; and phenyl; R ３ａ , R ３ｂ and R ３ｂ１ The others among them are: group b): hydrogen, and C １ -C ６ Selected from alkyl groups; or (iii) R ３ａ , R ３ｂ and R ３ｂ１ Each of them is independently of hydrogen or C １ -C ６ It is alkyl; R ３ｃ is hydrogen, or C １ -C ６ It is alkyl, R ３ｄ is hydrogen, or C １ -C ６ Alkyl; or R ３ｃ and R ３ｄ These atoms form a 3- to 8-membered saturated ring with the nitrogen atoms to which they are bonded, and the other 2- to 7 ring members are carbon atoms; HET1 is C ３ -C ８ It is heterocycloalkyl; Regarding ring (d), X ２ａ is either O or S; One X ２ CR ４ And other X ２ N and CR ２ｂ Selected independently of; R ４ is, -(CH ２ ) ０－３ NR ４ｂ C(O)R ４ａ ,-(CH ２ ) ０－２ NR ４ｂ S(O) ２ R ４ａ , -C(O)R ４ａ , -C(O)NR ４ｂ R ４ａ , -NR ４ｂ (C １ -C ６ Alkylene) NR ４ｂ１ C(O)R ４ａ ,-(CH ２ ) ０－３ NR ４ｂ C(O)(C １ -C ６ Alkylene) NR ４ｂ１ C(O)R ４ａ , -C(O)NR ４ｂ (C １ -C ６ Alkylene) NR ４ｂ１ C(O)R ４ａ , -C(O)-HET1-C(O)R ４ａ , -C(O)-HET1-NR ４ｂ C(O)R ４ａ ,-(CH ２ ) ０－３ NR ４ｂ C(O)-HET1-C(O)R ４ａ , -C(O)R ４ａ C replaced by ３ -C ８ Heterocycloalkyl (preferably the above C) ３ -C ８ Heterocycloalkyl is C ３ -C ８ (Bonded to the ring (d) via a carbon in the heterocycloalkyl ring); or -(CH ２ ) ０－２ HET2-C(O)R ４ａ And; R ４ａ , R ４ｂ and R ４ｂ１ is selected from (i), (ii), and (iii): (i) R ４ａ , R ４ｂ and R ４ｂ１ One of these is group a): alkyl substituted with one or two independently selected halos; cyano substituted C １ -C ６ Alkyl; C ２ -C ６ Alkenyl; C substituted with cyano ２ -C ６ Alkenyl; C substituted with halo ２ -C ６ Alkenyl; -CH=CH-CH ２ -NR ４ｃ R ４ｄ ;-CH=CH-CH ２ -O-C １ -C ６ Alkyl; C ３ -C ８ Cycloalkenyl; -C(O)-C ３ -C ８ Cycloalkyl; C ２ -C ６ Alkinyl; -CHΞCH-CH ２ -NR ４ｃ R ４ｄ ; CHΞCH-CH ２ -OH;CHΞCH-CH ２ -O-C １ -C ６ Selected from alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyradinyl, fluoropyradinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; R ４ａ , R ４ｂ and R ４ｂ１ The others among them are: group b): hydrogen, and C １ -C ６ Selected from alkyl groups; (ii) R ４ａ , R ４ｂ and R ４ｂ１ One of them is group a): hydrogen; alkyl; C ２ -C ６ Alkenil; C ３ -C ８ Cycloalkenyl; -C(O)-C ３ -C ８ Cycloalkyl; C ２ -C ６ Selected from alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; R ４ａ , R ４ｂ and R ４ｂ１ The others among them are: group b): hydrogen, and C １ -C ６ Selected from alkyl groups; or (iii) R ４ａ , R ４ｂ and R ４ｂ１ Each of them is independently of hydrogen or C １ -C ６ It is alkyl; R ４ｃ is hydrogen, or C １ -C ６ It is alkyl, R ４ｄ is hydrogen, or C １ -C ６ Alkyl; or R ４ｃ and R ４ｄ These atoms form a 3- to 8-membered saturated ring with the nitrogen atoms to which they are bonded, and the other 2- to 7 ring members are carbon atoms; HET1 is C ３ -C ８ It is heterocycloalkyl; HET2 has one or two R ２ｅ It is an 8, 9, or 10-membered bicyclic complex ring in which the following are arbitrarily substituted: Regarding rings (e) and (f), R ５ is replaced by Z, and R ２ｅ It is a five-membered monocyclic heteroaryl with arbitrary substitutions; R ５ is replaced by Z, and R ２ｅ It is a six-membered monocyclic heteroaryl with arbitrary substitutions; R ５ is -C(O)N(R ５ｂ ) Z is; R ５ is replaced by Z, and R ２ｅ It is a heterocycloalkyl group optionally substituted with; R ５ is, -(CH ２ ) ０－２ O-HET1-Z; or R ５ is, -(CH ２ ) ０－２ It is O-Z; Z is -(CH ２ ) ０－３ NR ５ｂ C(O)R ５ａ ,-(CH ２ ) ０－２ NR ５ｂ S(O) ２ R ５ａ , -C(O)R ５ａ , -S(O) ２ R ５ａ ,-(CH ２ ) ０－３ -C(O)NR ５ｂ R ５ａ ,-(CH ２ ) ０－３ NR ５ｂ (C １ -C ６ Alkylene) NR ５ｂ１ C(O)R ５ａ , -NR ５ｂ C(O)R ５ａ C replaced by ３ -C ８ Heterocycloalkyl, -S(O) ２ R ５ａ C replaced by ３ -C ８ Heterocycloalkyl, or -C(O)R ５ａ C replaced by ３ -C ８ It is heterocycloalkyl; R ５ａ , R ５ｂ and R ５ｂ１ is selected from (i), (ii), or (iii): (i) R ５ａ , R ５ｂ and R ５ｂ１ One of these is group a): C replaced by one or two independently selected halos. １ -C ６ Alkyl; cyano-substituted C １ -C ６ Alkyl; C ２ -C ６ Alkenyl; C substituted with cyano ２ -C ６ Alkenyl; C substituted with halo ２ -C ６ Alkenyl; -CH=CH-CH ２ -NR ５ｃ R ５ｄ ;-CH=CH-CH ２ -O-C １ -C ６ Alkyl; C ３ -C ８ Cycloalkenyl; -C(O)-C ３ -C ８ Cycloalkyl; C ２ -C ６ Alkinyl; -CHΞCH-CH ２ -NR ５ｃ R ５ｄ ; CHΞCH-CH ２ -OH;CHΞCH-CH ２ -O-C １ -C ６ Selected from alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyradinyl, fluoropyradinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl, R ５ａ , R ５ｂ and R ５ｂ１ The others among them are: group b): hydrogen, and C １ -C ６ Selected from alkyl groups; (ii) R ５ａ , R ５ｂ and R ５ｂ１ One of them is group a): hydrogen; C １ -C ６ Alkyl; C ２ -C ６ Alkenil; C ３ -C ８ Cycloalkenyl; -C(O)-C ３ -C ８ Cycloalkyl; C ２ -C ６ Selected from alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; R ５ａ , R ５ｂ and R ５ｂ１ The others among them are: group b): hydrogen, and C １ -C ６ Selected from alkyl groups; or (iii) R ５ａ , R ５ｂ and R ５ｂ１ Each of them is independently of hydrogen or C １ -C ６ It is alkyl; Each R ５ｃ These are, independently, hydrogen, or C １ -C ６ It is alkyl, R ５ｄ is hydrogen, or C １ -C ６ Alkyl; or R ５ｃ and R ５ｄ These atoms form a 3- to 8-membered saturated ring with the nitrogen atoms to which they are bonded, and the other 2- to 7 ring members are carbon atoms; HET1 is C ３ -C ８ It is heterocycloalkyl; Regarding ring (g), Q １ CR Ｑ１ Q ２ N is Q ３ is O; or Q １ CR Ｑ１ Q ２ O is Q ３ is N; or Q １ S is Q ２ N is Q ３ is N; or Q １ N is Q ２ N is Q ３ is O; or Q １ O is Q ２ N is Q ３ is N; R Ｑ１ is hydrogen, C(O)C １ -C ６ Alkyl or Cl; R ６ is replaced by Q, and R ２ｅ A 5 or 6-membered monocyclic heteroaryl optionally substituted with; or R ６ is Q; Q is - (CH ２ ) ０－３ NR ６ｂ C(O)R ６ａ ,-(CH ２ ) ０－２ NR ６ｂ S(O) ２ R ６ａ , -C(O)R ６ａ , -C(O)NR ６ｂ R ６ａ , or -C(O)R ６ａ C replaced by ３ -C ８ It is heterocycloalkyl; R ６ａ and R ６ｂ is selected from (i), (ii), or (iii): (i) R ６ａ and R ６ｂ One of these is group a): C replaced by one or two independently selected halos. １ -C ６ Alkyl; cyano-substituted C １ -C ６ Alkyl; C ２ -C ６ Alkenyl; C substituted with cyano ２ -C ６ Alkenyl; C substituted with halo ２ -C ６ Alkenyl; -CH=CH-CH ２ -NR ６ｃ R ６ｄ ;-CH=CH-CH ２ -O-C １ -C ６ Alkyl; C ３ -C ８ Cycloalkenyl; -C(O)cycloalkyl; alkynyl; -CHΞCH-CH ２ -NR ６ｃ R ６ｄ ; CHΞCH-CH ２ -OH;CHΞCH-CH ２ -O-C １ -C ６ Selected from alkyl; cyano-substituted spirocycloalkyl; chloropyridyl, fluoropyridyl, chloropyradinyl, fluoropyradinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; R ６ａ and R ６ｂ The others among them are: group b): hydrogen, and C １ -C ６ Selected from alkyl groups; (ii) R ６ａ and R ６ｂ One of them is group a): C １ -C ６ Alkyl; C ２ -C ６ Alkenil; C ３ -C ８ Selected from cycloalkenyl; -C(O)cycloalkyl; alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; R ６ａ and R ６ｂ The others among them are: group b): hydrogen, and C １ -C ６ Selected from alkyl groups; or (iii) R ６ａ and R ６ｂ These are, independently, hydrogen and C １ -C ６ It is alkyl; R ６ｃ is hydrogen, or C １ -C ６ It is alkyl, R ６ｄ is hydrogen, or C １ -C ６ Alkyl; or R ６ｃ and R ６ｄ These atoms form a 3- to 8-membered saturated ring with the nitrogen atoms to which they are bonded, and the other 2- to 7 ring members are carbon atoms; Each R ７ These are, independently, hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ８ (It is cycloalkyl); or its pharmaceutically acceptable salt(s); and / or its stereoisomers or mixtures thereof.

2. R １ C ３ -C ８ - A cycloalkylalkyl, and the C ３ -C ８ - Cycloalkylalkyl groups have 1, 2, or 3 R １ａ The above C is arbitrarily replaced by ３ -C ８ - Cycloalkylalkyl, or 1, 2, or 3 R １ｂ The compound according to claim 1, which is a phenyl optionally substituted with, wherein each R1b is optionally independently selected from hydrogen, halo, -C(O)OH, -C(O)(OCH3), C1-C6 alkyl, and C1-C6 alkoxy; or a pharmaceutically acceptable salt(s) thereof; and / or a mixture of stereoisomers thereof.

3. R １ is 1, 2, or 3 R １ｂ The compound according to claim 2, wherein phenyl is optionally substituted with, where each R1b is independently selected from hydrogen, halo, -C(O)OH, -C(O)(OCH3), C1-C6 alkyl, and C1-C6 alkoxy; or pharmaceutically acceptable salts thereof; and / or mixtures thereof of stereoisomers or stereoisomers.

4. R １ is 1, 2, or 3 R １ｂ A compound according to claim 1, which is a 5 or 6-membered monocyclic heteroaryl optionally substituted with, wherein each R1b is optionally independently selected from hydrogen, halo, -C(O)OH, -C(O)(OCH3), C1-C6 alkyl, and C1-C6 alkoxy; or a pharmaceutically acceptable salt(s) thereof; and / or a mixture of stereoisomers thereof.

5. R ２ teeth, 【Transformation 8】 The compound according to claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

6. R ２ teeth, 【Chemistry 9】 The compound according to claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

7. R ２ teeth, 【Chemistry 10】 And optionally, (c) is 【Chemistry 11】 The compound according to claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

8. R ２ｄ C １ -C ３ A compound according to claim 1, wherein each R 2b is optionally hydrogen; or a pharmaceutically acceptable salt thereof; and / or a stereoisomer thereof or a mixture of stereoisomers thereof.

9. R ３ is, -(CH ２ The compound according to claim 1, wherein the compound is -Y; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomer(s) thereof or mixture of stereoisomer(s).

10. Y is R Ｙ It is a five-membered monocyclic heteroaryl substituted with; Y is R Ｙ It is pyrazolyl substituted with; Y is R Ｙ It is an 8 or 9-membered biring complex ring substituted with; Y is 【Chemistry 12】 is; or Y is, 【Chemistry 13】 The compound according to claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

11. R Ｙ is, -(CH ２ ) ０－３ NHC(O)R ３ａ ,-(CH ２ ) ０－２ NHS (O) ２ R ３ａ , -C(O)R ３ａ , -S(O) ２ R ３ａ ,-(CH ２ ) ０－３ NH(C) １ -C ６ Alkilen NHC(O)R ３ａ ,-(CH ２ ) ０－３ NH(C) １ -C ６ Alkilen) NHS (O) ２ R ３ａ ,-(CH ２ ) ０－３ NHC(O)(C) １ -C ６ Alkilen NHC(O)R ３ａ ,-(CH ２ ) ０－３ NHC(O)(C) １ -C ６ Alkilen) NHS (O) ２ R ３ａ , or -C(O)R ３ａ C replaced by ３ -C ８ It is heterocycloalkyl; R ３ａ R is selected from group a), and optionally R 3a is -CH2 (halo); -(CH2)1-2CN; -CH2OCH(CF3)2; -CH2O (trifluorophenyl); -CH2O (tetrafluorophenyl); -CH2O (isoxazolyl) optionally substituted with 1 to 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, cyano, C3-8 cycloalkyl or C3-8 heterocycloalkyl; -CH2O (isoxazolyl) optionally substituted with 1 to 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, cyano, C3-8 cycloalkyl or C3-8 heterocycloalkyl. -CH2O (pyridyl) optionally substituted with 1 to 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, cyano, C3-8 cycloalkyl or C3-8 heterocycloalkyl; C2-C6 alkenyl; cyano-substituted C2-C4 alkenyl; halo-substituted C2-C4 alkenyl; -CH=CH-CH2-NR3cR3d; -CH=CH-CH2-O-C1-C6 alkyl; tetrafluorophenyl; trifluorophenyl; C2-C6 alkynyl; -CHΞCH-CH2-NR3cR3d; or -CHΞCH-CH2-O-C1-C6 A compound according to claim 1, which is alkyl; a pharmaceutically acceptable salt thereof; and / or a stereoisomer thereof or a mixture of stereoisomers thereof.

12. R Ｙ teeth, 【Chemistry 14】 The compound according to claim 1 or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer thereof or a mixture of stereoisomers thereof.

13. R ２ teeth, 【Chemistry 15】 The compound according to claim 1, wherein optionally one X2 is CR4, the other X2 is CH, and optionally X2a is O; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture thereof.

14. R ４ teeth, -(CH ２ ) ０－２ NHC(O)R ４ａ ; -NH(C) ２ -C ４ -Alkilen) NHC(O)R ４ａ ; C ３ -C ８ -C(O)R at the nitrogen ring atom in heterocycloalkyl groups ４ａ The C replaced by ３ -C ８ Heterocycloalkyl (preferably the C ３ -C ８ Heterocycloalkyl is C ３ -C ８ (Bonded to ring (d) via carbon in the heterocycloalkyl ring); -C(O)-HET1-C(O)R ４ａ (In the formula, -C(O)R ４ａ (It is bonded to the nitrogen ring atom in HET1); -C(O)-HET1-NHC(O)R ４ａ (In the formula, -C(O)- is bonded to the nitrogen ring atom in HET1); -C(O)NH(C １ -C ６ Alkilen NHC(O)R ４ａ ; - (CH ２ ) ０－２ HET2-C(O)R ４ａ (wherein HET2 is a 5-membered monocyclic heteroaryl, or an 8 or 9-membered bicyclic heterocyclic, -C(O)R ４ａ (It is bonded to HET2 via the nitrogen ring atom in HET2); - (CH ２ ) ０－３ NHC(O)(C) １ -C ６ Alkilen NHC(O)R ４ａ ;or - (CH ２ ) ０－３ NHC(O)-HET1-C(O)R ４ａ And; R ４ａ is selected from group a), and arbitrarily R 4a is CH 2 (halo); -(CH 2) 1-2 CN; C 2-C 6 alkenyl; cyano-substituted C 2-C 4 alkenyl; halo-substituted C 2-C 4 alkenyl; -CH=CH-CH 2-NR 4c R 4d; -CH=CH-CH 2-O-C 1-C 6 alkyl; tetrafluorophenyl; trifluorophenyl; C 2-C 6 alkynyl; -CHΞCH-CH 2-NR 4c R 4d; or -CHΞCH-CH 2-O-C 1-C 6 alkyl. The compound according to claim 13; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

15. R ４ teeth, 【Chemistry 16】 The compound according to claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

16. R ２ teeth, 【Chemistry 17】 The compound according to claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

17. R ２ teeth, [Chemistry 18] The compound according to claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

18. Z is, 【Chemistry 19】 The compound according to claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof. [Request Item 19] [Chemistry 20] 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound according to claim 1 or its stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts selected from the above.

20. Compounds of formula (I'), formula (Ii), and formula (Ih): 【Chemistry 21】 In the formula, R １ is 1, 2, or 3 R １ａ C arbitrarily replaced by ３ -C ８ -Cycloalkyl; C ３ -C ８ - A cycloalkylalkyl, and the C ３ -C ８ - Cycloalkyl groups have 1, 2, or 3 R groups. １ａ The above C is arbitrarily replaced by ３ -C ８ -Cycloalkylalkyl; 1, 2, or 3 R １ｂ Phenyl compounds optionally substituted with; 1, 2, or 3 R １ｂ Naphthyl optionally substituted with; 1, 2, or 3 R １ｂ A 5 or 6-membered monocyclic heteroaryl optionally substituted with; or 1, 2, or 3 R １ｂ It is an 8-10 membered bicyclic heteroaryl with arbitrary substitutions; Each R １ａ H, Halo, C １ -C ６ Alkoxy and C ３ -C ８ - Selected independently from cycloalkyloxy; Each R １ｂ H, Halo, C １ -C ６ Alkoxy, cyano, and C ３ -C ８ - Selected independently from cycloalkyloxy; R ２ teeth, 【Chemistry 22】 Selected from the group consisting of; In equation (I') and equation (Ih) 【Chemistry 23】 Regarding R ２ｂ is hydrogen or C １ -C ６ It is alkyl; One X １ is C(CH ２ R ２ｃ ) and the other two X １ N and CR ２ｅ Selected independently of; C (CH ２ R ２ｃ ) is R ２ｄ It is in a meta position relative to; R ２ｃ is one or two R ２ｃ１ It is a five-membered monocyclic heteroaryl with arbitrary substitutions; R ２ｃ is one or two R ２ｃ１ It is an 8 or 9-membered biring complex ring in which R is arbitrarily substituted; ２ｃ is 1, 2, or 3 R ２ｃ１ It is a six-membered monocyclic heteroaryl with arbitrary substitutions; R ２ｃ is 1, 2, or 3 R ２ｃ１ It is a 9-membered bicyclic heteroaryl with any substitution; or R ２ｃ is 1, 2, or 3 R ２ｃ１ It is a 10-membered bicyclic heteroaryl with arbitrary substitutions; Each R ２ｃ１ These are H, Halo, and C, which are independent of each other. １ -C ６ Alkyl, C １ -C ６ Alkylcarbonyl, -CN, C １ -C ６ Alkoxy, C ３ -C ８ Cycloalkyloxy, -(CH ２ ) ０－１ NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ ,-(CH ２ ) ０－１ NHC(O)R ２ｆ ,-(CH ２ ) ０－１ NHC(O)OR ２ｆ , a 5 or 6-membered monocyclic heteroaryl, or a 9 or 10-membered bicyclic heteroaryl; R ２ｆ C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C ３ -C ６ Cycloalkyl C １ -C ３ It is alkyl; In equation (I') and equation (Ii) 【Chemistry 24】 Regarding One X １ is C(CH ２ R ２ｃ ) and the other two X １ N and CR ２ｅ Selected independently of; R ２ｃ R ２ｃ２ Replaced with R ２ｃ３ It is a five-membered monocyclic heteroaryl with arbitrary substitutions; R ２ｃ is one or two R ２ｃ１ It is an 8 or 9-membered biring complex ring in which R is arbitrarily substituted; ２ｃ R ２ｃ２ Replaced with R ２ｃ３ It is an 8 or 9-membered biring complex ring in which R is arbitrarily substituted; ２ｃ R ２ｃ２ Replaced by and one or two R ２ｃ３ It is a six-membered monocyclic heteroaryl with arbitrary substitutions; R ２ｃ R ２ｃ２ Replaced by and one or two R ２ｃ３ It is a 9-membered bicyclic heteroaryl with any substitution; or R ２ｃ is 1, 2, or 3 R ２ｃ１ It is a 10-membered bicyclic heteroaryl with arbitrary substitutions; R ２ｃ２ C １ -C ６ Alkylcarbonyl, -CN, -CH ２ NH ２ , C １ -C ６ Alkoxy, -NH(C) １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ ien-CH ２ NHC(O)R ２ｆ ,-(CH ２ ) ０－１ NHC(O)OR ２ｆ , a 5 or 6-membered monocyclic heteroaryl, or a 9 or 10-membered bicyclic heteroaryl; R ２ｆ C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C ３ -C ６ Cycloalkyl C １ -C ３ It is alkyl; R ２ｃ３ These are H, Halo, and C, which are independent of each other. １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ８ It is a cycloalkyloxy; Each R ２ｃ１ These are H, Halo, and C, which are independent of each other. １ -C ６ Alkyl, C １ -C ６ Alkylcarbonyl, C １ -C ６ Alkoxy, C ３ -C ８ Cycloalkyloxy, -CN, -CH ２ NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ ien-CH ２ NHC(O)R ２ｆ ,-(CH ２ ) ０－１ NHC(O)OR ２ｆ , a 5 or 6-membered monocyclic heteroaryl, or a 9 or 10-membered bicyclic heteroaryl; R ２ｆ C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C ３ -C ６ Cycloalkyl C １ -C ３ It is alkyl; Regarding the ring (c) in equation (I'), One X １ is C(CH ２ R ２ｃ ) and the other two X １ N and CR ２ｅ Selected independently of; 【Chemistry 25】 teeth, 【Chemistry 26】 And; R ２ｃ is a 5-membered monocyclic heteroaryl optionally substituted with one or two R ２ｃ１ ; R ２ｃ is an 8- or 9-membered bicyclic heterocyclic optionally substituted with one or two R ２ｃ１ ; R ２ｃ is a 6-membered monocyclic heteroaryl optionally substituted with one, two, or three R ２ｃ１ ; R ２ｃ is a 9-membered bicyclic heteroaryl optionally substituted with one, two, or three R ２ｃ１ ; or R ２ｃ is a 10-membered bicyclic heteroaryl optionally substituted with one, two, or three R ２ｃ１ ; Each R ２ｃ１ is, independently, H, halo, C １ -C ６ alkyl, C １ -C ６ alkylcarbonyl, -CN, C １ -C ６ alkoxy, C ３ -C ８ cycloalkyloxy, -CH ２ NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -CH ２ NHCO(R) ２ｆ , -(CH ２ ) ０－１ NHCOOR ２ｆ , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; R ２ｆ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C ３ -C ６ cycloalkyl C １ -C ３ alkyl; R ２ｄ Hello, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C ３ -C ８ -It is a cycloalkyloxy; Each R ２ｅ These are, independently, hydrogen, halo, and C. １ -C ３ Alkyl, cyclopropyl, -CHF ２ , -CF ３ , C １ -C ４ Alkoxy, -OCHF ２ , or -OCF ３ That is, The compound described in claim 1; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

21. R １ is 1, 2, or 3 R １ｂ The compound according to claim 20, which is a phenyl optionally substituted with; or a pharmaceutically acceptable salt thereof; and / or a stereoisomer thereof or a mixture of stereoisomers thereof.

22. R １ is 1, 2, or 3 R １ｂ The compound according to claim 20, which is a 5 or 6-membered monocyclic heteroaryl optionally substituted with; or a pharmaceutically acceptable salt thereof; and / or a stereoisomer thereof or a mixture of stereoisomers thereof.

23. R １ is 1, 2, or 3 R １ｂ The compound according to claim 20, which is an 8-10 membered bicyclic heteroaryl optionally substituted with; or a pharmaceutically acceptable salt thereof; and / or a stereoisomer thereof or a mixture of stereoisomers thereof.

24. R ２ｄ C １ -C ６ Alkoxy, preferably C １ -C ３ The compound according to claim 20, wherein R 2e is an alkoxy, preferably a methoxy, and optionally R 2e is independently hydrogen, fluoro, C1-C3 alkyl, cyclopropyl, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, or -OCF3; or a pharmaceutically acceptable salt(s) thereof; and / or a mixture of stereoisomers thereof.

25. The aforementioned compound is given by formula (Ii): 【Chemistry 27】 The compound according to claim 20; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

26. R ２ｃ R is a 5-membered heteroaryl group (preferably pyrazolyl) condensed to an 8 or 9-membered bicyclic heterocyclic group, preferably a non-aromatic cyclic group, and ２ｃ is one or two R ２ｃ１ The compound according to claim 25, optionally substituted with; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

27. R ２ｃ R ２ｃ２ Replaced with R ２ｃ３ The compound according to claim 25, which is a five-membered monocyclic heteroaryl, preferably pyrazolyl, optionally substituted with; or a pharmaceutically acceptable salt thereof; and / or a stereoisomer thereof or a mixture of stereoisomers thereof.

28. R ２ｃ２ is C １ -C ６ alkylcarbonyl, -CN, -CH ２ NH ２ or -CH ２ NH C(O)R ２ｆ -(CH ２ ) ０－１ NH C(O)OR ２ｆ ; R ２ｆ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C ３ -C ６ cycloalkyl C １ -C ３ alkyl, the compound according to claim 25; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

29. The aforementioned compound is of formula (Ih): 【Chemistry 28】 The compound according to claim 20; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

30. The aforementioned compound is given by formula (Ij): 【Chemistry 29】 The compound according to claim 20; or pharmaceutically acceptable salt(s) thereof; and / or stereoisomers thereof or mixtures thereof.

31. Each R ２ｃ１ is hydrogen; or one R ２ｃ１ C １ -C ６ Alkylcarbonyl, -CN, -CH ２ NH ２ , and -CH ２ NHC(O)R ２ｆ ,-(CH ２ ) ０－１ NHC(O)OR ２ｆ Selected from, R ２ｆ C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C ３ -C ６ Cycloalkyl C １ -C ３ Alkyl; one or two other R ２ｃ１ Each is a hydrogen atom; or one R ２ｃ１ is -CN and the other one or two R ２ｃ１ The compound according to claim 25, wherein each of the elements is hydrogen; or a pharmaceutically acceptable salt(s) thereof; and / or a stereoisomer thereof or a mixture of stereoisomers thereof. 【Request Item 32】 【Chemistry 30】 【change】 A compound according to claim 20 or its positional isomers, stereoisomers, mixtures of stereoisomers, and / or pharmaceutically acceptable salts, selected from the above.

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 or its stereoisomer, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier.

34. A composition according to claim 33 for use in a method of treating a pathological condition, disease, or disorder by inhibiting MYST family lysine acetyltransferases, comprising KAT6A and KAT6B, wherein the method comprises administering a therapeutically effective amount of the composition to a patient in need thereof, the pathological condition, disease, or disorder being a hyperproliferative disorder or cancer, optionally, The aforementioned cancers include: leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, ductal carcinoma, colorectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical carcinoma, anal cancer, bladder cancer, hematological cancer, bone cancer, brain tumor, cancers of the female reproductive system, cancers of the male reproductive system (including testicular and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant One or more of the following are selected: fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system cancer, retinoblastoma, salivary gland cancer, skin cancer, biliary tract cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thyroid cancer, urinary tract cancer, uterine cancer, uterine sarcoma, vaginal cancer, endocrine cancer, neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal axial tumor, glioblastoma, brainstem glioma, pituitary adenoma, vascular system cancer, Waldenstrom macroglobulinemia and / or Wilms tumor, or The cancer is selected from one or more of the following: breast cancer including ER-positive breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, and hematological cancer (including leukemia or lymphoma), and the composition.

35. A method for inhibiting MYST family lysine acetyltransferases, comprising contacting a compound according to any one of claims 1 to 32; or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

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