WO2023192817A1 - Inhibitors of the myst family of lysine acetyl transferases - Google Patents

Inhibitors of the myst family of lysine acetyl transferases Download PDF

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Publication number
WO2023192817A1
WO2023192817A1 PCT/US2023/064984 US2023064984W WO2023192817A1 WO 2023192817 A1 WO2023192817 A1 WO 2023192817A1 US 2023064984 W US2023064984 W US 2023064984W WO 2023192817 A1 WO2023192817 A1 WO 2023192817A1
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alkyl
substituted
compound
optionally substituted
stereoisomers
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English (en)
French (fr)
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WO2023192817A9 (en
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Roopa Rai
Mark Bures
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Isosterix Inc
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Isosterix Inc
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Priority to CA3255313A priority Critical patent/CA3255313A1/en
Priority to KR1020247033402A priority patent/KR20250006833A/ko
Priority to JP2024557915A priority patent/JP2025511122A/ja
Priority to AU2023241822A priority patent/AU2023241822A1/en
Priority to CN202380043769.9A priority patent/CN119301096A/zh
Priority to EP23718952.7A priority patent/EP4499609A1/en
Application filed by Isosterix Inc filed Critical Isosterix Inc
Priority to IL315930A priority patent/IL315930A/en
Publication of WO2023192817A1 publication Critical patent/WO2023192817A1/en
Priority to MX2024011828A priority patent/MX2024011828A/es
Anticipated expiration legal-status Critical
Publication of WO2023192817A9 publication Critical patent/WO2023192817A9/en
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Definitions

  • the compounds of Formula (I) may be useful as inhibitors of the MYST family of lysine acetyltransferases (KATs) for the treatment of and/or prophylaxis of hyperproliferative diseases, disorders or conditions such as cancer.
  • KATs lysine acetyltransferases
  • the compounds of Formula (I) are useful for the inhibition of KAT6A and KAT6B which are enzymes frequently mutated, overexpressed, amplified and/or translocated in cancer, altering their normal expression, activity and function.
  • KAT6A and KAT6B enzymes frequently mutated, overexpressed, amplified and/or translocated in cancer, altering their normal expression, activity and function.
  • the use of the compounds of Formula (I) in the manufacture of pharmaceutical compositions or for treating cancers is further described, including for treating cancer in combination with other anti-cancer agents.
  • KATs Lysine acetyl transferases
  • HDACs histone deacetylases
  • Histones are key components of chromatin-DNA complex and their acetylation state is critical to 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 lysine on histone proteins. This acetylation confers an open conformation to the chromatin and typically promotes gene transcription.
  • MYST family One key family of KAT enzymes are known as the MYST family.
  • 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
  • Kat8 also known as, MOF or MYST1
  • the MYST family of KATs is particularly important in regulation of the cell cycle (Carrozza, et al., Trends in Genetics 2003, Vol 19, pp.321-329). [0005] Dysregulation of the expression of KAT6 proteins 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).
  • KAT6A Dysregulation through gene amplification, overexpression or mutation of KAT6A has been documented in multiple cancer types including breast, lung adenocarcinoma, ovarian, colon and rectal adenocarcinoma, and uterine 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). It is reported that the locus that contains the gene for KAT6A (8p11-p12 amplicon) is the 12 th most commonly amplified region of the genome across all cancer types (Zack, et al., 2013).
  • AML acute myeloid leukemia
  • KAT6A KAT6A
  • Translocation of KAT6A and fusion to a partner such as CBP, p300, TIF2 and NCOA3 are known to lead to aggressive forms of AML (Sheikh, et al., 2015).
  • 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 an acetyl donor.
  • One possible catalytic mechanism is the stepwise transfer of the acetyl group from acetyl co-enzyme A (Ac-CoA) to transiently form an acetyl-enzyme intermediate.
  • This acetyl-enzyme intermediate subsequently is the source of the acetyl group that is transferred to the substrate, typically a lysine on a histone (Wapenaar et al., 2016).
  • the MYST family of KATs there is a conserved cysteine that is acylated transiently as part of the catalytic cycle, as indicated with the arrow below.
  • the present disclosure provides compounds that may covalently bind to this conserved cysteine.
  • Enzyme inhibitors that covalently interact with conserved cysteines at or near the active site of an enzyme are an important therapeutic modality. Therapeutics which covalently and specifically react to form a covalent adduct with an active site cysteine offer potential advantages in potency, possible lower dose, and increased target engagement duration resulting in reduced dosing frequency.
  • KATs In addition to the role that KATs play in epigenetic regulation, KATs also acetylate non-histone proteins (Glozak, et al., 2005; Das and Kundu, 2008). Through modification of the acetylation state of non-histone proteins, KATs are involved modulating protein function and stability, protein-protein and protein-DNA interactions, and regulation 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) which may inhibit the MYST family of lysine acetyl transferases.
  • the compounds described in the present disclosure inhibit MYST family members, including KAT6A. In some embodiments, the inhibition is through covalent modification of a cysteine residue at the Ac-CoA binding site.
  • the compounds described herein are useful for the treatment of cancer 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 a standard of care treatment for a particular cancer.
  • SUMMARY [0010] Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, including hyperproliferative disorders and cancer.
  • R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; C 3 -C 8 -cycloalkyl-C 1 - C 6 alkyl where the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, or 3 R 1a ; phenyl optionally substituted with 1, 2, or 3 R 1b ; phenyl-C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 1b ; naphthyl optionally substituted with 1, 2, or 3 R 1b ; or 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; 8- to 10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; each R 1a is independently selected from hydrogen, halo, C 1 -C 6 alkoxy, and C 3 -C 8 -
  • R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; C 3 -C 8 -cycloalkyl-C 1 - C 6 alkyl where the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, or 3 R 1a ; phenyl optionally substituted with 1, 2, or 3 R 1b ; phenyl-C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 1b ; naphthyl optionally substituted with 1, 2, or 3 R 1b ; or 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; 8- to 10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; each R 1a is independently selected from hydrogen, halo, C 1 -C 6 alkoxy, and C 3 -C 8 -
  • a compound comprising an alkenyl-containing or alkynyl-containing electrophilic group capable of binding to KAT6A or KAT6B irreversibly and/or covalently. Also included are other electrophilic groups like nitrile and halomethyl ketone.
  • R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; C 3 -C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, or 3 R 1a ; phenyl 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 8-10- membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; each R 1a is independently selected from H, halo, C 1 -C 6 alkoxy, and C 3 -C 8 -cycloalkyloxy; each R 1b is independently selected from H, halo, C 1 -C 6 alkoxy, cyano, and
  • R 2 is selected from the group consisting of: wherein, for ring (a), R 2b is hydrogen or C 1 -C 6 alkyl; one X 1 is C(CH 2 R 2c ), and the other two X 1 are independently selected from N and CR 2e ; R 2c is a 5-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 2c1 ; R 2c is a 8- or 9-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; R 2c is a 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 ; R 2c is a 9-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 ; or R 2c is a 10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 ;
  • a compound provided herein e.g., of some or any of the embodiments, of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ib-1), (Ic-1), (Ic-2), (Id- 1), (I
  • a method of treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B comprising a) administering a therapeutically effective amount of a compound provided herein, e.g., of some or any of the embodiments, 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 specific compounds or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof or b) administering a therapeutically effective amount of a composition comprising a compound provided herein, e.g., of some or any of the embodiments, of Formula (I), (Ia)
  • R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; C 3 -C 8 -cycloalkyl-C 1 -C 6 alkyl where the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, or 3 R 1a ; phenyl optionally substituted with 1, 2, or 3 R 1b ; naphthyl optionally substituted with 1, 2, or 3 R 1b ; or 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; 8- to 10- membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; each R 1a is independently selected from hydrogen, halo, C
  • FIG.1 shows results of a test for reversibility/irreversibility for compounds provided herein (see, Biological Example 2).
  • a substituted alkyl group can be substituted, for example, with a cycloalkyl group, and the cycloalkyl group is not further substituted unless specified otherwise.
  • Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
  • Alkyl means a linear or branched hydrocarbon group having one to eight carbon atoms.
  • Lower alkyl or “C 1 -C 6 alkyl” means an alkyl group having one to six carbon atoms.
  • lower alkyl includes methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like.
  • a “C 0 ” alkyl (as in “C 0 -C 6 -alkyl”) is a covalent bond.
  • C 6 alkyl refers to, for example, n-hexyl, iso-hexyl, and the like.
  • Alkoxy means an –OR group where R is an alkyl group as defined herein. In some embodiments, R is C 1 -C 6 alkyl.
  • Alkyloxyalkyl means an alkyl group, as defined herein, substituted with one alkoxy, as defined herein. In some embodiments, alkyloxyalkyl is –CH 2 OCH 3 .
  • Alkenyl means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one double bond and includes ethenyl, propen-1-yl, propen-2-yl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like.
  • Lower alkenyl means an alkenyl group having two to six carbon atoms.
  • Alkynyl means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2- yl and the like.
  • “Lower alkynyl” means an alkynyl group having two to six carbon atoms.
  • Cycloalkyl means a monocyclic or polycyclic hydrocarbon radical having three to thirteen carbon atoms. The cycloalkyl can be saturated or partially unsaturated, but cannot contain an aromatic ring. In some embodiments, cycloalkyl is C 3 -C 8 cycloalkyl. In some embodiments, cycloalkyl is C 3 -C 6 cycloalkyl. In some embodiments, cycloalkyl includes fused, bridged, and spiro ring systems.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Cycloalkylalkyl means alkyl group substituted with one or two cycloalkyl group(s), as defined herein. In some embodiments, cycloalkylalkyl includes cyclopropylmethyl, 2-cyclobutyl-ethyl, and the like.
  • Spirocycloalkyl substituted with cyano means .
  • spirocycloalkyl substituted with cyano is In some embodiments, spirocycloalkyl substituted with cyano is In some embodiments, spirocycloalkyl substituted with cyano is [0033] “Cycloalkyloxy” means an –OR group where R is cycloalkyl, as defined herein. [0034] “Cycloalkenyl” means a cycloalkyl, as defined herein, which comprises at least one double bond, but wherein the ring is not aromatic.
  • Haloalkyl means an alkyl group, as defined herein, substituted with one or more halogens, for example one, two, three, four, or five halo atoms. Representative examples includes 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-1-fluoroethyl, and the like.
  • Haloalkoxy means an -OR’ group where R’ is haloalkyl as defined herein, in some embodiments, haloalkoxy is trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
  • Heteroaryl means a monocyclic or bicyclic, monovalent aromatic radical of 5-10 ring atoms containing one or more heteroatoms, for example one, two, or three ring heteroatoms, independently selected from oxygen, nitrogen, and sulfur and the remaining ring atoms being carbon. Unless stated otherwise, the point of attachment may be located on any atom of any ring of the heteroaryl group, valency rules permitting.
  • heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, tetrazoyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrazolyl, and the like, and an N-oxide thereof.
  • heteroaryl When the heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as 5-or 6-membered heteroaryl. “Heteroaryl” also includes “8-10- membered bicyclic heteroaryl,” as used herein.
  • Fused bicyclic radical includes bridged ring systems and spirocyclic ring systems. Unless otherwise stated, the point of attachment of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of attachment is located on a nitrogen atom, R y is absent.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2- oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroind
  • Bicyclic heterocyclic refers to a bicyclic ring system that contains one non-aromatic ring and one aromatic ring; wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of any of the ring atoms in the bicyclic ring system is a heteroatom(s) independently selected from O, S(O) 0-2 , and N, and the remaining ring atoms are carbon, and wherein the bicyclic heterocyclic contains 8-12 ring atoms (in some embodiments, 8, 9, or 10 ring atoms).
  • the term “bicyclic heterocyclic” does not include a fully aromatic bicyclic ring, i.e.
  • the bicyclic heterocyclic group does not include benzisoxazole, indazole, and the like.
  • the bicyclic heterocyclic group has 8 ring atoms. In some or any embodiments, the bicyclic heterocyclic group has 9 ring atoms. In some or any embodiments, the bicyclic heterocyclic ring comprises one, two, or three heteroatom(s) which are independently selected from nitrogen and oxygen. In some or any embodiments, the bicyclic heterocyclic ring comprises one or two heteroatom(s) which are oxygen. In some or any embodiments, the bicyclic heterocyclic ring comprises one, two, or three heteroatom(s) which are nitrogen (where the nitrogen can be substituted as described in any aspect or embodiment described herein).
  • the bicyclic heterocyclic comprises one heteroatom in the non-aromatic ring, or comprises one or two heteroatoms in the aromatic ring, or comprises two heteroatoms in the aromatic ring, or comprises two heteroatoms where one is in an aromatic ring and the other is in a non-aromatic ring or comprises two heteroatoms in the aromatic ring and one heteroatom in the nonaromatic ring.
  • the bicyclic heterocyclic group may be a bridged or non- bridged, and/or fused or not fused bicyclic group.
  • the bicyclic heterocyclic may be attached to the main structure at any heteroatom or carbon atom which results in a stable compound.
  • the bicyclic heterocyclic may be attached to the main structure through any of its rings, including any aromatic or nonaromatic ring, regardless of whether the ring contains a heteroatom.
  • the bicyclic heterocyclic includes a 5-membered heteroaryl group, preferably pyrazolyl, fused to a nonaromatic ring, preferably comprising a nitrogen ring atom, 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; in some or any embodiments, the rest of the Compound of Formula (I) is attached to the 5-membered heteroaryl group (preferably pyrazolyl), fused to a nonaromatic ring (preferably comprising a nitrogen ring atom), through the 5-membered heteroaryl portion, e.g.2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-1-yl, 2,4,5
  • the bicyclic heterocyclic When the bicyclic heterocyclic is substituted, it can be substituted on any ring, i.e. on any aromatic or nonaromatic ring comprised by the bicyclic heterocyclic.
  • the bicyclic heterocyclic includes, but is 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-isoindolin
  • 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 the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, which is 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 the compound can have one or more pharmaceutically acceptable salts associated with it.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as 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-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
  • Examples of a 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 and the like.
  • a metal ion such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Preferable 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.
  • 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, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • the term “substantially free of” or “substantially in the absence of” stereoisomers with respect to a composition refers to a composition that includes at least 85 or 90% by weight, in certain embodiments 95%, 98 %, 99% or 100% by weight, of a designated stereoisomer of a compound in the composition. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of stereoisomers.
  • the term “isolated” with respect to a composition refers to a composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of a specified compound, the remainder comprising other chemical species or stereoisomers.
  • the term “solvate,” as used herein, and 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. Where the solvent is water, the solvate is a hydrate.
  • isotopic composition refers to the amount of each isotope present for a given atom
  • “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.
  • the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or "hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.
  • isotopic enrichment refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance.
  • deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.
  • the isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
  • the term “isotopically enriched,” as used herein, and unless otherwise specified, refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • alkyl,” “cycloalkyl,” and “heterocycloalkyl” groups optionally comprise deuterium at one or more positions where hydrogen atoms are present, and wherein the deuterium composition of the atom or atoms is other than the natural isotopic composition.
  • alkyl,” “cycloalkyl,” and “heterocycloalkyl” groups optionally comprise carbon-13 at an amount other than the natural isotopic composition.
  • IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.
  • the terms “subject” and “patient” are used interchangeably.
  • the terms “subject” and “subjects” refer to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and in certain embodiments, a human.
  • the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat).
  • administering in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • administration in some embodiments, surgery, radiation, and chemotherapy, etc.
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • “Therapeutically effective amount” is an amount of a compound or composition, that when administered to a patient, is sufficient to effect such treatment for the condition, disease, or disorder, e.g.
  • a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof.
  • the term “therapeutic agent” includes a compound provided herein.
  • a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.
  • “Treating” or “treatment” of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e.
  • Treating” or “treatment” of any condition, disease, or disorder refers, in certain embodiments, to ameliorating a condition, disease, or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject.
  • “treating” or “treatment” includes modulating the condition, disease, or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both.
  • “treating” or “treatment” includes delaying the onset of the condition, disease, or disorder.
  • the terms “inhibiting” and “reducing,” or any variation of these terms includes any measurable decrease or complete inhibition to achieve a desired result.
  • the terms “prophylactic agent” and “prophylactic agents” refer to any agent(s) which can be used in the prevention of a condition, disease, or disorder or one or more symptoms thereof.
  • the term “prophylactic agent” includes a compound provided herein. In certain other embodiments, the term “prophylactic agent” does not refer a compound provided herein.
  • a prophylactic agent can be an agent which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression and/or severity of a condition, disease, or disorder.
  • prophylactically effective amount refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, 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).
  • the embodiments described herein include the recited compounds as well as a pharmaceutically acceptable salt or salts, hydrate, solvate, stereoisomer, tautomer, or mixture thereof.
  • 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).
  • 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).
  • 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).
  • Embodiment A In some or any embodiments, the Compound is that wherein R 1 is C 3 -C 8 -cycloalkyl-C 1 -C 6 alkyl; or phenyl optionally substituted with 1, 2, or 3 R 1b ; each R 1b is independently selected from hydrogen, alkyl, -C(O)OH, -C(O)O(C 1-3 alkyl), halo, and C 1 -C 6 alkoxy; R 2 is selected from the group consisting of: R 2a is hydrogen; each R 2b is independently hydrogen, C 1 -C 3 alkyl or -(CH 2 ) 0-2 OH; each R 2e is hydrogen; wherein, for rings (a) and (b) one X 1 is CR 3 and the other X 1 are each CH; R 2d is C 1 -C 3 alkoxy; R 3 is -(CH 2 ) 0-2 Y or -(CH 2 ) 0-2 -L-Y; L is
  • Embodiment 1 Provided is a compound according to Formula (I), wherein R 1 is C 3- C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a , or phenyl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein.
  • R 1 is C 3- C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a , or phenyl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein.
  • Embodiment 2 Provided is a compound according to Formula (I), wherein R 1 is C 3- C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a ; and all other groups are as defined in the Summary or in some or any embodiment provided herein.
  • Embodiment 3 Provided is a compound according to Formula (I), wherein R 1 is C 3- C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; and all other groups are as defined in the Summary or in some or any embodiment provided herein.
  • Embodiment 4 Provided is a compound according to Formula (I), wherein each R 1a is independently hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-3.
  • Embodiment 5 Provided is a compound according to Formula (I), wherein R 1 is phenyl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including Embodiment 1.
  • Embodiment 6 Provided is a compound according to Formula (I), wherein R 1 is phenyl-C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein.
  • Embodiment 7 Provided is a compound according to Formula (I), wherein R 1 is naphthyl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein.
  • Embodiment 8 Provided is a compound according to Formula (I), wherein R 1 is 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein.
  • Embodiment 9 Provided is a compound according to Formula (I), (wherein R 1 is 8- 10-membered bicyclic heteroaryl; and all other groups are as defined in the Summary or in some or any embodiment provided herein.
  • Embodiment 10 Provided is a compound according to Formula (I), wherein each R 1b is independently selected from hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyC 1-6 - alkyloxy, -O-alkylene-NR 1b1 R 1b4 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , -(CH 2 ) 0-2 C(O)OR 1b1 , -(CH 2 ) 0-2 C(O)NR 1b2 R 1b3 , and -(CH 2 ) 0- 2NR 1b1 C(O)R 1b3 ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1 and 5-9.
  • each R 1b is independently selected from hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyC 1-4 - alkyloxy, -C(O)OR 1b1 , -C(O)NHR 1b3 , and -NHC(O)R 1b3 .
  • each R 1b is independently selected from hydrogen, fluoro, ethyl, methoxy, hydroxyethyloxy, -C(O)OH, -C(O)O CH 3 , and - C(O)NHCH 3 .
  • R 1 , R 2a , R 2d , and X 1 and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R 2a is hydrogen or methyl.
  • a compound of Formula (I) according to Formula (Ia-1): 1 2a 2d 3 1 where R , R , R , R , and X and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R a is hydrogen or C 1 -C 3 alkyl.
  • Embodiment 11 provided is a compound of Formula (Ia) or (Ia-1), wherein R 2a is hydrogen or methyl. In some or any embodiments of Embodiment 11, provided is a compound of Formula (Ia) or (Ia-1), wherein R 2a is hydrogen. In some or any embodiments of Embodiment 11, provided is a compound of Formula (Ia) or (Ia-1), wherein R 2a is C 1 - C 6 alkyl. In some or any embodiments of Embodiment 11, provided is a compound of Formula (Ia) or (Ia-1), wherein R 2a is C 1 -C 3 alkyl.
  • Embodiment 11 provided is a compound of Formula (Ia) or (Ia-1), wherein R 2a is methyl.
  • Embodiment 12 Provided is a compound of Formula (I) according to Formula (Ib): where R 1 , R 2d , and X 1 and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R 1 , R 2d , R 3 , and X 1 and other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R 1 , R 2d , X 1 , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • a compound of Formula (I) according to Formula (Ic-1) where R 1 , R 2d , R 3 , X 1 , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • a compound of Formula (I) according to Formula (Ic-2) ere R 1 , R 2d wh , R 3 , X 1 , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • Embodiment 14 is a compound of Formula (I) according to Formula (Ic-2): ere R 1 , R 2d wh , R 3 , X 1 , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R 2d is hydrogen, halo, C 1 -C 6 alkyl, C 1-6 cycloalkyl, C 1 - C3alkoxy, or C 3 -C 6 -cycloalkyloxy and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-13.
  • the compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) is that wherein R 2d is halo, methyl, methoxy, isopropoxy, or cyclopropyloxy.
  • the compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) is that wherein R 2d is C 1 -C 6 alkoxy, C 1 -C 3 alkoxy, or methoxy.
  • each R 2b is hydrogen and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-14.
  • Embodiment 16 Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein one X 1 is CR 3 (optionally in the meta position with respect to R 2d ), one X 1 is N, and the other X 1 are CR 2b ; or wherein one X 1 is CR 3 (optionally in the meta position with respect to R 2d ) and the other X 1 are CR 2b (optionally CH); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-15. [0081] Embodiment 16a.
  • Embodiment 17a Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein R 3 is -(CH 2 )-Y; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-16b. [0084] Embodiment 17a.
  • Embodiment 17b Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein R 3 is -(CH 2 )-L-Y; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-16b.
  • Embodiment 17b Provided is a compound of Formula (Ib) or (Ib-1), wherein R 3 is - (CH 2 )-L-Y; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-16b.
  • Embodiment 17c Provided is a compound of Formula (Ib) or (Ib-1), wherein R 3 is - (CH 2 )-L-Y; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-16b.
  • Embodiment 17d Provided is a compound of Formula (Ib) or (Ib-1), wherein R 3 is - (CH 2 )-L-Y; L is -L 1 -L 2 -; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-16b.
  • Embodiment 17d Provided is a compound of Formula (Ib) or (Ib-1), wherein R 3 is - (CH 2 )-L-Y; L is -CH 2 -O- or -O-CH 2 -; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-16b.
  • Y is a 6-membered monocyclic aryl substituted with R Y and optionally substituted with 1 or 2 R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 6-membered monocyclic heteroaryl substituted with R Y and optionally substituted with 1 or 2 R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 8- membered bicyclic heteroaryl substituted with R Y and optionally substituted with 1 or 2 R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 9-membered bicyclic heteroaryl substituted with R Y and optionally substituted with 1, 2, or 3 R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 8- or 9-membered bicyclic heterocyclic (in some embodiments, (where R Y is -C(O)R 3a where R 3a is selected from group a)) substituted with R Y and optionally substituted with 1 or 2 R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 8- or 9-membered bicyclic heterocyclic (in some embodiments, Y (where R is - C(O)R 3a where R 3a is selected from group a)) substituted with R Y and optionally substituted with 1 or 2 R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 8- or 9-membered bicyclic heterocyclic (in some embodiments, (where R Y is - C(O)R 3a where R 3a is selected from group a)) substituted with R Y and optionally substituted with 1 or 2 R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 4-9- membered monocyclic or bicyclic heterocycloalkyl substituted with R Y and optionally substituted with 1 or 2 R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Embodiment 18a Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17. [0089] Embodiment 18a.
  • Embodiment 18b Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclic heteroaryl substituted with R Y ; Y is a pyrazolyl substituted with R Y ; Y is a 8- or 9-membered bicyclic heterocyclic substituted with R Y ; or Y is and R Y is -S(O) 2 R 3a or -C(O)R 3a , where R 3a is selected from group a); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 5-membered monocyclic heteroaryl substituted with R Y ; Y is a pyrazolyl substituted with R Y ; Y is a 8- or 9-membered bicyclic heterocyclic substituted with R Y ; Y is and R Y is -S(O) 2 R 3a or -C(O)R 3a , where R 3a is selected from group a); or Y is 4-9-membered monocyclic or bicyclic heterocycloalkyl substituted with R Y ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Y is a 5-membered monocyclic heteroaryl substituted with R Y ; Y is a pyrazolyl substituted with R Y ; Y is a 8- or 9-membered bicyclic heterocyclic substituted with R Y ; Y is and R Y is -C(O)R 3a , where R 3a is selected from group a); or Y is 4-9-membered monocyclic or bicyclic heterocycloalkyl substituted with R Y ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Embodiment 18d Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclic heteroaryl substituted with R Y ; Y is a pyrazolyl substituted with R Y ; Y is a 8- or 9-membered bicyclic heterocyclic substituted with R Y ; or Y is Y 3a 3a 3a and R is -S(O) 2 R or -C(O)R , where R is selected from group a); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-17.
  • Embodiment 19 Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is and R Y is -S(O) 2 R 3a or - C(O)R 3a , where 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 or in some or any embodiment provided herein, including any one of Embodiments 1-17. [0095] Embodiment 19.
  • Embodiment 20 Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein R 3b and R 3b1 are each hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-18a. [0096] Embodiment 20.
  • 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 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 , -(CH 2 ) 0- 3NR 3b C(O)(C 1 -
  • Embodiment 21 Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein R 3a is -CH 2 (halo); -(CH 2 ) 1-2 CN; -CH 2 OCH(CF 3 ) 2 ; - CH 2 O(trifluorophenyl); -CH 2 O(tetrafluorophenyl); -CH 2 O(isoxazolyl, optionally substituted with 1-3 substituents each independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 1 - 6alkoxy, cyano, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl); -CH 2 O(pyrimidinyl, optionally substituted with 1-3 substituents each independently selected from halo, C 1-6 alkyl, C 2 - 6 alkenyl, C 1-6 al
  • Embodiment 22 Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein R Y is and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-19.
  • Embodiment 22a Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein R Y is groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-19.
  • Embodiment 23 Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib- 1), (Ic-1), or (Ic-2), wherein R Y is groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Em
  • Embodiment 24 Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein each R 2e is hydrogen or -OH; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-22. [0102] Embodiment 24.
  • a compound of Formula (I) according to Formula (Id): 1 2a 2 where R , X , X , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • a compound of Formula (I) according to Formula (Id- 1): where R 1 , X 2a , R 4 , and X 2 and other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • Embodiment 25 Provided is a compound of Formula (I), (Id), or (Id-1), wherein each R 2b is hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10 and 24.
  • Embodiment 26 In some or any embodiments, one X 1 is CR 3 (optionally in the meta position with respect to R 2d ), one X 1 is N, and the other X 1 are CR 2b ; or wherein one X 1 is CR 3 (optionally in the meta position with respect to R 2d ) and the other X 1 are CR 2b (optionally CH) and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, 24, and 25.
  • one X 1 is CR 3 (optionally in the meta position with respect to R 2d ), one X 1 is N, and the other X 1 are CR 2b and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, 24, and 25.
  • one X 1 is CR 3 (optionally in the meta position with respect to R 2d ), one X 1 is CR 3 (optionally in the meta position with respect to R 2d ) and the other X 1 are CR 2b (optionally CH) and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, 24, and 25.
  • Embodiment 26 Provided is a compound of Formula (I), (Id), or (Id-1), wherein one X 2 is CR 4 and the other X 2 are CR 2b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, 24, and 25. In some or any embodiments, one X 2 is CR 4 and the other X 2 are CH.
  • Embodiment 27 Provided is a compound of Formula (I), (Id), or (Id-1), wherein X 2a is O; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 24-26.
  • Embodiment 28 Provided is a compound of Formula (I), (Id), or (Id-1), wherein X 2a is S; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 24-26.
  • Embodiment 28 Provided is a compound of Formula (I), (Id), or (Id-1), wherein R 4b and R 4b1 are each hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 24-27.
  • Embodiment 29 Provided is a compound of Formula (I), (Id), or (Id-1), wherein X 2a is S; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 24-26.
  • 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)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
  • Embodiment 29a Provided is a compound of Formula (I), (Id), or (Id-1), wherein R 4 is -(CH 2 ) 0-2 NHC(O)R 4a ; -NH(C 2 -C 4 -alkylene)NHC(O)R 4a ; C 3 -C 8 heterocycloalkyl substituted with -C(O)R 4a on a nitrogen ring atom in the C 3- C 8 heterocycloalkyl (preferably where the C 3 -C 8 heterocycloalkyl is attached to ring (d) through a carbon in the C 3 -C 8 heterocycloalkyl ring); -C(O)-HET1-C(O)R 4a where -C(O)R 4a is attached to a nitrogen ring atom in HET1; -C(O)-HET1-NHC(O)R 4a where -C(O)- is attached to a nitrogen ring atom in HET
  • Embodiment 31 Provided is a compound of Formula (I), (Id), or (Id-1), wherein HET1-C(O)R 4a is 4a HET1-NHC(O)R is and HET2- C(O)R 4a is whe 4a re R is selected from group a); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 24-30.
  • Embodiment 32 Provided is a compound of Formula (I), (Id), or (Id-1), wherein R 4 is groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 24-28.
  • Embodiment 32a Provided is a compound of Formula (I), (Id), or (Id-1), wherein R 4 is and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 24-28.
  • Embodiment 33 Provided is a compound of Formula (I) according to Formula (Ie): where R 1 , R 2b , R 5 , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R 1 , R 2b , R 5 , and other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R 1 , R 2b , R 5 , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • a compound of Formula (I) according to Formula (If- 1): where R 1 , R 2b , R 5 , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • Embodiment 35 Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein each R 2b is independently hydrogen or C 1 -C 3 alkyl; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10 and 34.
  • each R 2b is independently hydrogen or methyl.
  • Embodiment 36 Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein R 5 is pyridinyl, pyrazolyl, or imidazolyl; each of which is substituted with Z and optionally substituted with R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, 34, and 35. [0119] Embodiment 36a.
  • R 5 is –C(O)N(R 5b )Z where R 5b is selected from group b
  • R 5 is –C(O)N(R 5b )Z where R 5b is selected from group b
  • Embodiment 36b Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein R 5 is heterocycloalkyl (in some embodiments, pyrrolidinyl) substituted with Z and optionally substituted with R 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, 34, and 35.
  • Embodiment 36c Embodiment 36c.
  • Embodiment 36d Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein R 5 is -(CH 2 ) 0-2 O-HET1-Z; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, 34, and 35.
  • Embodiment 36d Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein R 5 is -(CH 2 ) 0-2 O-Z; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, 34, and 35.
  • Embodiment 37 Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein R 5 is -(CH 2 ) 0-2 O-Z; and all other groups are as defined in the Summary or in some or any embodiment
  • Embodiment 38 Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein each R 5b and R 5b1 are each hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 34-37. [0125] Embodiment 39.
  • Embodiment 40 Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein wherein Z is and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 34-36.
  • Embodiment 41 Provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1), wherein wherein Z is and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10, and 34-36.
  • a compound of Formula (I) according to Formula (Ig): ; (Ig); where R 1 , Q 1 , Q 2 , Q 3 , R 6 , R 7 , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • Embodiment 42 is a compound of Formula (I) according to Formula (Ig-1): 1 1 2 3 6 7 where R , Q , Q , Q , R , R , and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R Q1 is hydrogen, C(O)CH 3 , or Cl.
  • R Q1 is hydrogen. [0130] Embodiment 43.
  • Embodiment 45 Provided is a compound of Formula (I), (Ig), or (Ig-1), wherein R 6b is hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10 and 42.
  • Embodiment 46 Provided is a compound of Formula (I), (Ig), or (Ig-1), wherein one R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 1-10 and 45.
  • Embodiment 47 Provided is a compound of Formula (I), (Ig), or (Ig-1), wherein one R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl; and all other groups are as defined in the Summary or in some or any embodiment provided here
  • R 3c , R 3d , R 4c , R 4d , R 5c , R 5d , R 6c , and R 6d are each independently hydrogen or C 1 -C 3 alkyl; or where each pair of R 3c and R 3d , R 4c and R 4d , R 5c and R 5d , and R 6c and 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 or in some or any embodiment provided herein, including any one of preceding embodiments.
  • Embodiment 47b Provided is a compound 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), wherein R Y is
  • Embodiment 47c Provided is a compound 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), wherein R Y is
  • Embodiment 48 Provided is a compound where the 8- or 9-membered bicyclic heterocyclic (optionally substituted as provided herein) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8- membered bicyclic heterocyclic, which is optionally substituted as provided herein.
  • Embodiment 48 provided is a compound where the 8- or 9-membered bicyclic heterocyclic (optionally substituted as provided herein) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8- membered bicyclic heterocyclic group, which is optionally substituted as provided herein; and where the rest of the molecule is attached to the 5-membered heteroaryl group fused to the nonaromatic cyclic group through the 5-membered heteroaryl portion.
  • the 8- or 9-membered bicyclic heterocyclic is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8- membered bicyclic heterocyclic group, which is optionally substituted as provided herein; and where the rest of the molecule is attached to the 5-membered heteroaryl group fused to the nonaromatic
  • Embodiment 48 provided is a compound where the nonaromatic portion of the 8- or 9- membered bicyclic heterocyclic (optionally substituted as provided herein) comprises a heteroatom in the ring, preferably nitrogen.
  • Embodiment 49 Provided is a pharmaceutical composition comprising a Compound of any one of Embodiments 1-48 or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • Embodiment 50 Provided is a method of treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, comprising administering to a patient in need thereof a therapeutically effective amount of the Compound of any one of Embodiments 1-48 or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of the composition of Embodiment 4.
  • Embodiment 51 Provided is the method of embodiment 50 where the condition, disease, or disorder is a hyperproliferative disease, such as cancer.
  • the cancer is a particular 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, chrondrosarcoma, osteosarcoma).
  • carcinoma e.g. adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma
  • astrocytoma e.g. adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma
  • astrocytoma e.g. adenocarcinoma, hepatocellular carcinoma,
  • the cancer may be a MYST overexpressing cancer; the cancer may over-express MYST protein relative to non-cancerous tissue; the cancer may overproduce MYST mRNA relative to non-cancerous tissue; the cancer may be a MYST overexpressing cancer where the overexpressed MYST protein or MYST mRNA may be any one of KATs of the MYST family, e.g. KAT6A.
  • the cancer is selected from one or more of the following 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, breast ductal carcinoma, colon and rectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, cancer of the female genital system, cancer of the male genital 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 tract cancer, hair
  • 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 a leukemia or lymphoma).
  • Embodiment B In one embodiment is a compound of Formula (I) where R 1 is unsubstituted C 3-8 cycloalkylalkyl, preferably cyclohexylmethyl, or phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, preferably fluoro, and C 1-3 alkoxy, preferably methoxy; R 2 is ring (a) or ring (b); where one X 1 is C(CH 2 R 2c ), and the other two X 1 are each CH; preferably, the C(CH 2 R 2c ) is in the meta-position with respect to R 2d ; R 2b is hydrogen or C 1 -C 6 alkyl, preferably hydrogen or methyl; R 2c is
  • Embodiment 52 Provided is a compound of Formula (I) according to Formula (Ih): where R 1 , R 2b , R 2d , and X 1 and all other groups are as defined in the Summary or in some or any embodiment provided herein; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • R 2b is hydrogen or methyl.
  • Embodiment 54 Provided is a compound of Formula (I) according to Formula (Ij): 1 2d 1 2 where R , R , X , and X and all other groups are as defined in the Summary or in some or any embodiment provided herein; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
  • Embodiment 55 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein R 1 is C 3 -C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a , or phenyl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-54.
  • Embodiment 56 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein R 1 is C 3 -C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-54.
  • Embodiment 57 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein each R 1a is independently H; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-56.
  • Embodiment 58 Provided is a compound according to Formula (I), (Ih), (Ii), or (IIc), wherein R 1 is phenyl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-55.
  • Embodiment 59 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein R 1 is naphthyl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-54.
  • Embodiment 60 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein R 1 is 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-54.
  • Embodiment 60a Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein R 1 is 8-10-membered bicyclic heteroaryl; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-54.
  • Embodiment 61 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein each R 1b is independently selected from H, halo, and C 1 -C 6 alkoxy; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-55 and 58-60.
  • each R 1b is independently selected from H, halo, and C 1 -C 3 alkoxy.
  • Embodiment 62 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein R 2d is halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 3 -cycloalkyloxy; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-61.
  • R 2d is C 1 -C 6 alkoxy, preferably C 1 -C 3 alkoxy, preferably methoxy.
  • Embodiment 63 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein each R 2e is independently hydrogen, fluoro, C 1 -C 3 alkyl, cyclopropyl, -CHF 2 , -CF 3 , C 1 -C 4 alkoxy, -OCHF 2 , or -OCF 3 ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52-61.
  • Embodiment 64 Provided is a compound according to Formula (I) or (Ih), wherein R 2c is a 5-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 2c1 ; R 2c is a 8- or 9-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; R 2c is a 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 ; and 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 ) 0-1 NH 2 , -(CH 2 )
  • Embodiment 64 In a subembodiment of Embodiment 64, provided is a compound where R 2c is a 5-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 2c1 ; R 2c is a 8-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; or R 2c is a 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 . [0158] Embodiment 64a: In an embodiment of Embodiment 64, provided is a compound where each R 2c1 is hydrogen (i.e.
  • R 2c is not substituted); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • a subembodiment of Embodiment 64 provided is a compound where one R 2c1 is hydrogen and the other R 2c1 is selected from C 1 -C 6 alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2 , and –(CH 2 ) 0-1 NHC(O)R 2f , -(CH 2 ) 0-1 NHC(O)OR 2f ; wherein R 2f is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkylC 1 -C 3 alkyl; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 64 In a subembodiment of Embodiment 64, provided is a compound where one R 2c1 is hydrogen and the other R 2c1 is –CN; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63. [0159] Embodiment 64b: In a subembodiment of Embodiment 64 or 64a, provided is a compound where R 2c is pyrazolyl, pyridinyl, or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is optionally substituted with 1 or 2 R 2c1 .
  • a compound where R 2c is a 5-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 2c1 .
  • a compound where R 2c is a 8-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 .
  • a compound where R 2c is a 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 .
  • Embodiment 64c In an embodiment of Embodiment 64, provided is a compound where R 2c is pyrazolyl, preferably pyrazol-2-yl, and is unsubstituted (i.e. both R 2c1 are hydrogen) or is substituted with one R 2c1 which is preferably cyano (i.e. the other R 2c1 is hydrogen); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63. In an embodiment of Embodiment 64, provided is a compound where R 2c is pyridinyl, preferably pyridin-2-yl, and is unsubstituted (i.e.
  • both R 2c1 are hydrogen) or is substituted with one R 2c1 which is cyano (i.e. the other R 2c1 is hydrogen); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • 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 are hydrogen) or is substituted with one R 2c1 (i.e.
  • Embodiment 64d In an embodiment of Embodiment 64 or 64a, provided is a compound where R 2c is a 8- or 9-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 64d-1 In a sub-embodiment of Embodiment 64d, provided is a compound where the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic, which is optionally substituted with 1 or 2 R 2c1 .
  • the 8- or 9-membered bicyclic heterocyclic is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic, which is optionally substituted with 1 or 2 R 2c1 .
  • Embodiment 64d-2 In a sub-embodiment of Embodiment 64d, provided is a compound where the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group, which is optionally substituted with 1 or 2 R 2c1 ; and where the rest of the molecule is attached to the 5-membered heteroaryl group fused to the nonaromatic cyclic group through the 5-membered heteroaryl portion.
  • the 8- or 9-membered bicyclic heterocyclic is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group, which is optionally substituted with 1 or
  • Embodiment 64d-3 In a sub-embodiment of any one of Embodiments 64d, 64d-1, and 64d-2, provided is a compound where the nonaromatic portion of the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) comprises a heteroatom in the ring, preferably nitrogen.
  • Embodiment 64d-4 In a sub-embodiment of any one of Embodiments 64d, 64d-1, 64d-2, and 64d-3, provided is a compound where the 8- or 9-membered bicyclic heterocyclic is substituted with one R 2c1 which is hydrogen and a second R 2c1 which is selected from hydrogen and C 1 -C 6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl.
  • Embodiment 65 Provided is a compound according to Formula (I) or (Ii), wherein R 2c is a 5-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with R 2c3 ; R 2c is a 8- or 9-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; R 2c is a 8- or 9-membered bicyclic heterocyclic substituted with R 2c2 and optionally substituted with R 2c3 ; R 2c is a 6-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with 1 or 2 R 2c3 ; and R 2c2 is C 1 -C 6 alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2 , C 1 -C 6 alkoxy, -NH(C 1 - C 6 alkyl), -N(C 1 -C 6 alkyl) 2 ,
  • R 2c is a 5-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with R 2c3 ; 8-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; R 2c is a 8-membered bicyclic heterocyclic substituted with R 2c2 and optionally substituted with R 2c3 ; or R 2c is a 6-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with 1 or 2 R 2c3 .
  • Embodiment 65a In an embodiment of Embodiment 65, provided is a compound where each R 2c1 is hydrogen (i.e. R 2c is not substituted); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65 provides a compound where one R 2c1 is hydrogen and the other R 2c1 is selected from C 1 -C 6 alkylcarbonyl, -CN, -(CH 2 )0- 1 NH 2 , and –(CH 2 ) 0-1 NHC(O)R 2f , -(CH 2 ) 0-1 NHC(O)OR 2f ,; wherein R 2f is C 1 -C 6 alkyl, C 3 - C 6 cycloalkyl, or C 3 -C 6 cycloalkylC 1 -C 3 alkyl; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65 In a subembodiment of Embodiment 65, provided is a compound where one R 2c1 is hydrogen and the other R 2c1 is –CN; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65b In an embodiment of Embodiment 65, provided is a compound where R 2c2 is C 1 -C 6 alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2 , or –(CH 2 ) 0-1 NHC(O)R 2f , -(CH 2 )0- 1 NHC(O)OR 2f ; wherein R 2f is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkylC 1 -C 3 alkyl; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65c In an embodiment of Embodiment 65 or 65b, provided is a compound where each R 2c3 is hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65d In a subembodiment of Embodiment 65, 65b, or 65c, provided is a compound where R 2c is pyrazolyl, pyridinyl, or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is substituted with R 2c2 and optionally substituted with R 2c3 ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65, 65b, or 65c provided is a compound where R 2c is a 5-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with R 2c3 .
  • R 2c is a 8-membered bicyclic heterocyclic substituted with R 2c2 and optionally substituted with R 2c3 .
  • Embodiment 65e In an embodiment of Embodiment 65, provided is a compound where R 2c is pyrazolyl, preferably pyrazol-2-yl, substituted R 2c2 which is cyano and R 2c3 is hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65 provided is a compound where R 2c is pyridinyl, preferably pyridin-2-yl, substituted with R 2c2 which is cyano and R 2c3 is hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65 provided is a compound where R 2c is 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably 2,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-2-yl, substituted with R 2c2 where R 2c2 is alkylcarbonyl, preferably, methylcarbonyl or ethylcarbonyl and where R 2c3 is hydrogen; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65f In an embodiment of Embodiment 65, provided is a compound where R 2c is a 8- or 9-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65f-1 In a sub-embodiment of Embodiment 65f, provided is a compound where the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic, which is optionally substituted with 1 or 2 R 2c1 .
  • the 8- or 9-membered bicyclic heterocyclic is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic, which is optionally substituted with 1 or 2 R 2c1 .
  • Embodiment 65f-2 In a sub-embodiment of Embodiment 65f, provided is a compound where the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group, which is optionally substituted with 1 or 2 R 2c1 ; and where the rest of the molecule is attached to the 5-membered heteroaryl group fused to the nonaromatic cyclic group through the 5-membered heteroaryl portion.
  • the 8- or 9-membered bicyclic heterocyclic is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group, which is optionally substituted with 1 or
  • Embodiment 65f-3 In a sub-embodiment of any one of Embodiments 65f, 65f-1, and 65f-2, provided is a compound where the nonaromatic portion of the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) comprises a heteroatom in the ring, preferably nitrogen.
  • Embodiment 65f-4 In a sub-embodiment of any one of Embodiments 65f, 65f-1, 65f-2, and 65f-3, provided is a compound where the 8- or 9-membered bicyclic heterocyclic is substituted with one R 2c1 which is hydrogen and a second R 2c1 which is selected from hydrogen and C 1 -C 6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl.
  • Embodiment 65g In an embodiment of Embodiment 65, provided is a compound where R 2c is a 8- or 9-membered bicyclic heterocyclic substituted with R 2c2 and optionally substituted with R 2c3 ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 65g-1 In a sub-embodiment of Embodiment 65g, provided is a compound where the 8- or 9-membered bicyclic heterocyclic (substituted with R 2c2 and optionally substituted with R 2c3 ) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic, which is substituted with R 2c2 and optionally substituted with R 2c3 .
  • the 8- or 9-membered bicyclic heterocyclic is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic, which is substituted with R 2c2 and optionally substituted with R 2c3 .
  • Embodiment 65g-2 In a sub-embodiment of Embodiment 65g, provided is a compound where the 8- or 9-membered bicyclic heterocyclic (substituted with R 2c2 and optionally substituted with R 2c3 ) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group, which is substituted with R 2c2 and optionally substituted with R 2c3 ; and where the rest of the molecule is attached to the 5-membered heteroaryl group fused to the nonaromatic cyclic group through the 5-membered heteroaryl portion.
  • Embodiment 65g-3 In a sub-embodiment of any one of Embodiments 65g, 65g-1, and 65g-2, provided is a compound where the nonaromatic portion of the 8- or 9-membered bicyclic heterocyclic (substituted with R 2c2 and optionally substituted with R 2c3 ) comprises a heteroatom in the ring, preferably nitrogen.
  • Embodiment 65g-4 In a sub-embodiment of any one of Embodiments 65g, 65g-1, 65g-2, and 65g-3, provided is a compound where the 8- or 9-membered bicyclic heterocyclic is substituted with C 1 -C 6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl, and R 2c3 is hydrogen.
  • Embodiment 66 In a subembodiment of Embodiment 66, provided is a compound where R 2c is a 5-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 2c1 ; R 2c is a 8-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; or R 2c is a 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 . [0183] Embodiment 66a: In an embodiment of Embodiment 66, provided is a compound where each R 2c1 is hydrogen (i.e.
  • R 2c is not substituted); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • a subembodiment of Embodiment 66 provided is a compound where one R 2c1 is hydrogen and the other R 2c1 is selected from C 1 -C 6 alkylcarbonyl, -CN, -(CH 2 )0- 1 NH 2 , and –(CH 2 ) 0-1 NHC(O)R 2f , -(CH 2 ) 0-1 NHC(O)OR 2f ,; wherein R 2f is C 1 -C 6 alkyl, C 3 - C 6 cycloalkyl, or C 3 -C 6 cycloalkylC 1 -C 3 alkyl; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 66 In a subembodiment of Embodiment 66, provided is a compound where one R 2c1 is hydrogen and the other R 2c1 is –CN; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63. [0184] Embodiment 66b: In a subembodiment of Embodiment 66 or 66a, provided is a compound where R 2c is pyrazolyl, pyridinyl, or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is optionally substituted with 1 or 2 R 2c1 .
  • a compound where R 2c is a 5-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 2c1 .
  • a compound where R 2c is a 8-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 .
  • a compound where R 2c is a 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 .
  • Embodiment 66c In an embodiment of Embodiment 66, provided is a compound where R 2c is pyrazolyl, preferably pyrazol-2-yl, and is unsubstituted (i.e. both R 2c1 are hydrogen) or is substituted with one R 2c1 which is preferably cyano (i.e. the other R 2c1 is hydrogen); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63. In an embodiment of Embodiment 66, provided is a compound where R 2c is pyridinyl, preferably pyridin-2-yl, and is unsubstituted (i.e.
  • both R 2c1 are hydrogen) or is substituted with one R 2c1 which is cyano (i.e. the other R 2c1 is hydrogen); and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • 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 are hydrogen) or is substituted with one R 2c1 (i.e.
  • Embodiment 66d In an embodiment of Embodiment 66 or 66a, provided is a compound where R 2c is a 8- or 9-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 55-63.
  • Embodiment 66d-1 In a sub-embodiment of Embodiment 66d, provided is a compound where the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic, which is optionally substituted with 1 or 2 R 2c1 .
  • the 8- or 9-membered bicyclic heterocyclic is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic, which is optionally substituted with 1 or 2 R 2c1 .
  • Embodiment 66d-2 In a sub-embodiment of Embodiment 66d, provided is a compound where the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group, which is optionally substituted with 1 or 2 R 2c1 ; and where the rest of the molecule is attached to the 5-membered heteroaryl group fused to the nonaromatic cyclic group through the 5-membered heteroaryl portion.
  • the 8- or 9-membered bicyclic heterocyclic is a 5-membered heteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group, which is optionally substituted with
  • Embodiment 66d-3 In a sub-embodiment of any one of Embodiments 66d, 66d-1, and 66d-2, provided is a compound where the nonaromatic portion of the 8- or 9-membered bicyclic heterocyclic (optionally substituted with 1 or 2 R 2c1 ) comprises a heteroatom in the ring, preferably nitrogen.
  • Embodiment 66d-4 In a sub-embodiment of any one of Embodiments 66d, 66d-1, 66d-2, and 66d-3, provided is a compound where the 8- or 9-membered bicyclic heterocyclic is substituted with one R 2c1 which is hydrogen and a second R 2c1 which is selected from hydrogen and C 1 -C 6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl.
  • Embodiment 67 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein one X 1 is C(CH 2 R 2c ), and the other two X 1 are each CR 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52 to 66d-4.
  • each CR 2e is CH.
  • C(CH 2 R 2c ) is in the meta-position with respect to R 2d .
  • Embodiment 68 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein one X 1 is C(CH 2 R 2c ), the second X 1 is N, and the third X 1 is CR 2e ; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52 to 66d-4.
  • CR 2e is CH.
  • C(CH 2 R 2c ) is in the meta-position with respect to R 2d .
  • Embodiment 69 Provided is a compound according to Formula (I), (Ih), (Ii), or (Ij), wherein one X 1 is C(CH 2 R 2c ), and the other two X 1 are each N; and all other groups are as defined in the Summary or in some or any embodiment provided herein, including any one of Embodiments 52 to 66d-4.
  • C(CH 2 R 2c ) is in the meta-position with respect to R 2d .
  • Embodiment 70 Provided is a pharmaceutical composition comprising a Compound of any one of Embodiments 52-69 or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • Embodiment 71 Provided is a method of treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including Kat6a and Kat6b, comprising administering to a patient in need thereof a therapeutically effective amount of the Compound of any one of Embodiments 52-69 or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of the composition of Embodiment 70.
  • Embodiment 72 Provided is the method of embodiment 71 where the condition, disease, or disorder is a hyperproliferative disease, such as cancer.
  • the cancer is a particular 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, chrondrosarcoma, osteosarcoma).
  • carcinoma e.g. adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma
  • astrocytoma e.g. adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma
  • astrocytoma e.g. adenocarcinoma, hepatocellular carcinoma,
  • the cancer may be a MYST overexpressing cancer; the cancer may over-express MYST protein relative to non-cancerous tissue; the cancer may overproduce MYST mRNA relative to non-cancerous tissue; the cancer may be a MYST overexpressing cancer where the overexpressed MYST protein or MYST mRNA may be any one of KATs of the MYST family, e.g. KAT6A.
  • the cancer is selected from one or more of the following 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, breast ductal carcinoma, colon and rectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, cancer of the female genital system, cancer of the male genital 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 tract cancer, hair
  • 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 a leukemia or lymphoma).
  • provided herein are: (a) compounds as described herein, e.g., 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 as described herein, e.g., of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1),
  • Optically Active Compounds [0198] It is appreciated that compounds provided herein have several chiral centers and may exist in and be isolated in optically active and racemic forms. It is to be understood that any racemic, optically-active, diastereomeric, tautomeric, or stereoisomeric form, or mixtures thereof, of a compound provided herein, which possess the useful properties described herein is within the scope of the invention. It being well known in the art how to prepare optically active forms (in certain embodiments, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • stereoisomers includes diastereomers, enantiomers, rotamers, atropisomers, regioisomers, and geometric isomers; and mixtures thereof.
  • methods to obtain optically active materials include at least the following. i) physical separation of crystals - a technique whereby macroscopic crystals of the individual stereoisomers are manually separated.
  • This technique can be used if crystals of the separate stereoisomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual stereoisomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the stereoisomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an stereoisomerically pure or enriched synthetic precursor of the desired stereoisomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired stereoisomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the stereoisomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) stereospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired stereoisomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the stereoisomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and stereoisomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the stereoisomers are separated by virtue of preferential dissolution of one stereoisomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby 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 such as concentration or pressure differential 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.
  • isotopically enriched compounds including but not limited to isotopically enriched di-substituted pyrazoles.
  • Isotopic enrichment of a drug 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 needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrees the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
  • Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction.
  • KIE Kinetic Isotope Effect
  • DKIE Deuterium Kinetic Isotope Effect
  • 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 where deuterium is substituted for hydrogen.
  • the DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen.
  • High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy.
  • tritium As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements, including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 O or 18 O for oxygen, may lead to a similar kinetic isotope effect. [0207] For example, the DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride.
  • such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
  • CYPs cytochrome P450 enzymes
  • esterases proteases
  • reductases reductases
  • dehydrogenases dehydrogenases
  • monoamine oxidases to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
  • compositions and Methods of Administration [0210]
  • 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 the appropriate pharmaceutical composition and be administered by a suitable route of administration.
  • the methods provided herein encompass administering pharmaceutical compositions containing at least one compound as described herein, including 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, if appropriate in a salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent for the treatment of a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B.
  • the second agent can be formulated or packaged with the compound provided herein.
  • the second agent will only be formulated with the compound provided herein when, according to the judgment of those of skill in the art, such co- formulation should not interfere with the activity of either agent or the method of administration.
  • the compound provided herein and the second agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art.
  • the active agents provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g. in the form of aerosols).
  • the compound provided herein is administered orally.
  • Use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules.
  • the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
  • These compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release.
  • Use may be made, as liquid compositions for oral administration, of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin.
  • compositions can also comprise substances other than diluents, in certain embodiments, wetting, sweetening or flavoring products.
  • the compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, in certain embodiments, ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, in certain embodiments, using a bacteriological filter, by radiation or by heating.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semi- synthetic glycerides or polyethylene glycols.
  • compositions can also be aerosols.
  • the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle.
  • 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 a typically one or more pharmaceutically acceptable carriers.
  • prophylactic or therapeutic agents e.g., a compound provided herein, or other prophylactic or therapeutic agent
  • the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Any embodiment described for “excipient”.
  • Such pharmaceutical carriers can be sterile liquids, 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. Water can be used as a carrier when the pharmaceutical composition is administered intravenously.
  • Typical pharmaceutical compositions and dosage forms comprise 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, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. 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 way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form.
  • Lactose free compositions can comprise excipients that are well known in the art and are listed, in certain embodiments, in the U.S. Pharmacopeia (USP 36– NF 31 S2).
  • lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp.37980.
  • water and heat accelerate the decomposition of some compounds.
  • 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 comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • stabilizers include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • the pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such compositions and dosage forms will 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 so as to provide the form for proper administration to the subject.
  • the formulation should suit the mode of administration.
  • the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, in certain embodiments, an animal subject, such as a mammalian subject, in certain embodiments, a human subject.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration.
  • 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, intra-tumoral, intra-synovial and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; 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 a 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.
  • suspensions e.g., aqueous or non-
  • composition, shape, and type of dosage forms provided herein will typically vary depending on their use.
  • a dosage form used in the initial treatment of viral infection may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
  • compositions are supplied either separately or mixed together in unit dosage form, in certain embodiments, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food.
  • Particular dosage forms can 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 the active compound.
  • compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may 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; 22 edition (September 15, 2012).
  • the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein. However, the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • 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.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed.
  • tablets can be coated by standard aqueous or non-aqueous techniques.
  • dosage forms can be prepared by any of the methods of pharmacy.
  • compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable 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, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • 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, pre gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (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 carboxymethyl cellulose sold as AVICEL RC 581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103TM and Starch 1500 LM.
  • Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment.
  • Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions.
  • a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • 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, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can 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 oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, in certain embodiments, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a 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. Delayed Release Dosage Forms [0244] Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art.
  • Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, in certain embodiments, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • 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.
  • single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gel caps, and caplets that are adapted for controlled release.
  • controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition, disease, or disorder in a minimum amount of time.
  • Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance.
  • controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • controlled release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • drug active ingredient
  • Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may 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)).
  • polymeric materials can be used.
  • a controlled release system can be placed in a subject at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol.2, pp.115-138 (1984)).
  • the active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vin
  • parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject.
  • 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.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.
  • 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.
  • 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 poly
  • Transdermal, Topical & Mucosal Dosage Forms [0251] 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 one of skill in the art.
  • 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 permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g., carriers and diluents
  • other materials 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 particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • 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 lotions, tinctures, creams, emulsions, gels or ointments, which are nontoxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
  • penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; 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).
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its 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 alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent.
  • doses are from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to 50 mg per day for an adult. In certain embodiments, doses are from about 5 to about 400 mg per day or 25 to 200 mg per day per adult. In certain embodiments, dose rates of from about 50 to about 500 mg per day are also contemplated.
  • a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, in a subject by administering, to a subject in need thereof, an effective amount of a compound provided herein, or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof.
  • an effective amount of a compound provided herein, or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof The amount of the compound or composition which will be effective in the treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the condition, disease, or disorder, and the route by which the active ingredient is administered.
  • the frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).
  • the dosage administered to a subject is 0.140 mg/kg to 3 mg/kg of the subject’s body weight, based on weight of the active compound.
  • the dosage administered to a subject is between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg/kg of the subject’s body weight.
  • the recommended daily dose range of a composition provided herein for the condition, disease, or disorder described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • a daily dose range should be from about 10 mg to about 200 mg per day, in other embodiments, between about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day, in further embodiments, between about 100 and about 300 mg per day.
  • the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.
  • the daily dosage of the composition provided herein, based on 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, about 300 mg/kg, about 325
  • the daily dosage of the composition provided herein, based on 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 between (inclusive) 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.
  • the twice daily dosage of the composition provided herein, based on 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.
  • the twice daily dosage of the composition provided herein, based on 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 between (inclusive) 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 [0262]
  • administration of the same composition may be repeated 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.
  • unit dosages comprising a compound, or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail herein.
  • the unit dosage comprises 1 to 1000 mg, 5 to 250 mg or 10 to 50 mg active ingredient.
  • the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient. Such unit dosages can be prepared according to techniques familiar to those of skill in the art.
  • dosages of the second agents to be used in a combination therapy are provided herein.
  • dosages lower than those which have been or are currently being used to treat a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B are used in the combination therapies provided herein.
  • the recommended dosages of second agents can be obtained from the knowledge of those of skill in the art.
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart.
  • the therapies are administered no more than 24 hours apart or no more than 48 hours apart. In certain embodiments, two or more therapies are administered within the same patient visit. In other embodiments, the compound provided herein and the second agent are administered concurrently. [0266] In other embodiments, the compound provided herein and the second agent are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart. [0267] In certain embodiments, administration of the same agent may be repeated 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.
  • administration of the same agent may be repeated and the administration may be separated by at least 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.
  • a compound provided herein and a second agent are administered to a patient, in certain embodiments, a mammal, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise.
  • the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • the compound provided herein and the second active agent exert their effect at times which overlap.
  • Each second active agent can be administered separately, in any appropriate form and by any suitable route.
  • the compound provided herein is administered before, concurrently or after administration of the second active agent.
  • the compound provided herein and the second agent are cyclically administered to a patient.
  • Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agent) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment. [0270] In certain embodiments, the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • courses of treatment are administered concurrently to a patient, i.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent.
  • one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks.
  • the second agent can act additively or synergistically with the compound provided herein.
  • the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition.
  • a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions.
  • a compound provided herein is administered prior to or subsequent to administration of a second agent.
  • administration of a compound provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral.
  • kits for use in methods of treatment of a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B.
  • kits can include a compound or composition provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained.
  • a unit dose of a compound or composition provided herein, or a second agent or composition can 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 1 day.
  • a compound or composition can be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition.
  • suitable packaging includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.
  • Inhibitors of post-translational lysine acetylation mediated by KATs of the MYST family are considered to be promising anti-neoplastic agents and therefore may be useful therapeutic agents, e.g. for use in the treatment of cancer. Such agents may also be useful as therapeutic agents for the treatment of cancers which exhibit overexpression of MYST proteins.
  • a method for treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, in a subject which comprises contacting the subject with a therapeutically effective amount of a compound disclosed 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, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers, an individual geometric isomer, a mixture of geometric isomers
  • kits for treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, in a subject encompass the step of administering to the subject in need thereof an amount of a compound effective for the treatment of a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, in combination with a second agent.
  • the compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein.
  • the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.
  • Diseases which can be treated with the Compound according to any of the Formulas described herein, including Compounds 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, breast ductal carcinoma, colon and rectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, cancer of the female genital system, cancer of the male genital system (including testicular cancer and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyos
  • Compounds can be assayed for efficacy in treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, according to any assay known to those of skill in the art. Exemplary assay methods are provided elsewhere herein.
  • Second Therapeutic Agents [0280] In certain embodiments, the compounds and compositions provided herein are useful in methods of treatment of a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, that comprise further administration of a second agent.
  • the second agent can be any agent known to those of skill in the art to be effective for the treatment of a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, including those currently approved by the United States Food and Drug Administration, or other similar body of a country foreign to the United States.
  • the disease is cancer and the second agent is a cancer treatment.
  • the disease is cancer and the second agent is the standard of care treatment for the particular cancer to be treated.
  • the disease is cancer and the second agent is a chemotherapeutic agent.
  • the second agent is selected from an alkylating agent (e.g.
  • cyclophosphamide mechlorethamine, chlorambucil, melphalan, dacarbazine (DTIC), a nitrosoureas, temozolomide (oral dacarbazine); an anthracycline (e.g. daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin); a cytoskeletal disruptor (a taxane, e.g. paclitaxel, Albumin-bound paclitaxel and docetaxel); epothilone; an Histone Deacetylase inhibitor (e.g.
  • Vorinostat and romidepsin an inhibitor of Topoisomerase I (e.g. irinotecan and topotecan); an inhibitor of Topoisomerase II (e.g. etoposide, teniposide, and tafluposide); a kinase inhibitor (e.g. sorafenib, cobimetinib, cabozantanib, lapatinib, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and vismodegib); a nucleotide analog and precursor analog (e.g.
  • Topoisomerase I e.g. irinotecan and topotecan
  • Topoisomerase II e.g. etoposide, teniposide, and tafluposide
  • a kinase inhibitor e.g. sorafenib, c
  • eribulin e.g. letrozole, anastrozole, and exemestane
  • an aromatase inhibitor e.g. letrozole, anastrozole, and exemestane
  • rituximab ibritumomab
  • prednisone a kinase inhibitor e.g.
  • the disease is cancer and the second agent is a CDK1, 4, and/or 6 inhibitor.
  • the disease is cancer and the second agent is palbociclib, ribociclib, or abemaciclib.
  • the disease is cancer and the second agent is immunotherapy, such as a checkpoint inhibitor (e.g. pembrolizumab, nivolumab and atezolizumab.
  • a checkpoint inhibitor e.g. pembrolizumab, nivolumab and atezolizumab.
  • the disease is breast cancer and the second agent is fulvestrant.
  • the disease is breast cancer (e.g.
  • 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.
  • platinum agents cisplatin, carboplatin
  • vinorelbine cisplatin, carboplatin
  • capecitabine capecitabine
  • liposomal doxorubicin gemcitabine
  • mitoxantrone ixabepilone
  • albumin-bound paclitaxel
  • the disease is liver cancer (e.g. hepatocellular carcinoma, hepatocellular carcinoma not amenable to surgical or locoregional therapy) and the second agent is sorafenib.
  • the disease is prostate cancer and the second agent is radiation, abiraterone, or enzalutamide.
  • the disease is pancreatic adenocarcinoma and the second agent is radiation.
  • the disease is ovarian cancer and the second agent is bevacizumab, olaparib, radiation, an aromatase inhibitor (e.g.
  • the disease is B cell lymphoma and the second agent is rituximab, radiation, ibritumomab, cyclophosphamide, doxorubicin, vincristine, or prednisone.
  • a compound provided herein is administered in combination with one second agent. In further embodiments, a compound provided herein is administered in combination with two second agents. In still further embodiments, a compound provided herein is administered in combination with two or more second agents.
  • the term “in combination” includes the use of more than one therapy (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 such as a compound provided herein
  • a first therapy 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 subsequent 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 after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.
  • a second therapy e.g., a prophylactic or therapeutic agent
  • the term “synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disorder.
  • a therapy e.g., a prophylactic or therapeutic agent
  • a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder.
  • a synergistic effect of a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • the active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an agent effective in the treatment of a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B.
  • an effective dosage of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially.
  • the dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition, disease, or disorder to be treated.
  • General Scheme 1A describes the preparation of a Compound of Formula (I) where R 2 is ring (b); one X 1 is CR 3 , and the other two are CH; and all other groups are as defined in the Summary or in any embodiments described herein.
  • General Scheme 1B describes the preparation of a Compound of Formula (I) where R 2 is ring (b); one X 1 is CR 3 , and the other two are CH; R 3 is -(CH 2 )Y; Y is and all other groups are as defined in the Summary or in any embodiments described herein.
  • Scheme (A) describes a way to prepare the appropriately substituted benzo[d]isoxazole compounds where in Step 1, a 2-fluorobenzonitrile can be converted to a benzo[d]isoxazol-3-amine scaffold by reacting with N-hydroxyacetamide in presence of a base like potassium t-butoxide. In Step 2, the free amine is reacted with R 1 S(O) 2 Cl in presence of a base such as triethylamine, pyridine or sodium hydride.
  • a base such as triethylamine, pyridine or sodium hydride.
  • Scheme (B) describes a synthesis of compounds where R 3 is -(CH 2 )Y and Y is an appropriately substituted 5-membered heteroaryl such as a pyrazole. This synthesis can be extended to other heteroaryls, including C-linked heteroaryls by those skilled in the art.
  • the synthesis of the benzo[d]isoxazole compounds can be started with an appropriately substituted 2-fluoro-4-(hydroxymethyl)benzonitrile. The hydroxy group can be converted to a substituted pyrazole moiety by reacting with a compound of formula Ms-X (where Ms-X is ) in presence of a base such as CsCO 3 as shown in Step 1 above.
  • the fluorobenzonitrile can be converted to the benzo[d]isoxazol-3-amine scaffold by its reaction with N-hydroxyacetamide in presence of a base like potassium t-butoxide (Step 2 above).
  • a base like potassium t-butoxide
  • the free amine is reacted with R 1 S(O) 2 Cl in presence of a base such as triethylamine, pyridine or sodium hydride.
  • Step 4 The final steps involve deprotection of the amine (Step 4) followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine in Step 5.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • the [1,2,4]triazolo[4,3-a]pyridine compounds can be prepared by starting with an appropriately substituted methyl-2-chloroisonicotinate.
  • a reducing agent like LiBH4
  • the ester can be reduced to an alcohol (Step 1 above).
  • the hydroxy group can be converted to a substituted pyrazole moiety by reacting with a 1-(methylsulfonyl)-1H- pyrazole of formula X in presence of a base such as CsCO 3 as shown in Step 2 above.
  • the resulting 2-chloropyridine can be converted to the corresponding 2-hydrazinopyridine by heating in presence of hydrazine hydrate (Step 3).
  • Step 4 reaction with cyanogen bromide can lead to the assembly of the [1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold.
  • Reaction with R 1 S(O) 2 Cl in the presence of a base such as triethyl amine, pyridine or sodium hydride can lead to the N-linked pyrazole substituted compounds.
  • the final steps involve deprotection of the amine (Step 4) followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine in Step 6.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • a slightly altered Scheme (B) can be used for the C-linked heteroaryl substituted final compounds.
  • the main difference is that the hydroxymethyl pyridine can be converted to a bromomethyl group using phosphorus tribromide (Step 2).
  • this bromomethyl group can be subjected to Negishi coupling conditions with a 2-bromohetero aryl compound (2-bromopyridine in Scheme (B)), through the mediation of zinc dust followed by a palladium catalyst such as tetrakis(triphenylphosphine)palladium.
  • a palladium catalyst such as tetrakis(triphenylphosphine)palladium.
  • GENERAL SCHEME 3 General Scheme 3 describes the preparation of a Compound of Formula (I) where R 2 is ring R 3 i Y s -(CH 2 )Y and Y is pyrazolyl substituted with R and optionally substituted with R 2e ; and all other groups are as defined in the Summary or in any embodiments described herein.
  • the [1,2,3]triazolo[1,5-a]pyridine compounds can be synthesized using a substituted 2-cyanopyridine compound.
  • the introduction of the N-linked pyrazole moiety (Steps 1 and 2) can use procedures described above for the [1,2,4]triazolo[4,3-a]pyridine compounds.
  • the assembly of the core scaffold is described in Steps 3 and 4 above.
  • the 2-cyano pyridine can be converted to a 1-amino 2-cyano pyridine by reacting with a sulfonylated hydroxyl amine (Step 3), followed by cyclization in the presence of hydroxylamine and acetic anhydride.
  • Step 5 the free amine can be reacted with R 1 S(O) 2 Cl in presence of a base such as triethyl amine, pyridine or sodium hydride.
  • R Y can be a group that harbors an amine with an appropriate protecting group.
  • the final steps can involve deprotection of the amine followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • GENERAL SCHEME 4 General Scheme 4 describes the preparation of a Compound of Formula (I) where R 2 is ring (a) and R 3 is -(CH 2 )Y; and all other groups are as defined in the Summary or in any embodiments described herein.
  • the benzopyrazole compounds can be synthesized by using an appropriately substituted 2-fluorobenzonitrile as starting material. Steps 1, 2 and 3 can be done as described previously in General Schemes 2 and 3 above.
  • the fluoro benzonitrile intermediate can be converted to the N-methyl benzopyrazole (Step 4, using methyl hydrazine) or unsubstituted benzopyrazole (Step 5, using hydrazine) as shown above.
  • Step 6 the free amine can be reacted with R 1 S(O) 2 Cl in presence of a base such as triethyl amine, pyridine or sodium hydride.
  • a base such as triethyl amine, pyridine or sodium hydride.
  • Y can be a heteroaryl with a substituent R Y that harbors an amine with an appropriate protecting group.
  • the final steps can involve deprotection of the amine followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • Step(s) 1 constitute reduction of the aldehyde with NaBH4 to the alcohol followed by substitution with leaving group, such as methylsulfonyl or a halide, and can be done as described previously in Steps 2 and 3 of General Scheme 4. Reduction in Step 2 can be accomplished by treating the picolinonitrile with LAH in THF.
  • Step 3 Treatment of the 2-aminomethyl pyridine intermediate with cyanogen bromide in toluene (Step 3) can afford the imidazo[1,5-a]pyridin-3-amine intermediate which can be converted to the desired Compound of Formula I with R 1 S(O) 2 Cl and a base such as pyridine, triethylamine or sodium hydride as shown in Step 2 and described in General Scheme 1(A).
  • Y can be a heteroaryl with a substituent R Y that harbors an amine with an appropriate protecting group.
  • the final steps can involve deprotection of the amine followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • the final sulfonamide products can result by reacting this amine with R 1 S(O) 2 Cl and a base such as pyridine, triethylamine or sodium hydride as shown in Step 6 and described in General Scheme 1.
  • Y can be a heteroaryl with a substituent R Y that harbors an amine with an appropriate protecting group.
  • the final steps can involve deprotection of the amine followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • GENERAL SCHEME 7 General Scheme 7 describes the preparation of a Compound of Formula (I) where R 2 is ring (d); X 2a is O; one X 2 is CR 4 and the other X 2 are each CH; and all other groups are as defined in the Summary or in any embodiments described herein.
  • the synthesis of the benzofuran compounds can be started with an appropriately substituted 2-hydroxybenzaldehyde compound. Cyclization to the benzofuran compound (Step 1) occurs by heating with ethyl bromoacetate in presence of a base such as K 2 CO 3 .
  • 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 presence of a base.
  • an amide coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art, in presence of a base.
  • the synthesis of the acyl sulfonamide in Step 3 can be accomplished by deprotonating the primary amide with a base like NaH and then reacting with an appropriately substituted sulfonyl chloride.
  • Step 4 constitutes deprotection of the amine protecting group followed by Step 5 where 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 triethyl amine.
  • R 4 can be a linker that harbors an amine with an appropriate protecting group.
  • the final steps can involve deprotection of the amine followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • GENERAL SCHEME 8 General Scheme 8 describes the preparation of a Compound of Formula (I) where R 2 is ring (e) or ring (f); and all other groups are as defined in the Summary or in any embodiments described herein.
  • the synthesis of the N’-benzoyl sulfonyl hydrazide compounds of Formula (I) can be started with a Suzuki coupling of an appropriately substituted 2-bromoheteroaryl or a Chan-Lam coupling of an appropriately substituted pyrazole (for example) with methyl or ethyl 3-carboxyphenyl boronic acid/ester (Step 1).
  • the ester can be reacted with hydrazine hydrate under heating to convert to the corresponding hydrazide.
  • the hydrazide can be converted to the sulfonyl hydrazide by reacting with an appropriately substituted sulfonyl chloride in the presence of a base like pyridine.
  • R 5 can be a 5- or 6-membered monocyclic heteroaryl substituted with Z and optionally substituted with R 2e .
  • Z harbors an amine with an appropriate protecting group.
  • the final steps can involve deprotection of the amine followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • Ring (g) can be assembled by reaction of an appropriately substituted phenyl- heteroaryl amine with R 1 S(O) 2 Cl in presence of a base such as triethyl amine, pyridine or sodium hydride.
  • R 6 is a monocyclic heteroaryl substituted with Q and optionally substituted with R 2e ; or R 6 is Q.
  • Step 1 the final steps can involve deprotection of the amine followed by amide formation (either via a reaction with R 3a C(O)Cl, where R 3a is selected from group a), or via activation of R 3a C(O)OH, where R 3a is selected from group a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a is selected from group a)) in the presence of a base such as triethyl amine.
  • a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to those skilled in the art
  • R 3a S(O) 2 Cl where R 3a is selected from group a
  • Step 1(A) The assembly of the key intermediate (phenyl-heteroaryl amine) shown in Step 1(A) can be done through various means, as known to persons skilled in the art. Some examples are drawn in the Scheme 9(B).
  • 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, then reacting with guanidine.
  • the cyclization to the aminoheteroaryl intermediate can accomplished through the mediation of iodobenzene diacetate.
  • an appropriately substituted benzaldehyde can be condensed with semicarbazide/thiosemicarbazide in the presence, but not limited to NaOAc.
  • the oxidative cyclization to the key aminoheteroaryl intermediate can be accomplished in the presence of iodine and a base such as K 2 CO 3 or Cs 2 CO 3 .
  • an appropriately substituted methylbenzoate ester can be converted to the corresponding 3-oxo-3- phenylpropanenitrile using a base such as LDA and reacting with acetonitrile. Cyclization to the amino isoxazole compound occurs in the presence of hydroxyl amine.
  • Row 4 illustrates another general method to assemble this key intermediate.
  • a 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 phenyl boronic acid (or boronic ester). Subsequent deprotection of the amine can afford the desired key intermediate.
  • GENERAL SCHEME 10 [0312] General Scheme 10 describes the preparation of a Compound of Formula (I) where R 2 is ring (b); one X 1 is C(CH 2 R 2c ), and the other two X 1 are CR 2e ; and R 2c is pyrazol-1-yl substituted with two R 2c1 ; and all other groups are as defined in the Summary or in any embodiments described herein.
  • the synthesis of the benzo[d]isoxazole compounds can be started with an appropriately substituted 2-fluoro-4-(hydroxymethyl)benzonitrile.
  • the hydroxy group can be converted to a substituted pyrazole moiety by reacting with a 1-(methylsulfonyl)-1H-pyrazole of formula X in presence of a base such as CsCO 3 as shown in Step 1 above.
  • the fluorobenzonitrile can be converted to the benzo[d]isoxazol-3-amine scaffold by its reaction with N-hydroxyacetamide in presence of a base like potassium t-butoxide (Step 2 above).
  • Step 3 the free amine can be reacted with R 1 S(O) 2 Cl in presence of a base such as triethylamine, pyridine or sodium hydride.
  • a base such as triethylamine, pyridine or sodium hydride.
  • General Scheme 11 describes the preparation of a Compound of Formula (I) where R 2 is ring (c); ; one X 1 is C(CH R 2c ), and t 1 2e 2 he other two X are CR ; and R 2c is pyrazol-1-yl substituted with two R 2c1 ; and all other groups are as defined in the Summary or in any embodiments described herein.
  • the [1,2,4]triazolo[4,3-a]pyridine compounds can be prepared by starting with an appropriately substituted methyl-2-chloroisonicotinate.
  • a reducing agent like LiBH4
  • the ester can be reduced to an alcohol (Step 1 above).
  • the hydroxy group can be converted to a substituted pyrazole moiety by reacting with a 1-(methylsulfonyl)-1H- pyrazole of formula X in presence of a base such as CsCO 3 as shown in Step 2 above.
  • the resulting 2-chloropyridine can be converted to the corresponding 2-hydrazinopyridine by heating in presence of hydrazine hydrate (Step 3).
  • Step 4 reaction with cyanogen bromide can lead to the assembly of the [1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold.
  • Reaction with R 1 S(O) 2 Cl in the presence of a base such as triethyl amine, pyridine or sodium hydride can lead to the N-linked pyrazole substituted final compounds.
  • a slightly altered Scheme (B) can be used for the C-linked heteroaryl substituted final compounds. In this case, the main difference is that the hydroxymethyl pyridine can be converted to a bromomethyl group using phosphorus tribromide (Step 2).
  • the [1,2,3]triazolo[1,5-a]pyridine compounds can be synthesized using a substituted 2-cyanopyridine compound.
  • the introduction of the N-linked pyrazole moiety (Steps 1 and 2) can use procedures described above for the [1,2,4]triazolo[4,3-a]pyridine compounds.
  • the assembly of the core scaffold is described in Steps 3 and 4 above.
  • the 2-cyano pyridine can be converted to a 1-amino 2-cyano pyridine by reacting with a sulfonylated hydroxyl amine (Step 3), followed by cyclization in the presence of hydroxylamine and acetic anhydride.
  • Step 5 the free amine can be reacted with R 1 S(O) 2 Cl in presence of a base such as triethyl amine, pyridine or sodium hydride.
  • a base such as triethyl amine, pyridine or sodium hydride.
  • General Scheme 13 describes the preparation of a Compound of Formula (I) where R 2 is ring (a); one X 1 is C(CH 2 R 2c ), and the other two X 1 are CR 2e ; and R 2c is pyrazol-1-yl substituted with two R 2c1 ; and all other groups are as defined in the Summary or in any embodiments described herein.
  • the benzopyrazole compounds can be synthesized by using an appropriately substituted 2-fluorobenzonitrile as starting material. Steps 1, 2 and 3 can be done as described previously in the synthesis of the [1,2,4]triazolo[4,3-a]pyridine compounds (General Schemes 2 and 3 above).
  • the fluoro benzonitrile intermediate can be converted to the N-methyl benzopyrazole (Step 4, using methyl hydrazine) or unsubstituted benzopyrazole (Step 5, using hydrazine) as shown above.
  • Step(s) 1 constitute reduction of the aldehyde with NaBH4 to the alcohol followed by substitution with R 2c -LG, where R 2c is as defined in any aspect or embodiment provided herein, and LG is a leaving group, such as methylsulfonyl or a halide, and can be done as described previously in Steps 2 and 3 of General Scheme 13.
  • Reduction in Step 2 can be accomplished by treating the picolinonitrile with LAH in THF.
  • Step 3 Treatment of the 2-aminomethyl pyridine intermediate with cyanogen bromide in toluene (Step 3) can afford the imidazo[1,5-a]pyridin-3-amine intermediate which can be converted to the desired Compound of Formula II with R 1 S(O) 2 Cl and a base such as pyridine, triethylamine or sodium hydride as shown in Step 4 and described in General Scheme 10.
  • Step 2 Synthesis of cyclohexyl methane sulfonyl chloride (3): [0331] To a stirred solution of N-chlorosuccinimide (2.7 g, 20.3 mmol) in 2N HCl (1.7 mL) at 0 o C was added a pre-dissolved solution of compound 2 (1 g, 0.58 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo and the residue was extracted with diethyl ether. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the reaction mixture was then allowed to warm slowly 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 2 Cl 2 (2.2 mL, 28.8 mmol) in hexane (20 mL) was added drop wise manner while keeping the internal temperature below 3 °C.
  • the reaction mixture was then stirred at 0 °C for 1 h and the solids were collected by filtration and washed with cold hexane.
  • the solids were partitioned between diethyl ether and water, the layers were separated; the aqueous layer was further extracted with diethyl ether.
  • 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 was added NaHMDS (8.6 mL, 8.62 mmol) followed by methane sulfonyl chloride (0.72 mL, 9.40 mmol) and the resulting reaction mixture was allowed to stir at the room temperature for 3 h.
  • reaction mixture was again cooled to room temperature, basified with sat. NaHCO 3 solution and extracted with DCM. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude residue which was triturated with di- ethyl ether/pentane to afford the title compound (100 mg, 67.10%, isolated as inseparable regioisomeric mixture) as a white solid which was used in the next reaction without further purification.
  • LCMS Calculated for C 21 H 27 N 5 O 4 S: 445.54; Found: 446.50 (M+1). 1 H NMR is complicated and indicates a regioisomeric mixture.
  • reaction mixture was stirred at the room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and diluted with water and extracted with 5% MeOH/DCM. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by using reverse phase HPLC to afford the title compound (7 mg, 9.9%, isolated as inseparable regioisomeric mixture) as an off-white solid. TLC: 5% MeOH/DCM (Rf: 0.5). (See analytical data in Table 1).
  • reaction mixture was concentrated under reduced pressure, added water and extracted with 5% MeOH/DCM. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by prep HPLC to afford the title compound (5 mg, 7.4%, isolated as inseparable regioisomeric mixture, ⁇ 75% regioisomer as drawn) as an off-white solid.
  • TLC 5% MeOH/DCM (Rf: 0.5). (See analytical data in Table 1).
  • the isomers were further separated by using Chiral HPLC (Method: Chiral-Met-B 30%_1.0 ml.Icm; Mobile phase: A; 0.1% DEA in n-Hexane; B; DCM: MeOH (50:50) A:B, 70:30; Injection volume: 10 ⁇ L; Flow rate: 1.0 mL/min; Column: CHIRAL PAK IG (250*4.6 mm, 5 ⁇ m); Duration up to 25 min.) to afford the title compound (27 mg, 31%) as a white solid.
  • TLC 100% EtOAc (R f : 0.5). (See Table 1 for analytical data). Minor isomer was not isolated in enough quantity due to merged impurities.
  • the isomers were further separated by using Chiral HPLC (Method: Chiral-Met-B 30% 1.0 ml.Icm; Mobile phase: A; 0.1% DEA in n-Hexane; B; DCM:MEOH (50:50) A:B, 70:30; Injection volume: 5 ⁇ L; Flow rate: 1.0 mL/min; Column: CHIRAL PAK IG (250*4.6 mm, 5 ⁇ m); Duration up to 25 min.) to afford the title compound (18 mg, 20%) as an off-white solid.
  • TLC 100% EtOAc (Rf: 0.5). (See Table 1 for analytical data). Minor isomer was not isolated in enough quantity due to merged impurities.
  • reaction mixture was allowed to stir at 160 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, acidified with 1N HCl (up to pH ⁇ 4-5) and extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure to afford 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 (Rf: 0.5).
  • reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure. The crude compound was purified by prep HPLC to afford the title compound (6 mg, 5%) as an off-white solid.
  • TLC 10% MeOH/DCM (R f : 0.5). (Analytical data in Table1).
  • reaction mixture was concentrated under reduced pressure, quenched with ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • reaction was allowed to stir at room temperature for 16 h. After completion (reaction monitored by TLC), the reaction mixture was concentrated under reduced pressure, quenched with ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • reaction mixture was quench with ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by using chiral HPLC to afford the title compound 27b (12 mg, 2.02%) as an off white solid and 27a (9 mg, 1.51%) as an off-white solid.
  • TLC 5% MeOH/DCM (Rf: 0.6). (Analytical data in Table1).
  • reaction mixture was basified with sat. NaHCO 3 solution and extracted with DCM. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude residue, which was triturated with di-ethyl ether/pentane to afford a mixture (100 mg, 67.10%, isolated as inseparable regioisomeric mixture) as a white solid which was purified using chiral HPLC to get the title compounds 28a: (6.5 mg, 4.42%) as a white solid and 28b: (12 mg, 8.16%) as a white solid.
  • the regio-isomeric mixture was again purified by chiral HPLC to afford the tile compounds as 30a (8 mg, 5.5%) as an off-white solid and 30b (8.5 mg, 5.8%) as an off-white solid (Analytical data in Table1).
  • reaction mixture was stirred at 90 °C for 12 h. After completion (reaction monitored by TLC), the reaction mixture was cooled to room temperature, added water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by combi flash chromatography using a gradient method of 0-30% EtOAc/Heptane to afford the title compound 73 (1.0 g, 72%) as a pale yellow solid. TLC: 50% EtOAc/Heptane (R f : 0.5).
  • reaction mixture was allowed to stir at 70 °C for 16 h. After completion f 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 dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the title compound 88 (0.550 g, 71.52%) as an off-white solid.
  • TLC 90% EtOAc/Heptane (Rf: 0.40). 1H NMR is complicated and indicates a regioisomeric mixture.
  • reaction mixture was allowed to stir at 60 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by combi flash chromatography (230-400 mesh silica) using a gradient method of 1-5% MeOH in DCM to afford the title compound 89 (800 mg, 92 %) as a brown semi-solid. TLC: 5% MeOH/DCM (Rf: 0.40).
  • reaction mixture was allowed to stir at 70 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the tert-butyl ((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4- yl) methyl) (methyl)carbamate 93 (0.4 g, 77.36%) as a brown semi-solid. TLC: 50% EtOAc/Heptane (Rf: 0.20).
  • the reaction was allowed to stir at room temperature for 16h. After completion (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude compound was purified by using combi flash chromatography (230-400 mesh) using a gradient of 70-80% ethyl acetate/heptane to afford the title compound 105 (300mg, 34.09%) as a white solid.
  • reaction mixture was stirred 15 min followed by addition of propiolic acid (13 mg, 0.195 mmol) and T 3 P 50% solution in EtOAc (0.311 mL, 0.489 mmol). The reaction mixture was allowed to stir at the room temperature for 3h. After completion (reaction monitored by TLC), the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude compound was purified by using preparative HPLC to afford the title compound (23 mg, 28.04%) as an off-white solid. TLC: 10 % MeOH/DCM (Rf: 0.5).
  • reaction mixture was degassed with Argon followed by addition of Pd(dppf)Cl 2 (33 mg, 0.0451 mmol) and degassed again for 5 min.
  • the reaction mixture was stirred at 80 °C for 12h.
  • the reaction mixture was diluted with ethyl- acetate filtered on a Celite pad and concentrated under reduced pressure.
  • the crude compound was purified by combi flash-chromatography using a gradient method of 0-30% EtOAc/Heptane to afford the title compound 118 (180 mg, 64.05 %) as a pale-yellow solid.
  • TLC 40% EtOAc/Heptane (Rf: 0.4).
  • the reaction mixture was degassed with Argon followed by addition of Pd(dppf)Cl 2 (33 mg, 0.0451 mmol) and degassed again for 5 min .
  • the reaction mixture was stirred at 80 °C for 12h. After completion (monitored by TLC), the reaction mixture was diluted with ethyl- acetate filtered on Celite pad and the filtrate was concentrated under reduced pressure.
  • the crude compound was purified by combi flash-chromatography using a gradient method of 10- 50% EtOAc/Heptane to afford the title compound 120 (220 mg, 72.36 %) as a pale-yellow solid.
  • reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by Combi-flash chromatography using a gradient method of 40-70% EtOAc/Heptane to afford the title compound 128 (0.180 g, 68.70%) as a brown semi solid.
  • TLC 80% EtOAc/Heptane (Rf: 0.45).
  • LCMS Calculated for C17H21FN2O3: 320.15; Found: 321.02 (M+1).
  • reaction mixture was allowed to stir at 0 °C for 3 h. After completion (monitored by TLC), reaction mixture was diluted with DCM, water was added and extracted with Ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by Combi flash column chromatography using a gradient method of 40-60% EtOAc/Heptane to afford the title compound 150 (130 mg, 56.76%) as an off-white solid. TLC: 80% EtOAc/Heptane (Rf: 0.35). LCMS Calculated for C27H33N5O7S: 571.21; Found: 578.03 (M+1).
  • reaction mixture was degassed with Argon atmosphere followed by addition of Pd(dppf)Cl 2 (58 mg, 0.0725 mmol) and further degassed for 5 min.
  • the reaction mixture was stirred at 80 °C for 16h.
  • the reaction mixture was diluted with ethyl-acetate, filtered on Celite pad and concentrated under reduced pressure.
  • the crude was purified by combi flash-chromatography using a gradient method of 0-30% EtOAc/Heptane to afford the title compound 153 (380 mg, 86.75%) as a pale brown solid.
  • TLC 80% EtOAc/Heptane (Rf: 0.4).
  • reaction mixture was purged with nitrogen for 10 min followed by addition of Copper(I) iodide (82 mg, 0.434 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (61 mg, 0.43467 mmol).
  • the reaction mixture was stirred at 150°C for 2h under microwave irradiation. After completion (monitored by TLC), the reaction was quenched with ice cold water and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over sodium sulphate filtered and concentrated under reduced pressure to get crude compound.
  • reaction mixture was stirred at 85 °C for 16h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to get crude. The crude was triturated with DCM/Pentane (20 mL, 1:9 ratio) to offer title compound 188 (120 mg, 88.88% yield) as a brown solid. This was used in the next step without further characterization.
  • reaction mixture was stirred at RT for 2h. After completion (monitored by TLC), reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous N a 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by using prep HPLC to afford the title compound (4.3 mg, 4.1%) as a brown gummy solid. TLC: 10% MeOH/DCM (R f : 0.4). (See Table 1 for analytical data).
  • reaction mixture was purged under nitrogen atmosphere followed by addition of Pd(PPh 3 ) 4 (0.120 g, 0.1039 mmol).
  • Pd(PPh 3 ) 4 (0.120 g, 0.1039 mmol).
  • the reaction mixture was stirred at 100 °C for 16h.
  • the reaction mixture was filtered through a pad of celite, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by combi flash chromatography (using a gradient method of 0-30% EtOAc/Heptane) to afford the title compound 191 (350 mg, 60%) as a yellow solid.
  • TLC 50% EtOAc/Heptane (Rf: 0.5).
  • reaction mixture was purged under nitrogen atmosphere followed by addition of Pd(PPh 3 ) 4 (71 mg, 0.0623 mmol).
  • Pd(PPh 3 ) 4 71 mg, 0.0623 mmol.
  • the resulting reaction mixture was stirred at 90 °C for 12 h.
  • the reaction mixture was filtered through a pad of celite, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by combi flash chromatography (using a gradient method of 0-50% EtOAc/Heptane) to afford the title compound 192 (394 mg, 80.24%) as a pale-yellow solid.
  • the reaction mixture was degassed with nitrogen atmosphere for 10 min, followed by addition of bis(triphenylphosphine)palladium chloride (79 mg, 0.112 mmol).
  • the reaction mixture was stirred at 90 °C for 12h.
  • the reaction mixture was quenched with ice cold water, filtered through a pad of celite and filtrate was extracted with ethyl acetate.
  • the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by using combi flash chromatography using a gradient method of 0-30% EtOAc/Heptane to afford the title compound 204 (800 mg, 86.95%) as a pale-yellow solid.
  • reaction mixture was allowed to stir at 60 o C for 16h. After completion (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude was purified by using trituration with diethyl ether/pentane to afford the title compound 210 (900 mg, 74%) as an off-white solid.
  • reaction mixture was purged with nitrogen gas for 10 min followed by addition of [Pd(PPh 3 ) 4 ] (0.117 g, 0.143 mmol).
  • the resulting reaction mixture was stirred at 80 °C for 16h.
  • the reaction mixture was filtered through a pad of celite. The filtrate was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by combi flash chromatography (using a gradient method of 0-30% EtOAc/Heptane) to afford the title compound 207 (0.1 g, 12.93%) as a yellow solid.
  • reaction mixture was degassed with Argon atmosphere followed by addition of Pd(dppf)Cl 2 (73 mg, 0.0906 mmol).
  • the reaction mixture was stirred at 80 °C for 12h. After completion (monitored by TLC), the reaction mixture was diluted with ethyl acetate filtered through a Celite pad and the reaction mixture was concentrated under reduced pressure.
  • reaction mixture was concentrated under reduced pressure, triturated with diethyl ether to afford the title crude compound 215 (160 mg, TFA salt) as a gummy brown solid.
  • TLC 5% MeOH/DCM (Rf: 0.2). This mixture of regioisomers was used in the next step without further characterization.

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WO2024199254A1 (zh) * 2023-03-27 2024-10-03 北京康辰药业股份有限公司 磺酰胺化合物、其药物组合物和应用
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US12091406B2 (en) 2021-11-16 2024-09-17 Insilico Medicine Ip Limited Lysine acetyltransferase 6A (KAT6A) inhibitors and uses thereof
WO2024199254A1 (zh) * 2023-03-27 2024-10-03 北京康辰药业股份有限公司 磺酰胺化合物、其药物组合物和应用
WO2025036382A1 (zh) * 2023-08-14 2025-02-20 上海复宏汉霖生物医药有限公司 一种磺酰胺类化合物、其制备方法及用途
WO2025072423A1 (en) * 2023-09-27 2025-04-03 Isosterix, Inc. Myst inhibitors
WO2025098417A1 (zh) * 2023-11-08 2025-05-15 再和医药科技（苏州）有限公司 磺酰胺类化合物及其应用

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TW202400593A (zh) 2024-01-01
WO2023192817A9 (en) 2024-10-03
EP4499609A1 (en) 2025-02-05
MX2024011828A (es) 2024-11-08
AU2023241822A1 (en) 2024-09-26

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