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WO2025006391A1 - Petites molécules pour le traitement de troubles auto-immuns - Google Patents

Petites molécules pour le traitement de troubles auto-immuns Download PDF

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Publication number
WO2025006391A1
WO2025006391A1 PCT/US2024/035260 US2024035260W WO2025006391A1 WO 2025006391 A1 WO2025006391 A1 WO 2025006391A1 US 2024035260 W US2024035260 W US 2024035260W WO 2025006391 A1 WO2025006391 A1 WO 2025006391A1
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Prior art keywords
optionally substituted
compound
group
alkyl
alkoxy
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David G. Ho
Iordanis KARAGIANNIDIS
Phithi NGUYEN
Dimitrios Iliopoulos
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Athos Therapeutics Inc
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Athos Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • autoimmune disorders typically involve the use of immunosuppressive agents, anti-inflammatory drugs, or a combination thereof. While these approaches can provide symptomatic relief and help manage the disease, they often have limitations such as adverse side effects, incomplete efficacy, and the potential for long-term complications. Additionally, some patients may develop resistance to conventional treatments or experience relapses, necessitating alternative therapeutic options.
  • SUMMARY [0004] Several embodiments disclosed herein pertain to bicyclic compounds and tricyclic compounds, and their use in treating autoimmune disorders or inflammatory disorders. Some embodiments pertain to methods of manufacturing bicyclic compounds and tricyclic compounds, and methods of using bicyclic compounds and tricyclic compounds as therapeutics for treating inflammatory disease states.
  • Several embodiments comprise, consist of, or consist essentially of a tricyclic compound of Formula (I) (or any other structure disclosed herein), their pharmaceutically acceptable salts, enantiomers, methods of manufacture, and/or their methods of use in treating disease states.
  • Several embodiments comprise, consist of, or consist essentially of a bicyclic compound of Formula (II) (or any other structure disclosed herein), their pharmaceutically acceptable salts, enantiomers, methods of manufacture, and/or their methods of use in treating disease states.
  • the disease state is associated with inflammation.
  • the disease state is associated with an autoimmune disorder.
  • Several embodiments pertain to a compound, or a pharmaceutically acceptable salt thereof, having a structure represented by Formula I: .
  • R2 is selected from the group consisting of -H, -OH, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 haloalkyl
  • R 3 is selected from the group consisting of -CN, -OH, optionally substituted C 1 -C 10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 alkynyl, optionally substituted alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and –NR5R6;
  • R4 is selected from the group consisting of -H, -(CO)CH3, optionally substituted C1-C10 alkyl; and R5
  • R 7 , R 8 , R 9 , R 10 R 11 , and R 12 are each independently selected from the group consisting of -H, -OH, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C 1-6 haloalkyl;
  • R 13 is selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C1-20 alkylene, and absent;
  • R14 is selected from the group consisting of optionally substituted 3-20 membered heterocyclyl, – NR 15 R 16 , and absent; and R 15 and R 16 are each optionally substituted C 1-6 alkyl.
  • R7, R8, R11, and R12 are each -H; and R9 and R10 are each halogen. In further embodiments, R9 and R10 are each -F. In some embodiments, R4 is - H. In other embodiments, R 4 is -(CO)CH 3 . In some embodiments, R 13 is an optionally substituted C 1-20 alkylene. In further embodiments, R 13 is selected from the group consisting of ethylene and propylene. In some embodiments, R14 is an optionally substituted 5-membered heterocyclyl. In some embodiments, R 14 is . In other embodiments, R 14 is –NR 15 R 16 .
  • R 15 and R 16 are each independently selected from the group consisting of methyl, ethyl, and propyl.
  • R13 is an optionally substituted C1-6 alkyl.
  • R 13 is -CH 3 .
  • the structure of Formula I, or a pharmaceutically acceptable salt thereof is further represented by a formula selected from any one of the following compounds: ,
  • R 18 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C1-20 alkylene, and absent;
  • R19 is selected from the group consisting of optionally substituted 3-20 membered heterocyclyl, –NR21R22, and absent;
  • R20 is selected from the group consisting of -H and optionally substituted 3-4 membered heterocyclyl; and
  • R 21 and R 22 are each optionally substituted C 1-6 alkyl.
  • R20 is a 4-membered heterocyclyl.
  • R20 is .
  • R17 is halogen. In further embodiments, R 17 is -Cl. In some embodiments, R 18 is an optionally substituted C 1-20 alkylene. In further embodiments, R 18 is selected from the group consisting of ethylene and propylene. In some embodiments, R19 is an optionally substituted 5-membered heterocyclyl. In further embodiments, R19 is . In other embodiments, R19 is –NR21R22. In further embodiments, R21 each independently selected from the group consisting of methyl, ethyl, and propyl. In some embodiments, R 18 is an optionally substituted C 1-6 alkyl. In further embodiments, R 18 is -CH 3 .
  • the structure of Formula II, or a pharmaceutically acceptable salt thereof is further represented by a formula selected from any one of the , or inflammatory disorder comprising administering to a subject requiring treatment a compound as disclosed herein.
  • the subject is suffering from an autoimmune disorder or inflammatory disorder.
  • the compound as disclosed herein does not substantially inhibit G9a.
  • Some embodiments pertain to a method of manufacturing a compound as disclosed herein, the method comprising functionalizing a bicyclic compound starting material with one or more substituents.
  • Some embodiments pertain to the use of a compound as disclosed herein, for the preparation of a medicament to treat an autoimmune disorder or inflammatory disorder.
  • FIG. 2A is a graph showing the percent weight change of mice with 2,4,6- trinitrobenzenesulfonic acid (TNBS)-induced colitis after treatment with selected compounds.
  • FIG. 2B is a chart showing the colon lengths of mice with TNBS-induced colitis after exposure to selected conditions.
  • FIG. 2C is a chart showing the histological score of mice with TNBS- induced colitis after exposure to selected conditions.
  • FIG. 2D is a chart showing the clinical score of mice with TNBS-induced colitis after exposure to selected conditions.
  • DETAILED DESCRIPTION [0024]
  • the compounds are bicyclic compounds.
  • the compounds are tricyclic compounds.
  • the bicyclic compound comprises at least two aromatic rings.
  • the tricyclic compound comprises at least two aromatic rings.
  • multiple functionalities are bound the at least one aromatic ring.
  • Several embodiments comprise, consist of, or consist essentially of a tricyclic compound of Formula (I) (or any other structure disclosed herein), their pharmaceutically acceptable salts, enantiomers, methods of manufacture, and/or their methods of use in treating an autoimmune disorder or inflammatory disorder.
  • prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug a compound which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • prodrug a compound which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H.
  • pro-drug ester refers to derivatives of the compounds disclosed herein formed by the addition of any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • pro-drug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.
  • Other examples of pro-drug ester groups can be found in, for example, T. Higuchi and V.
  • Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the temperature of a reaction is expressed as “20 o C, 30 o C, 40 o C, 50 o C, or ranges including and/or spanning the aforementioned values,” this includes the particular temperature provided or temperature ranges spanning from 20 o C to 50 o C, 20 o C to 40 o C, 20 o C to 30 o C, 30 o C to 50 o C, 30 o C to 40 o C, or 40 o C or 50 o C.
  • Ca to Cb in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heteroaryl group.
  • a “C1 to C6 alkyl” group refers to all alkyl groups having from 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6). If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl, or heteroaryl group, the ranges described in these definitions are included (including the broadest ranges). [0034] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl moiety may be branched or straight chain.
  • Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like.
  • Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
  • the alkyl group may have 1 to 20 carbon atoms (as disclosed elsewhere herein, whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; for example, “1 to 20 carbon atoms” means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
  • the “alkyl” group may also be a medium size alkyl having 1 to 12 carbon atoms.
  • the “alkyl” group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds may be designated as “C1-6 alkyl” or similar designations.
  • C1-4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, and t-butyl.
  • C1-C5 alkyl indicates that there are one to five carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), etc.
  • Typical alkyl groups include, but are in no way limited to, methyl (“Me” or -CH 3 ), ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
  • alkyl group may be unsubstituted or substituted.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. As noted in the definition of “alkyl”, an alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. As noted in the definition of “alkyl”, an alkynyl group may be unsubstituted or substituted.
  • alkylene refers to a bivalent fully saturated straight chain aliphatic hydrocarbon group.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene.
  • An alkylene group may be represented by , followed by the number of carbon atoms, followed by a “*”. For to represent ethylene.
  • the alkylene group may have 1 to 20 carbon atoms herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated).
  • the alkylene group may also be a medium size alkyl having 1 to 12 carbon atoms.
  • the alkylene group could also be a lower alkyl having 1 to 6 carbon atoms.
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a C 3-6 monocyclic cycloalkyl group - ).
  • certain radical naming conventions can include radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
  • a substituent identified as alkyl that requires two points of attachment includes di-radicals such as –CH2–, –CH2CH2–, –CH2CH(CH3)CH2–, and the like.
  • radical is a di-radical such as “alkylene” or “alkenylene.”
  • An alkylene group may be substituted or unsubstituted.
  • halogen or “halo,” as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine (-F), chlorine (- Cl), bromine (-Br), or iodine (-I).
  • haloalkyl refers to a straight- or branched-chain alkyl group, substituting one or more hydrogens with halogens.
  • haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , - CH2CH2F, -CH2CH2Cl, -CH2CF2CF3 and other groups that in light of the ordinary skill in the art and the teachings provided herein, would be considered equivalent to any one of the foregoing examples.
  • the haloalkyl may be a medium sized or lower haloalkyl.
  • An haloalkyl group may be substituted or unsubstituted.
  • alkoxy refers to the formula –OR wherein R is an alkyl as is defined above, such as “C1-9 alkoxy”, including but not limited to methoxy, ethoxy, n- propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like. An alkoxy group may be substituted or unsubstituted.
  • polyethylene glycol refers to the wherein n is an integer greater than one and R is a hydrogen or alkyl. units “n” may be indicated by referring to a number of members.
  • “2- to 5- membered polyethylene glycol” refers to n being an integer selected from two to five.
  • R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • heteroalkyl refers to a straight or branched hydrocarbon chain (e.g., alkyl) containing one or more heteroatoms.
  • a heteroatom is given its plain and ordinary meaning in organic chemistry, which includes an element other than carbon, including but not limited to, nitrogen (e.g., amino, etc.), oxygen (e.g., alkoxy, ether, hydroxyl, etc.), sulfur, and halogens.
  • the heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated.
  • the heteroalkyl group may also be a medium size heteroalkyl having 1 to 12 carbon atoms.
  • the heteroalkyl group could also be a lower heteroalkyl having 1 to 6 carbon atoms.
  • the heteroalkyl may have from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom.
  • the heteroalkyl group of the compounds may be designated as “C 1-4 heteroalkyl” or similar designations.
  • the heteroalkyl group may contain one or more heteroatoms.
  • C1-4 heteroalkyl indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
  • a heteroalkyl group may be substituted or unsubstituted.
  • aromatic refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
  • aryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic.
  • the aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms.
  • the aryl group may be designated as “C6-10 aryl,” “C6 or C10 aryl,” or similar designations.
  • the aryl group can be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C6 aryl group.
  • Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
  • aryl group may be substituted or unsubstituted.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an aryl as is defined above, such as “C6-10 aryloxy” or “C6-10 arylthio” and the like, including but not limited to phenyloxy.
  • An aryloxy or arylthio group may be substituted or unsubstituted.
  • an “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such “C7-14 aralkyl” and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C 1-6 alkylene group).
  • An aralkyl or arylalkyl group may be substituted or unsubstituted.
  • heteroaryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone.
  • heteroaryl is a ring system, every ring in the system can be aromatic.
  • the heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heteroaryl” where no numerical range is designated.
  • the heteroaryl group can contain 4 to 14 ring members (atoms in the ring(s)), 5 to 10 ring members (atoms in the ring(s)), 5 to 7 ring members (atoms in the ring(s)), 5 to 6 ring members (atoms in the ring(s)).
  • the heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar designations.
  • a heteroaryl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom.
  • a heteroaryl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom.
  • heteroaryl rings include, but are not limited to, furan (e.g., furyl), furazan (e.g., furazanyl), thiophene (e.g., thienyl), benzothiophene (e.g., benzothienyl), phthalazine (e.g., phthalazinyl), pyrrole (e.g., pyrrolyl), oxazole (e.g., oxazolyl), benzoxazole (e.g,.
  • benzoxazolyl 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole (e.g., thiazolyl), 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole (e.g., benzothiazolyl), imidazole (e.g., imidazolyl), benzimidazole (e.g., benzimidazolyl), indole (e.g., indolyl), isoindole (e.g., isoindolyl), indazole, pyrazole (e.g., pyrazolyl), benzopyrazole, isoxazole (e.g., isoxazolyl), benzoisoxazole, isothiazole (e.g., isothiazolyl), triazole (e.g., triazolyl), benzotriazole, thiadiazole (e.g., thi
  • Heteroaryl rings may also include bridge head nitrogen atoms.
  • pyrazolo[1,5-a]pyridine imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine.
  • a heteroaryl group may be substituted or unsubstituted.
  • a “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group.
  • Carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion.
  • Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic.
  • carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated.
  • the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as “C 3-6 carbocyclyl” or similar designations.
  • carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • a carbocyclyl group may be substituted or unsubstituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion.
  • Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s), or as otherwise noted herein.
  • a cycloalkyl group may be unsubstituted or substituted.
  • Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • a “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as “C 4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
  • the alkylene group is a lower alkylene group.
  • cycloalkenyl means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl. cycloalkenyl groups can contain 4 to 10 atoms in the ring(s). A cycloalkenyl group may be substituted or unsubstituted.
  • heterocyclyl or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, eleven-, twelve-, thirteen-, up to 20-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the heteroatom(s) may be present in either a non- aromatic or aromatic ring in the ring system.
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo- systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
  • heterocyclyl or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3- dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine
  • the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
  • the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
  • the heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations.
  • a heterocyclyl group may be substituted or unsubstituted.
  • a heterocyclyl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom.
  • a heterocyclyl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom.
  • the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
  • heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3- dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4- oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydride
  • a sulfur of the heterocyclyl ring may be provided as a dioxide (e.g., -S(O)2-).
  • a “(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
  • a “(heterocyclyl)alkynyl” is a heterocyclyl group connected, as a substituent, via an alkynylene group.
  • R is hydrogen, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
  • An acyl group may be substituted or unsubstituted.
  • An O-carboxy can be substituted or unsubstituted.
  • R is selected from hydrogen, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a C-carboxy can be substituted or unsubstituted.
  • the term “hydroxy” refers to a –OH group.
  • a “cyano” group refers to a “-CN” group.
  • a “cyanato” group refers to an “-OCN” group.
  • An “isocyanato” group refers to a “-NCO” group.
  • a “thiocyanato” group refers to a “-SCN” group.
  • An “isothiocyanato” group refers to an “ -NCS” group.
  • R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a sulfinyl can be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “-SO2R” or “-SO2-” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a sulfonyl can be provided in a heterocyclyl ring.
  • a sulfonyl can be substituted or unsubstituted.
  • S-sulfonamido refers to a “-SO2NRARB” group in which RA and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • RA and RB may be taken together to provide a heteroaryl or heterocycle.
  • a S-sulfonamido can be substituted or unsubstituted.
  • N-sulfonamido refers to a “-N(R A )SO 2 R B ” group in which R A and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • R A and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An N-sulfonamido can be substituted or unsubstituted.
  • R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An N-carbamyl can be substituted or unsubstituted.
  • An O-thiocarbamyl can be substituted or unsubstituted.
  • R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An N-thiocarbamyl can be substituted or unsubstituted.
  • a C- amido can be substituted or unsubstituted.
  • R A and R B may be taken together to provide a heteroaryl or heterocycle.
  • An N-amido can be substituted or unsubstituted.
  • a carbamido may be substituted or unsubstituted.
  • An “amino” group refers to a “-NR A R B ” group in which R A and R B are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • RA and R B may be taken together to provide a heteroaryl or heterocycle.
  • An amino can be substituted or unsubstituted.
  • An “alkamino” group refers to a “-NRARB” group in which RA is alkyl and RB is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An alkamino can be substituted or unsubstituted.
  • An “aminoalkyl” group refers to an amino group connected via an alkylene group. An aminoalkyl can be substituted or unsubstituted.
  • alkoxyalkyl refers to an alkoxy group connected via an alkylene group, such as a “C2-8 alkoxyalkyl” and the like.
  • An alkoxyalkyl can be substituted or unsubstituted.
  • a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • a group is deemed to be “substituted,” it is meant that the group is substituted with one or more substituents independently selected from C 1 -C 6 alkyl (optionally substituted with –OH or C-carboxy), C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, –OH, C1-C6 alkyl, C1-C6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), C 3 -C 7 -carbocyclyl-C 1 -C 6 -alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- 10 membered heterocyclyl (option
  • substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen.
  • substituents may come together with the atom or atoms to which they are attached to form a ring that is spiro or fused with the rest of the compound.
  • any “R” group(s) such as, without limitation, R 1 , R 2 , R 3 , etc., represent substituents that can be attached to the indicated atom.
  • An R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together” (or similar language), the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl or heterocycle.
  • R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) “together with the atom to which they are attached,” it is meant that the collective unit of the atom and the two R groups are the recited ring.
  • the ring is not otherwise limited by the definition of each R group when taken individually.
  • R 1 and R 2 are de cted from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl
  • R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure: [0086] where ring A is a containing the depicted nitrogen.
  • R 1a and R 1b of an NR 1a R 1b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring: .
  • a cyclic structure using provided using the following structure (or a similar structure with a different ring size, heteroatoms, etc.):
  • the R group may be attached to any position of the ring by replacing an –H of the ring with –R.
  • the following ring includes any of the following ring where “ ” indicates a bond to a remaining portion of the structure.
  • the following where “ ” indicates a bond to a rem f the structure and n is 1 to 5 any of the structures are envisioned or other variations (as would be readily appreciated by the one of skill in the art): .
  • R 1 and R 2 are defined as selected consisting of hydrogen and alkyl, or R 1 and R 2 together with the atoms to which they are attached form an aryl or carbocyclyl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure: where A is an aryl ring or a depicted double bond.
  • a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.
  • a substituent A depicted as –AE– or E includes the substituent being oriented such that the “A” is attached at the point of the molecule as well as the case in which “A” is attached at the rightmost attachment point of the molecule.
  • certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context.
  • a substituent e.g., in a genus structure
  • the substituent is a di-radical.
  • a substituent identified as aminoalkyl that requires two points of attachment includes di-radicals such as –NHCH 2 –, –NHCH 2 CH 2 –, –NHCH 2 CH(CH 3 )CH 2 –, and the like.
  • Other examples a substituent may require two points of attachment include alkoxy, aryl, heteroaryl, carbocyclyl, heterocyclyl, etc.
  • a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
  • a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof. It is understood that, in any compound described herein having one or more chiral centers, all possible diastereomers are also envisioned. It is understood that, in any compound described herein all tautomers are envisioned. It is also understood that, in any compound described herein, all isotopes of the included atoms are envisioned.
  • any instance of hydrogen may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes;
  • any instance of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes;
  • any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes;
  • any instance of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes;
  • any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.
  • the term “inhibitor” means any compound, molecule or composition that inhibits or reduces the activity of a target biomolecule.
  • the inhibition can be achieved by, for example, blocking phosphorylation of the target (e.g., competing with adenosine triphosphate (ATP), a phosphorylating entity), by binding to a site outside the active site, affecting its activity by a conformational change, or by depriving kinases of access to the molecular chaperoning systems on which they depend for their cellular stability, leading to their ubiquitylation and degradation.
  • the term “vanin-1” shall be given its ordinary meaning in the art and shall refer to an enzyme with pantetheinase activity, which catalyzes the hydrolysis of pantetheine into pantothenic acid and cysteamine.
  • Vanin-1 is member of a larger vanin family, consisting of three human (VNN1, VNN2 and VNN3) and two mouse (Vnn1 and Vnn3) orthologous genes. Vanins play a role in inflammation, oxidative stress and cell migration processes that are mediated via vanin-dependent cysteamine production.
  • “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given its ordinary meaning and shall also refer to an organism that has VNN1 proteins. This includes mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals.
  • Diagnosis shall be given its ordinary meaning and shall also include determination of a subject's susceptibility to a disease or disorder, determination as to whether a subject is presently affected by a disease or disorder, prognosis of a subject affected by a disease or disorder (e.g., identification of cancer or cancerous states, stages of cancer, or responsiveness of cancer to therapy), and use of therametrics (e.g., monitoring a subject’s condition to provide information as to the effect or efficacy of therapy).
  • sample or “biological sample” shall be given its ordinary meaning and also encompasses a variety of sample types obtained from an organism and can be used in an imaging, a diagnostic, a prognostic, or a monitoring assay.
  • the term encompasses blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof.
  • the term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components.
  • the term encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.
  • a “natural amino acid side chain” refers to the side-chain substituent of a naturally occurring amino acid.
  • Naturally occurring amino acids have a substituent attached to the ⁇ –carbon.
  • Naturally occurring amino acids include Arginine, Lysine, Aspartic acid, Glutamic acid, Glutamine, Asparagine, Histidine, Serine, Threonine, Tyrosine, Cysteine, Methionine, Tryptophan, Alanine, Isoleucine, Leucine, Phenylalanine, Valine, Proline, and Glycine.
  • a “non-natural amino acid side chain” refers to the side- chain substituent of a non-naturally occurring amino acid.
  • Non-natural amino acids include ⁇ - amino acids ( ⁇ 3 and ⁇ 2 ), Homo-amino acids, Proline and Pyruvic acid derivatives, 3-substituted Alanine derivatives, Glycine derivatives, Ring-substituted Phenylalanine and Tyrosine Derivatives, Linear core amino acids and N-methyl amino acids.
  • Non-limiting examples of non-natural amino acids are available from Sigma-Aldridge, listed under “unnatural amino acids & derivatives.” See also, Travis S. Young and Peter G. Schultz, “Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon,” J. Biol. Chem. 2010 285: 11039-11044, which is incorporated by reference in its entirety.
  • agent includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms “agent”, “substance”, and “compound” are used interchangeably herein.
  • analog is used herein to refer to a molecule that structurally resembles a reference molecule but which has been modified in a targeted and controlled manner, by replacing a specific substituent of the reference molecule with an alternate substituent. Compared to the reference molecule, an analog would be expected, by one skilled in the art, to exhibit the same, similar, or improved utility. Synthesis and screening of analogs, to identify variants of known compounds having improved characteristics (such as higher binding affinity for a target molecule) is an approach that is well known in pharmaceutical chemistry.
  • the “patient” or “subject” treated as disclosed herein is, in some embodiments, a human patient, although it is to be understood that the principles of the presently disclosed subject matter indicate that the presently disclosed subject matter is effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms “subject” and “patient.” Suitable subjects are generally mammalian subjects. The subject matter described herein finds use in research as well as veterinary and medical applications. The term “mammal” is used in its usual biological sense.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • an “effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition.
  • “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
  • “Treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • therapeutic treatment refers to administering treatment to a subject.
  • the term “weight percent,” when referring to a component, is the weight of the component divided by the weight of the composition that includes the component, multiplied by 100%. For example, the weight percent of component A when 5 grams of component A is added to 95 grams of component B is 5% (e.g., 5 g A / (5 g A + 95 g B) x 100%).
  • control refers shall be given its ordinary meaning and shall also include a sample or standard used for comparison with a sample which is being examined, processed, characterized, analyzed, etc. In several embodiments, the control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor.
  • control is a historical control or standard reference value or range of values. In several embodiments, the control is a comparison to a wild-type VNN1 arrangement or scenario.
  • the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide non-limiting instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention.
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise.
  • the tricyclic compound is a compound having the structure of Formula (I) (or a pharmaceutically acceptable salt thereof): OR 4 N .
  • R 3 is selected from the group consisting of -CN, -OH, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 alkenyl, optionally substituted C 1 -C 10 alkynyl, optionally substituted alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and –NR 5 R 6 ;
  • R 4 is selected from the group consisting of -CN, -OH, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 alkenyl, optionally substituted C 1 -C 10 alkynyl, optionally substituted alkoxy, optionally substituted 3-10 membered carbo
  • R 1 is selected from the group consisting of - H, -OH, -CH3, or -OCH3. In some embodiments, R1 is -H. In some embodiments, R1 is -OH. In some embodiments, R1 is -CH3. In some embodiments, R1 is -OCH3.
  • R 2 is selected from the group consisting of -H, -OH, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C1-6 haloalkyl. In some embodiments, R2 is -H. In some embodiments, R2 is -OH. In some embodiments, R 2 is optionally substituted C 1-6 alkyl.
  • R 2 is optionally substituted C 1-6 alkoxy. In some embodiments, R 2 is optionally substituted C 1-6 haloalkyl.
  • R3 is selected from the group consisting of - CN, -OH, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 alkenyl, optionally substituted C 1 -C 10 alkynyl, optionally substituted alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3- 10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and –NR5R6.
  • R 3 is -CN. In some embodiments, R 3 is -OH. In some embodiments, R 3 is optionally substituted C 1 -C 10 alkyl. In some embodiments, R 3 is optionally substituted C 1 -C 10 alkenyl. In some embodiments, R3 is optionally substituted C1-C10 alkynyl. In some embodiments, R 3 is optionally substituted alkoxy. In some embodiments, R 3 is optionally substituted 3-10 membered carbocyclyl. In some embodiments, R 3 is optionally substituted 6- 10 membered aryl. In some embodiments, R3 is optionally substituted 3-10 membered heterocyclyl.
  • R3 is optionally substituted 5-10 membered heteroaryl. In some embodiments, R 3 is –NR 5 R 6 . In certain embodiments, R 5 and R 6 are each optionally substituted C1-6 alkyl. In some embodiments, R5 is optionally substituted C1-6 alkyl. In some embodiments, R6 is optionally substituted C1-6 alkyl. [0117] In some embodiments, R 4 is selected from the group consisting of -H, - (CO)CH3, optionally substituted C1-C10 alkyl. In some embodiments, R4 is -H. In some embodiments, R4 is -(CO)CH3. In some embodiments, R4 is optionally substituted C1-C10 alkyl.
  • the structure of Formula (I), or a pharmaceutically acceptable salt thereof is further represented by Formula (Ia): .
  • Formula (Ia) In are each independently selected from the group consisting of -H, -OH, halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C1-6 haloalkyl;
  • R13 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 1-20 alkylene, and absent;
  • R 14 is selected from the group consisting of optionally substituted 3-20 membered heterocyclyl, – NR15R16, and absent; and R15 and R16 are each optionally substituted C1-6 alkyl.
  • R 4 is selected from the group consisting of -H, - (CO)CH 3, optionally substituted C 1 -C 10 alkyl. In some embodiments, R 4 is -H. In some embodiments, R4 is -(CO)CH3. In some embodiments, R4 is optionally substituted C1-C10 alkyl.
  • R7, R8, R9, R10 R11, and R12 are each independently selected from the group consisting of -H, -OH, halogen, optionally substituted C 1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C1-6 haloalkyl.
  • R 7 is selected from the group consisting of -H, -OH, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C1-6 haloalkyl.
  • R 7 is -H. In some embodiments, R 7 is -OH. In some embodiments, R7 is halogen. In some embodiments, R7 is optionally substituted C1-6 alkyl. In some embodiments, R7 is optionally substituted C1-6 alkoxy. In some embodiments, R7 is optionally substituted C 1-6 alkyl. In some embodiments, R 7 is optionally substituted C 1-6 alkoxy. In some embodiments, R7 is optionally substituted C1-6 haloalkyl.
  • R8 is selected from the group consisting of -H, -OH, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 haloalkyl.
  • R8 is -H.
  • R8 is -OH.
  • R8 is halogen.
  • R8 is optionally substituted C1-6 alkyl.
  • R 8 is optionally substituted C 1-6 alkoxy.
  • R 8 is optionally substituted C1-6 alkyl.
  • R8 is optionally substituted C1-6 alkoxy. In some embodiments, R8 is optionally substituted C1-6 haloalkyl.
  • R 9 is selected from the group consisting of -H, -OH, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C1-6 haloalkyl. In some embodiments, R 9 is -H. In some embodiments, R 9 is -OH. In some embodiments, R 9 is halogen. In some embodiments, R 9 is optionally substituted C 1-6 alkyl.
  • R9 is optionally substituted C1-6 alkoxy. In some embodiments, R9 is optionally substituted C1-6 alkyl. In some embodiments, R9 is optionally substituted C1-6 alkoxy. In some embodiments, R 9 is optionally substituted C 1-6 haloalkyl. [0125] In some embodiments, R10 is selected from the group consisting of -H, -OH, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 haloalkyl. In some embodiments, R10 is -H. In some embodiments, R10 is -OH.
  • R10 is halogen. In some embodiments, R10 is optionally substituted C1-6 alkyl. In some embodiments, R 10 is optionally substituted C 1-6 alkoxy. In some embodiments, R 10 is optionally substituted C 1-6 alkyl. In some embodiments, R 10 is optionally substituted C 1-6 alkoxy. In some embodiments, R10 is optionally substituted C1-6 haloalkyl.
  • R11 is selected from the group consisting of -H, -OH, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C1-6 haloalkyl.
  • R11 is -H.
  • R11 is -OH.
  • R 11 is halogen.
  • R 11 is optionally substituted C 1-6 alkyl.
  • R11 is optionally substituted C1-6 alkoxy.
  • R11 is optionally substituted C1-6 alkyl.
  • R11 is optionally substituted C1-6 alkoxy. In some embodiments, R 11 is optionally substituted C 1-6 haloalkyl.
  • R 12 is selected from the group consisting of -H, -OH, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or optionally substituted C1-6 haloalkyl. In some embodiments, R 12 is -H. In some embodiments, R 12 is -OH. In some embodiments, R12 is halogen. In some embodiments, R12 is optionally substituted C1-6 alkyl.
  • R12 is optionally substituted C1-6 alkoxy. In some embodiments, R12 is optionally substituted C 1-6 alkyl. In some embodiments, R 12 is optionally substituted C 1-6 alkoxy. In some embodiments, R12 is optionally substituted C1-6 haloalkyl. [0128] In some embodiments, R13 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 1-20 alkylene, and absent. In some embodiments, R 13 is optionally substituted C 1-6 alkyl. In further embodiments, R 13 is -CH 3 . In some embodiments, R13 is optionally substituted C1-20 alkylene.
  • R13 is selected from the group consisting of ethylene and propylene. In some embodiments, R13 is ethylene. In some embodiments, R 13 is propylene. In some embodiments, R 13 is absent. [0129] In some embodiments, R14 is selected from the group consisting of optionally substituted 3-20 membered heterocyclyl, –NR15R16, and absent. In some embodiments, R 14 is optionally substituted 3-20 membered heterocyclyl. In some embodiments, R14 is an optionally substituted 5-membered heterocyclyl. In further embodiments, R14 some embodiments, R14 is –NR15R16. In some embodiments, R 14 embodiments, R 15 and R 16 are each optionally substituted C 1-6 alkyl.
  • R 15 is optionally substituted C 1-6 alkyl. In some embodiments, R16 is optionally substituted C1-6 alkyl. In further embodiments, R15 and R16 are each independently selected from the group consisting of methyl, ethyl, and propyl. In some embodiments, R 15 is selected from the group consisting of methyl, ethyl, and propyl. In some embodiments, R15 is methyl. In some embodiments, R15 is ethyl. In some embodiments, R15 is propyl. In some embodiments, R16 is selected from the group consisting of methyl, ethyl, and propyl. In some embodiments, R 16 is methyl. In some embodiments, R 16 is ethyl.
  • R16 is propyl.
  • R 7 , R 8 , R 11 , and R 12 are each -H; and R 9 and R 10 are each halogen.
  • R 9 and R 10 are each -F.
  • R 9 is - F.
  • R10 is -F.
  • the bicyclic compound is a compound having the structure of Formula (II) (or a pharmaceutically acceptable salt thereof): .
  • R 18 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C1-20 alkylene, and absent;
  • R19 is selected from the group consisting of optionally substituted 3-20 membered heterocyclyl, –NR 21 R 22 , and absent;
  • R 20 is selected from the group consisting of -H and optionally substituted 3-4 membered heterocyclyl; and
  • R 21 and R22 are each optionally substituted C1-6 alkyl.
  • R17 is selected from the group consisting of -H, -OH, and halogen. In some embodiments, R 17 is -H. In some embodiments, R 17 is -OH. In some embodiments, R 17 is halogen. In further embodiments, R 17 is -Cl. In some embodiments, R 17 is -F. In some embodiments, R17 is -Br. In some embodiments, R17 is -I. [0136] In some embodiments, R 18 is selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C1-20 alkylene, and absent. In some embodiments, R18 is optionally substituted C1-6 alkyl. In further embodiments, R18 is -CH3.
  • R 19 is R 21 and R 22 are each optionally substituted C 1-6 alkyl. In some embodiments, R 21 is optionally substituted C 1-6 alkyl. In some embodiments, R 22 is optionally substituted C1-6 alkyl. In some embodiments, R21 and R22 are each independently selected from the group consisting of methyl, ethyl, and propyl. In some embodiments, R 21 is selected from the group consisting of methyl, ethyl, and propyl. In some embodiments, R 21 is methyl. In some embodiments, R21 is ethyl. In some embodiments, R21 is propyl. In some embodiments, R 22 is selected from the group consisting of methyl, ethyl, and propyl.
  • R 22 is methyl. In some embodiments, R 22 is ethyl. In some embodiments, R 22 is propyl. [0139] In some embodiments, R20 is selected from the group consisting of -H and optionally substituted 3-4 membered heterocyclyl. In some embodiments, R 20 is -H. In some embodiments, R 20 is optionally substituted 3-4 membered heterocyclyl. In some embodiments, R 20 is a 4-membered heterocyclyl. In further embodiments, R 20 . [0140] In several embodiments, Formula (II) may be represented by one or more of the following compounds (or others): , .
  • the structure of Formula (II) is selected from one or more of the following: 2-chloro-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4- amine (also “Compound 1”); 2-chloro-6-methoxy-N-(oxetan-3-yl)-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-amine (also “Compound 4”); and 2-chloro-6,7-dimethoxy-N-(oxetan-3-yl)quinazolin-4-amine (also “Compound 6”).
  • the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present technology, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA).
  • a daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof has a half-maximal inhibitory concentration (IC50) activity of, of about, less than, or less than about 20 ⁇ M, 15 ⁇ M, 10 ⁇ M, 5 ⁇ M, 4 ⁇ M, 3 ⁇ M, 2 ⁇ M, 1.9 ⁇ M, 1.8 ⁇ M, 1.7 ⁇ M, 1.6 ⁇ M, 1.5 ⁇ M, 1.4 ⁇ M, 1.3 ⁇ M, 1.2 ⁇ M, 1.1 ⁇ M, 1 ⁇ M, 0.9 ⁇ M, 0.8 ⁇ M, 0.7 ⁇ M, 0.6 ⁇ M, 0.5 ⁇ M, 0.4 ⁇ M, 0.3 ⁇ M, 0.2 ⁇ M, 0.1 ⁇ M, 0.09 ⁇ M, 0.08 ⁇ M, 0.07 ⁇ M, 0.06 ⁇ M, 0.05 ⁇ M, 0.04 ⁇ M, 0.03 ⁇ M, 0.02 ⁇ M, or 0.01 ⁇ M,
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof has a half-maximal inhibitory concentration (IC50) activity of or of about in any one of the following ranges: about 1 ⁇ M to about 10 ⁇ M, about 5 ⁇ M to about 15 ⁇ M, about 5 ⁇ M to about 10 ⁇ M, about 10 ⁇ M to about 20 ⁇ M, about 0.5 ⁇ M to about 1 ⁇ M, about 1 ⁇ M to about 5 ⁇ M, about 0.1 ⁇ M to about 1 ⁇ M, about 0.01 ⁇ M to about 0.9 ⁇ M, about 1 ⁇ M to about 2 ⁇ M, or about 0.8 ⁇ M to about 0.9 ⁇ M.
  • IC50 half-maximal inhibitory concentration
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments. [0150] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions.
  • compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • a pharmaceutically-acceptable carrier for example, a pharmaceutically-acceptable carrier.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al.
  • substances which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers
  • compositions described herein are preferably provided in unit dosage form.
  • a “unit dosage form” is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy.
  • Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • a single administration is not specifically excluded.
  • the skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
  • compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, subcutaneous, or other parental routes of administration.
  • the compositions may be in a form suitable for subcutaneous administration.
  • oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used.
  • Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • suitable solvents preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose
  • binders such as starch, gelatin and sucrose
  • disintegrants such as starch, alginic acid and croscar
  • Capsules typically comprise one or more solid diluents disclosed above.
  • the selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above. [0159] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • Compositions described herein may optionally include other drug actives.
  • Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose.
  • Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween 80.
  • various useful vehicles may be used in the ophthalmic preparations disclosed herein.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid.
  • the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
  • Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
  • Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran.
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • compositions for intravenous administration may be provided to caregivers in the form of one or more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • the compositions are provided in solution ready to administer parenterally.
  • the compositions are provided in a solution that is further diluted prior to administration.
  • the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
  • the actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • the compounds and compositions described herein may be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
  • a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compounds and compositions described herein are formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01 to about 99.99 wt % of a compound of the present technology based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below.
  • Formulation Examples [0171] The following are representative pharmaceutical formulations containing a compound of Formula I.
  • Formulation Example 1 -- Tablet formulation [0172] The following ingredients are mixed intimately and pressed into single scored tablets.
  • a suppository of total weight 2.5 g is prepared by mixing the compound of the present technology with Witepsol ® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: Ingredient Amount Methods of Treatment [0177]
  • the compounds of Formula (I) and Formula (II) disclosed herein or their tautomers and/or pharmaceutically acceptable salts thereof can effectively treat an autoimmune disorder or inflammatory disorder.
  • Some embodiments provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.
  • Some embodiments provide a method of preventing, treating, or ameliorating one or more inflammatory or autoimmune diseases in a subject.
  • the method includes administering one or more of the compounds disclosed herein to a subject in need thereof. In some embodiments, the method includes administering a pharmaceutically acceptable salt thereof of one or more of the compounds disclosed herein to a subject in need thereof. In some embodiments, the is suffering from an autoimmune disorder. In some embodiments, the is suffering from an inflammatory disorder. [0179] In several embodiments, the disclosed compound is used to prevent, treat, or ameliorate ulcerative colitis, Crohn’s disease, rheumatoid arthritis, atopic dermatitis, psoriasis, lupus (e.g., systemic erythematosus lupus), atherosclerosis, and Type 1 diabetes.
  • ulcerative colitis Crohn’s disease
  • rheumatoid arthritis atopic dermatitis
  • psoriasis lupus (e.g., systemic erythematosus lupus), atherosclerosis, and Type 1 diabetes.
  • Some embodiments provide a method preventing, treating, or ameliorating Lupus, rheumatoid arthritis, atopic dermatitis, and psoriasis.
  • the method includes administering one or more of the compounds disclosed herein to a subject in need thereof.
  • the method includes administering a pharmaceutically acceptable salt thereof of one or more of the compounds disclosed herein to a subject in need thereof.
  • the disclosed compound is used to treat a cancer.
  • the cancer is selected from the group consisting of colon cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, prostate cancer, breast cancer, cholangiocarcinomas, sarcomas, or acute myeloid leukemia.
  • the method includes administering one or more of the compounds disclosed herein to a subject in need thereof.
  • the method includes administering a pharmaceutically acceptable salt thereof of one or more of the compounds disclosed herein to a subject in need thereof.
  • the method of administering one or more of the compounds disclosed herein results in the prevention, treatment, or amelioration, of an inflammatory or autoimmune disease.
  • the method of administering one or more of the compounds disclosed herein results in the prevention, treatment, or amelioration, of ulcerative colitis, Crohn’s disease, atopic dermatitis, psoriasis, systemic erythematosus lupus, atherosclerosis, and Type 1 diabetes.
  • the method includes administering a pharmaceutically acceptable salt thereof of one or more of the compounds disclosed herein.
  • the method of administering one or more of the compounds disclosed herein does not substantially inhibit G9a (also “Euchromatic Histone- Lysine N-Methyltransferase 2” or “EHMT2”).
  • the method of administering one or more of the compounds disclosed herein does not inhibit G9a.
  • Some embodiments provide a use of the compounds disclosed herein for the preparation of a medicament to treat an autoimmune disorder or inflammatory disorder. Some embodiments provide a use of the compounds disclosed herein for the treatment of an autoimmune disorder or inflammatory disorder. In some embodiments, the use comprises the treatment of an autoimmune disorder. In some embodiments, the use comprises the treatment of an inflammatory disorder. [0184] Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament.
  • co- administration it is meant that the two or more agents may be found in the patient’s bloodstream at the same time, regardless of when or how they are actually administered.
  • the agents are administered simultaneously.
  • administration in combination is accomplished by combining the agents in a single dosage form.
  • the agents are administered sequentially.
  • the agents are administered through the same route, such as orally.
  • the agents are administered through different routes, such as one being administered subcutaneously, another being administered orally and another being administered i.v.
  • TLC Thin layer chromatography
  • Merck Kieselgel 60 F254 230-400 mesh fluorescent treated silica which were visualized under ultraviolet light (254 nm), or by staining with potassium permanganate or ninhydrin solution as appropriate.
  • All Nuclear Magnetic Resonance (NMR) spectra were acquired on a Bruker Avance III HD 400 MHz NMR spectrometer; chemical shifts are reported in ppm ( ⁇ ).
  • HPLC/MS was performed on a Sciex 5500 Qtrap mass spectrometry coupled with Shimadzu Nexera X2 UHPLC using Phenomenex Luna C18 column (50 x 2.0 mm, 3 ⁇ m particle size) via following method:
  • the gradient mobile phase A contains 0.1% formic acid in water and mobile phase B contains 0.1% formic acid in acetonitrile;
  • A/B (95:5) from 0 to 0.9 minutes; to A/B (5:95) from 0.9 to 2.2 minutes;
  • the flow rate was 0.4 mL/min and the column temperature maintained at 35 °C and autosampler temperature at 4 °C.
  • Ion spray voltage, drying gas temperature, ion source gas 1, and ion source gas 2 settings were 4500V, 500 °C, 35V, and 45V with ESI set in positive mode using full scan. All compounds purity was analyzed on Agilent 1260 Infinity II Lab LC Series HPLC (1260 Quat pum, 1260 vial autosampler, ICC column oven, 1260 DAD WR detector). Samples were injected into Phenomenex Synergi Polar RP column (150 x 4.6 mm, 4 ⁇ m, 80 ⁇ ).
  • the gradient mobile phase (A: water with 0.1% trifluoroacetic acid, B: acetonitrile with 0.1% trifluoroacetic acid; A/B (99:1) from 0 minute; to A/B (1:99) from 0 to 15 minutes; A/B (1:99) from 15 to 18 minutes; A/B (99:1) from 18 to 18.1 minutes; A/B (99:1) from 18.1 to 20 minutes) pumped at a flow rate of 1 mL/min.
  • UV detector was set to 254 nm with column oven at 35 °C. Injection volume was 10 ⁇ L, unless otherwise specified. All compounds that were evaluated in biological assay had ⁇ 90% and animal study had ⁇ 95% purity.
  • Example 2 Synthesis of 2-chloro-6-methoxy-N-(oxetan-3-yl)-7-(3-(pyrrolidin-1- yl)propoxy)quinazolin-4-amine (Compound 1) [0187] To a 2,4-dichloro-6-methoxy-7-(3- (pyrrolidine-1-yl)propoxy)quinazoline (2.00 g, 5.61 mmol) and 3-oxetanamine (0.62 g, 8.42 mmol) in anhydrous DMF (15 mL) was added DIPEA (2.93 mL, 16.84 mmol). The sealed tube was heated to 50 o C for 3 days under argon atmosphere. The cooled reaction was quenched with sat.
  • Example 3 Synthesis of (5-(4,4-difluoropiperidin-1-yl)-9-methoxy-8-(3-(pyrrolidin-1- yl)propoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanol (Compound 2) [0188] To a 3-yl)-7-(3-(pyrrolidin-1- yl)propoxy)quinazolin-4-amine (0.20 g, 0.51 mmol) and 4,4-difluoropiperdine hydrochloride (0.40 g, 2.55 mmol) in anhydrous 2-butanol (4 mL) was added DIPEA (0.06 g, 0.51 mmol).
  • the sealed tube was heated to 90 o C under argon atmosphere for 5 days. Then a drop of concentrate hydrochloride acid added and continued heating overnight. After completion monitored by TLC, the cooled mixtures were quenched with sat. NaHCO 3 and extracted with 8:2 dichloromethane/isopropanol mixtures (3 x 50 mL) then washed once with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
  • Example 4 Synthesis of (5-(4,4-difluoropiperidin-1-yl)-9-methoxy-8-(3-(pyrrolidin-1- yl)propoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methyl acetate (Compound 3) [0189] To a 1-yl)-9-methoxy-8-(3- (pyrrolidin-1-yl)propoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanol (0.015 g, 0.031 mmol) and DIPEA (0.008 g, 0.063 mmol) in anhydrous THF (1 mL) was added acetyl chloride (0.004 g, 0.047 mmol) in ice-bath under argon atmosphere.
  • the sealed tube was heated to 50 o C for 3 days under argon atmosphere.
  • the cooled reaction was quenched with sat. NaHCO3 and extracted with 8:2 dichloromethane/isopropanol mixtures (3 x 50 mL) then washed once with brine.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Example 6 Synthesis of (5-(4,4-difluoropiperidin-1-yl)-9-methoxy-8-(2-(pyrrolidin-1- yl)ethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanol (Compound 5) [0191] To a 3-yl)-7-(2-(pyrrolidin-1- yl)ethoxy)quinazolin-4-amine (0.20 g, 0.51 mmol) and 4,4-difluoropiperdine hydrochloride (0.58 g, 3.70 mmol) in anhydrous 2-butanol (10 mL) was added DIPEA (0.82 g, 6.33 mmol).
  • the sealed tube was heated to 90 o C under argon atmosphere for 5 days. After completion monitored by TLC, the cooled mixtures were quenched with sat. NaHCO3 and extracted with 8:2 dichloromethane/isopropanol mixtures (3 x 50 mL) then washed once with brine. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the sealed tube was heated to 90 o C under argon atmosphere for 5 days. After completion monitored by TLC, the cooled mixtures were quenched with sat. NaHCO3 and extracted with 8:2 dichloromethane/isopropanol mixtures (3 x 50 mL) then washed once with brine. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Example 9 Testing on Mice with DSS-induced Colitis
  • DSS dextran sulfate sodium
  • FIG. 1A is a graph showing the percent weight change of mice with DSS- induced colitis after treatment with Compound 2, compared to the control group that received vehicle alone. The results demonstrated that Compound 2 resulted in increased weight, compared to mice that were administered solely the vehicle.
  • FIG. 1B illustrates the percent weight change of mice with DSS-induced colitis after exposure to Compound 2, compared to mice that were administered solely the vehicle.
  • mice were sacrificed at d12 after DSS induction, colon length was increased in mice that received Compound 2 and not in mice that were treated solely with vehicle controls, as demonstrated in FIG. 1C.
  • Example 10 Testing on Mice with TNBS-induced Colitis
  • the effect of Compound 2 was determined on the outcome of mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis.
  • a control group received vehicle alone (“Vehicle”).
  • FIG.2A is a graph showing the percent weight change of mice with TNBS- induced colitis after treatment with Compound 2.
  • FIG.2B is a chart showing the colon lengths of mice with TNBS-induced colitis after exposure to Compound 2. Colon length was increased in mice that received Compound 2, compared to mice that were treated solely with vehicle controls, as demonstrated in FIG. 2B.
  • FIG. 2C is a chart showing the histological score of mice with TNBS-induced colitis after exposure to Compound 2
  • FIG.2D is a chart showing the clinical score of mice with TNBS-induced colitis after exposure to Compound 2.

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Abstract

L'invention concerne des composés bicycliques et tricycliques, y compris des compositions pharmaceutiques qui comprennent un ou plusieurs de ces composés. L'invention concerne également des procédés de fabrication de composés bicycliques et tricycliques fonctionnalisés. L'invention concerne en outre des méthodes de traitement de maladies et/ou d'affections (par exemple, inflammatoires et/ou auto-immunes) avec les composés bicycliques selon l'invention.
PCT/US2024/035260 2023-06-26 2024-06-24 Petites molécules pour le traitement de troubles auto-immuns Pending WO2025006391A1 (fr)

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