Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• Ribonucleotide reductase also known as ribonucleotide diphosphate reductase (rNDP)
• rNDP ribonucleotide diphosphate reductase
• RNR is a highly regulated enzyme in the deoxyribonucleotide synthesis pathway that is ubiquitously present in human, bacteria, yeast, and other organisms.
• RNR is responsible for the de novo conversion of ribonucleotide diphosphate to 2’-deoxyribonucleotide diphosphate, a process that is essential for DNA synthesis and repair.
• RNR is directly involved in DNA synthesis and repair, tumor growth, metastasis, and drug resistance.
• numerous correlations have been reported with overexpression of M2 and their prognosis.
• cell growth inhibition by inhibiting RNR and anti-tumor effect in vivo have been reported in cell lines derived from several cancer types and in nonclinical models.
• dNTPs deoxyribonucleotide triphosphates
• a compound of Formula (Ia), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof Formula (Ia); wherein R 6’ is hydrogen or C 1 -C 6 alkyl.
• a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
• Also disclosed herein is a method of treating cancer in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
• a method of inhibiting ribonucleotide reductase in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
• the inhibition of ribonucleotide reductase occurs in a tumor cell in the subject in need thereof.
• Also disclosed herein is a method for treating a tumor or tumor cells in a subject, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount sufficient to induce replication stress in the tumor or tumor cells; and administering a cancer-targeted therapeutic agent; wherein the tumor or tumor cells have an ecDNA signature; and wherein growth or size of the tumor or growth or number of tumor cells is reduced.
• Also disclosed herein is a method of treating an ecDNA-associated tumor or tumor cells comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject identified as having a tumor or tumor cells having ecDNA, wherein growth or size of the tumor or growth or number of the tumor cells is decreased as a result of treatment.
• the method further comprises administering a cancer-targeted therapeutic agent.
• the cancer-targeted therapeutic agent inhibits a gene or gene product comprised on ecDNA in the tumor or tumor cells.
• Also disclosed herein is a method for treating a tumor or tumor cells in a subject, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount sufficient to induce replication stress in the tumor or tumor cells, wherein the tumor or tumor cells comprises ecDNA or have an ecDNA signature; and wherein growth or size of the tumor or growth or number of tumor cells is reduced.
• Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms.
• Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1- pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl,
• C 1 -C 6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
• the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, aC 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C 1 alkyl.
• an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
• alkyl is optionally substituted with halogen. In some embodiments, the alkyl is optionally substituted with -COOH, -COOMe, -CONH 2 , -CONHMe, or -CONMe 2 .
• Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
• a numerical range such as “C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
• the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
• an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
• alkenyl is optionally substituted with halogen. In some embodiments, the alkenyl is optionally substituted with - COOH, -COOMe, -CONH 2 , -CONHMe, or -CONMe 2 .
• Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
• C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers alkynyl is a C 2 - C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
• an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
• the alkynyl is optionally substituted with halogen. In some embodiments, the alkynyl is optionally substituted with -COOH, -COOMe, -CONH 2 , -CONHMe, or -CONMe 2 .
• Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 . In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is optionally substituted with -COOH, -COOMe, -CONH 2 , -CONHMe, or - CONMe 2 .
• Alkoxy refers to a radical of the formula -Oalkyl where alkyl is as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. In some embodiments, the alkoxy is optionally substituted with -COOH, -COOMe, -CONH 2 , -CONHMe, or -CONMe 2 .
• Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines.
• Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
• “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
• the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
• the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl.
• Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
• the aryl is phenyl.
• an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is optionally substituted with -COOH, -COOMe, -CONH 2 , -CONHMe, or -CONMe 2 .
• Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
• Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 - C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
• the cycloalkyl is a 3- to 6-membered cycloalkyl.
• the cycloalkyl is a 5- to 6-membered cycloalkyl.
• Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
• Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
• a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
• the cycloalkyl is optionally substituted with halogen.
• the cycloalkyl is optionally substituted with -COOH, -COOMe, -CONH 2 , -CONHMe, or -CONMe 2 .
• “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms.
• Deuteroalkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 .
• the deuteroalkyl is CD 3 .
• “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen atoms.
• the alkyl is substituted with one, two, or three halogen atoms.
• the alkyl is substituted with one, two, three, four, five, or six halogen halogens.
• Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
• the haloalkyl is trifluoromethyl.
• Halo or halogen refers to bromo, chloro, fluoro or iodo.
• halogen is fluoro or chloro.
• halogen is fluoro.
• halogen is chloro.
• halogen is bromo. In some embodiments, halogen is iodo.
• “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
• a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
• Examples of such heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , or -CH(CH 3 )OCH 3 .
• a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 .
• a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. In some embodiments, the heteroalkyl is optionally substituted with -COOH, -COOMe, - CONH 2 , -CONHMe, or -CONMe 2 . [0036] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl.
• the alkyl is substituted with one, two, or three hydroxyls.
• Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
• “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated, not fully aromatic ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen and oxygen.
• the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
• heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl), or two to four carbon atoms (C 2 - C 4 heterocycloalkyl).
• the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl.
• the cycloalkyl is a 5- to 6-membered heterocycloalkyl.
• heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, t
• heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
• a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. In some embodiments, the heterocycloalkyl is optionally substituted with -COOH, -COOMe, -CONH 2 , -CONHMe, or -CONMe 2 .
• Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring comprising at least one heteroatom.
• the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
• the heteroaryl is a 5- to 10-membered heteroaryl.
• the heteroaryl is a 5- to 6-membered heteroaryl.
• Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
• a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
• a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
• a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. In some embodiments, the heteroaryl is optionally substituted with -COOH, -COOMe, -CONH 2 , -CONHMe, or -CONMe 2 . [0039]
• the term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents.
• the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. [0040]
• the terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results.
• beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
• Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
• a disorder including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.
• an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
• an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms.
• an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.
• ecDNA signature generally refers to one or more characteristics common to tumors or tumor cells that are ecDNA+ (contain extrachromosomal DNA (ecDNA)).
• the ecDNA signature is selected from the group consisting of a gene amplification; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation signature (TIS); a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof.
• ecDNA signature includes a detection or identification of ecDNA using an imaging technology. In some cases, ecDNA signature does not include any imaging or direct detection of ecDNA.
• the compound is of Formula: .
• the compound is of Formula: .
• the compound is of Formula: .
• the compound is of Formula: .
• the compound is of Formula: .
• Ring A is a 5-membered ring comprising 1 or 2 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 2 or 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 2-4 heteroatoms selected from the group consisting of O, S, and N.
• Ring A is a 5-membered ring comprising 1-3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 3 or 4 heteroatoms selected from the group consisting of O, S, and N. [0055] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 1 heteroatom selected from the group consisting of O, S, and N.
• Ring A is a 5-membered ring comprising 2 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 4 heteroatoms selected from the group consisting of O, S, and N.
• Ring A is a 5-membered ring comprising 1 or 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 2 or 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-1)- (I-4), Ring A is a 5-membered ring comprising 2-4 heteroatoms selected from the group consisting of O and N.
• Ring A is a 5-membered ring comprising 1-3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 3 or 4 heteroatoms selected from the group consisting of O and N. [0057] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered ring comprising 1 heteroatom selected from the group consisting of O and N.
• Ring A is a 5-membered ring comprising 2 heteroatoms selected from the group consisting of O and N.
• Ring A is a 5-membered ring comprising 3 heteroatoms selected from the group consisting of O and N.
• Ring A is a 5-membered ring comprising 4 heteroatoms selected from the group consisting of O and N.
• Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (I-1)- (I-4), Ring A is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (I- 1)-(I-4), Ring A is a 5-membered heterocycloalkyl comprising one to four heteroatoms selected from the group consisting of O, S, and N.
• Ring A is a 5-membered heterocycloalkyl comprising two to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered heterocycloalkyl comprising three to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered heteroaryl.
• Ring A is a 5-membered heteroaryl comprising one to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered heteroaryl comprising two to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 5-membered heteroaryl comprising three to four heteroatoms selected from the group consisting of O, S, and N.
• Ring A is a triazole or tetrazole. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a triazole. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a tetrazole. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), Ring A is a 2,3-dihydro-1,3,4-oxadiazole.
• each R 6 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R 6 on the same atom are taken together to form an oxo.
• each R 6 is independently deuterium, halogen, or C 1 -C 6 alkyl; or two R 6 on the same atom are taken together to form an oxo.
• each R 6 is independently C 1 -C 6 alkyl; or two R 6 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), each R 6 is independently C 1 -C 6 alkyl. [0062] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), two R 6 on the same atom are taken together to form an oxo. [0063] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 0-2.
• n is 0 or 1. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 1 or 2. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 2 or 3. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 0. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 1. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 2.
• n is 3.
• the compound is of Formula (Ia): Formula (Ia); wherein R 6’ is hydrogen or C 1 -C 6 alkyl.
• R 6’ is hydrogen or C 1 -C 6 alkyl.
• the compound is of Formula: .
• X 1 is N.
• X 1 is CR 1 .
• X 2 is N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X 2 is CR 2 . [0068] In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X 3 is N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X 3 is CR 3 . [0069] In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X 4 is N.
• X 4 is CR 4 .
• Ring C is a 5- to 7- membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
• Ring C is a 6- to 7-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
• Ring C is a 5- to 6-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
• Ring C is a 5-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
• Ring C is a 6-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
• Ring C is a 5- to 7- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N.
• Ring C is a 6- to 7- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), Ring C is a 5- to 6- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), Ring C is a 5-membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N.
• Ring C is a 6-membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), Ring C is a 7-membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), Ring C is a 8-membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N.
• Ring C is a 5- to 7- membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), Ring C is a 6- to 7-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (I-1)- (I-4), Ring C is a 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), Ring C is a 5-membered heterocycloalkyl.
• Ring C is a 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), Ring C is a 7-membered heterocycloalkyl.
• the compound is of Formula (Ib): Formula (Ib); wherein R 6’ is hydrogen or C 1 -C 6 alkyl; and each R 5’ is independently hydrogen or R 5 .
• the compound is of Formula: .
• each R 5’ is independently hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or 2 R 5 on the same carbon are taken together to form an oxo.
• each R 5’ is independently hydrogen, deuterium, halogen, or C 1 -C 6 alkyl.
• each R 5’ is independently hydrogen or C 1 -C 6 alkyl.
• each R 5’ is hydrogen.
• each R 5’ is independently hydrogen or deuterium.
• the compound is of Formula (Ic): Formula (Ic); wherein R 6’ is hydrogen or C 1 -C 6 alkyl.
• the compound is of Formula: .
• the compound is of Formula (Id): Formula (Id); wherein R 6’ is hydrogen or C 1 -C 6 alkyl.
• the compound is of Formula: .
• R 6 is hydrogen.
• each R 5 is independently deuterium, halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or 2 R 5 on the same carbon are taken together to form an oxo.
• each R 5 is independently deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R 5 is independently deuterium. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R 5 is independently C 1 -C 6 alkyl. [0082] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 0 or 1.
• p is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 0. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I- 4), p is 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 3.
• R 1 , R 2 , R 3 , and R 4 are independently hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
• R 1 , R 2 , R 3 , and R 4 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
• R 1 , R 2 , R 3 , and R 4 are independently hydrogen, or halogen, -OR a .
• R 1 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R 1 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R 1 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is halogen.
• R 2 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R 2 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R 2 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is halogen.
• R 3 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R 3 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R 3 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is halogen.
• R 4 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R 4 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
• R 4 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is halogen.
• R 7 is deuterium, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
• R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl.
• R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
• R 7 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl.
• R 7 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C 1 -C 6 alkyl or cycloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C 1 -C 6 alkyl.
• R 7 is methyl.
• R 8 is hydrogen or C 1 -C 6 alkyl.
• R 8 is hydrogen.
• Ring B is aryl or heteroaryl.
• Ring B is phenyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is 5- membered heteroaryl.
• Ring B is 6-membered heteroaryl.
• each R 9 is independently halogen or C 1 -C 6 alkyl.
• m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0 or 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0-2.
• m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 2.
• m is 3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 4.
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl.
• each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
• each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl.
• each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
• each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R a is hydrogen.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
• each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are hydrogen.
• each R 9 , R 9a , R a , R b , R c , R d , and the heterocycloalkyl formed when R c and R d are taken together is independently substituted with one, two, three, or four substituents as defined herein.
• R 9 , R 9a , R a , R b , R c , R d , and the heterocycloalkyl formed when R c and R d are taken together is independently substituted with one, two, or three substituents as defined herein.
• R 9 , R 9a , R a , R b , R c , R d , and the heterocycloalkyl formed when R c and R d are taken together is independently substituted with one or two substituents as defined herein.
• R 9 , R 9a , R a , R b , R c , R d , and the heterocycloalkyl formed when R c and R d are taken together is independently substituted with one substituent as defined herein.
• R 9 , R 9a , R a , R b , R c , R d , and the heterocycloalkyl formed when R c and R d are taken together is independently substituted with two substituents as defined herein.
• R 9 , R 9a , R a , R b , R c , R d , and the heterocycloalkyl formed when R c and R d are taken together is independently substituted with three substituents as defined herein.
• the compound is selected from a compound of Table 1: TABLE 1
• the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
• mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
• the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
• dissociable complexes are preferred.
• the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
• Labeled compounds [00105] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
• the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
• the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds described herein, or a solvate, tautomer, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
• Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
• isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
• the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is prepared by any suitable method.
• the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
• Pharmaceutically acceptable salts [00107] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
• the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
• Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,
• the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
• those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
• a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
• Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
• bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
• Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like of the tetrazole.
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
• Solvates [00113] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates.
• Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
• the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
• Tautomers [00115] In some situations, compounds exist as tautomers.
• the compounds described herein include all possible tautomers within the formulas described herein.
• Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. In some embodiments, the tetrazoles disclosed herein exists as either of its tautomers: .
• Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L.
• the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
• a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
• the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
• Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.
• an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
• Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
• the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, and epidural and intranasal administration.
• Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
• the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.
• the pharmaceutical composition is formulated for oral administration.
• the pharmaceutical composition is formulated for intravenous injection.
• the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.
• the pharmaceutical composition is formulated as a tablet.
• Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
• the present method involves the administration of about 0.1 ⁇ g to about 50 mg of at least one compound described herein per kg body weight of the subject.
• dosages of from about 10 ⁇ g to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response.
• the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day.
• the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.
• Methods of Treatment [00126] Disclosed herein are methods for treating cancer in a subject in need thereof, including administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
• the RNR-related cancer includes malignant tumors whose incidence can be decreased or whose symptom is in remission or alleviated and/or completely cured by deleting or suppressing and/or inhibiting functions of RNR.
• Malignant tumors of interest is, but not limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, etc.), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumor and the like.
• gastrointestinal cancer esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbla
• cancer is used in accordance with its plain ordinary meaning in light of the present disclosure and refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas, and sarcomas.
• lymphoma e.g., Mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zona lymphoma, Burkitt’ s lymphoma
• sarcoma bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin (trastuzumab) resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma) ,
• lymphoma e.g., Mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zona lympho
• Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer
• the cancer is selected from ovarian cancer, prostate cancer, esophageal cancer, salivary gland cancer, breast cancer, liver cancer, pancreatic cancer, stomach cancer, lung cancer, bladder cancer, colon cancer, and uterine cancer.
• the cancer is selected from muscle cancer, brain cancer, lymph node cancer, thyroid cancer, kidney cancer, and adrenal gland cancer.
• ecDNA mediates an important and clinically distinct mechanism of resistance to targeted therapies.
• the one or more RNR inhibitor described herein may be used to treat an ecDNA+ cancer, ecDNA+ tumor or ecDNA+ tumor cells.
• One or more RNR inhibitor described herein may be used to treat tumors, such as with one or more amplified oncogenes (e.g. FGFR, EGFR, MET, KRAS, MDM2 amplifications), in some cases, the one or more amplified oncogenes comprise non-mutant forms of the oncogene and in some cases, the amplified oncogenes comprises mutant forms of the oncogenes.
• the tumor comprises one or more amplified oncogenes present on ecDNA and the one or more RNR inhibitor described herein are used to treat the tumor in combination with a therapeutic agent targeted to (e.g., an inhibitor of) the one or more amplified oncogenes on the ecDNA.
• One or more RNR inhibitor described herein may be used to treat tumors for which there are no approved targeted therapies or for which highly efficacious therapies are lacking.
• One or more RNR inhibitor described herein may be used to treat tumors that have developed resistance to another therapy such as a resistance to a targeted agent.
• a tumor (or tumor cells) treated with one or more targeted agents develops resistance to a targeted agent, such as a targeted agent directed to an oncogene or a targeted agent that directly inhibits activating mutant forms of certain oncoproteins (e.g.
• the one or more RNR inhibitor described herein may be used to treat such tumors or tumor cells, alone or in combination with an additional therapeutic agent.
• the one or more RNR inhibitor described herein may be used to treat such tumors or tumor cells, alone or in combination with an additional therapeutic agent.
• Provided herein are methods wherein inhibition of RNR by the one or more RNR inhibitors described herein exhibits synthetic lethality with a cancer-targeted agent.
• synthetic lethality arises with one or more RNR inhibitors described herein in combination with a cancer targeted agent.
• a tumor background is identified as hyper-sensitive to a RNR inhibitor and allows a sufficient therapeutic index to enable tolerated doses that are efficacious.
• synthetic lethality arises with one or more RNR inhibitors described herein in combination with a cancer targeted agent where the tumor or tumor cells are ecDNA+.
• RNR inhibition results in reduced ecDNA copy number.
• RNR inhibition results in enhanced cytotoxicity in ecDNA+ cells.
• enhanced cytotoxicity results from the combination of RNR inhibition and inhibition of a cancer- target, such as an oncogene, for example an oncogene amplified on ecDNA.
• a tumor or tumor cells to be treated are ecDNA+. In some cases, such tumor or tumor cells are determined to have an ecDNA signature.
• a tumor or tumor cells are determined to have an ecDNA signature when the tumor or tumor cells have one or more characteristics associated with ecDNA+ tumors or tumor cells.
• the ecDNA signature is selected from the group consisting of a gene amplification; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation signature (TIS); a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof.
• the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in combination with a second therapeutic agent or a cancer-targeted agent.
• the method further comprises administering a cancer-targeted therapeutic agent, directed to an activity of a protein product of a target gene.
• the treatment with the cancer-targeted therapeutic agent and the RNR inhibitor disclosed herein reduces amplification or expression of the target gene in the tumor or tumor cells.
• the cancer-targeted therapeutic agent is administered prior to the RNR inhibitor.
• the cancer-targeted therapeutic agent is administered concurrently with the RNR inhibitor.
• the tumor or tumor cells have an ecDNA signature.
• the tumor or tumor cells develop the ecDNA signature after administration of the cancer-targeted therapeutic agent.
• the tumor or tumor cells develop the ecDNA signature prior to treatment.
• the method prevents an increase of ecDNA in the tumor or tumor cells.
• the second therapeutic includes antimetabolites, platinum drugs, plant alkaloid drugs, and molecular targeting drugs.
• the antimetabolites include 5-fluorouracil, 5-fluoro-2’-deoxyuridine, tegafur, tegafur-uracil, tegafur-gimeracil-oteracil, pemetrexed, trifluridine, trifluridine-tipiracil hydrochloride, fludarabine (or an active metabolite fludarabine nucleoside), cytarabine, gemcitabine, capecitabine, nelarabine, clofarabine, and DNA methylation inhibitors (decitabine, guadecitabine, azacitidine, etc.).
• the platinum drugs include cisplatin, oxaliplatin, carboplatin, and nedaplatin.
• the plant alkaloid drugs include microtube inhibiting drugs such as paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, and eribulin, and topoisomerase inhibiting drugs such as irinotecan (or an active metabolite SN-38), nogitecan, and etoposide.
• the molecular targeting drugs include ATR (ataxia telangiectasia and Rad3 related protein) inhibitors, Chk1 (checkpoint kinase 1) inhibitors, HSP (heat shock protein) 90 inhibitors, PARP (poly ADP ribose polymerase) inhibitors, EGFR (epidermal growth factor receptor) inhibitors, Her2 inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MET inhibitors, AXL inhibitors, RET inhibitors, FLT3 (fms-related tyrosine kinase 3) inhibitors, KIT inhibitors, CSF1R (colony-stimulating factor 1 receptor) inhibitors, TIE2 (tunica interna endothelial cell kinase 2) inhibitors, TRKB inhibitors, and CDK4/6 inhibitors.
• ATR ataxia telangiectasia and Rad3 related protein
• Chk1 checkpoint
• the ATR inhibitors include AZD6738, berzosertib, BAY1895344, and VX-803.
• the Chk1 inhibitors include prexasertib, SCH900776, GDC-0575, and CCT245737.
• the HSP90 inhibitors include luminespib, ganetespib, and onalespib.
• the PARP inhibitors include olaparib, rucaparib, niraparib, veliparib, and talazoparib.
• the EGFR inhibitors include small molecule inhibitors such as lapatinib, gefitinib, erlotinib, afatinib, and vandetanib, and anti- EGFR antibodies such as cetuximab and panitumumab.
• the Her2 inhibitors include small molecule inhibitors such as lapatinib, and anti-Her2 antibodies such as trastuzumab, pertuzumab, and trastuzumab emtansine.
• the VEGFR inhibitors are inhibitors of at least one of VEGFR1, VEGFR2, and VEGFR3 and include small molecule inhibitors such as sunitinib, cabozantinib, midostaurin, sorafenib, vandetanib, pazopanib, lenvatinib, and axitinib, and anti-VEGFR antibodies such as ramucirumab.
• the PDGFR inhibitors are PDGFR ⁇ and/or PDGFR ⁇ inhibitors and include sunitinib, midostaurin, pazopanib, lenvatinib, and sorafenib.
• the MET inhibitors include cabozantinib, crizotinib, and tepotinib.
• the AXL inhibitors include cabozantinib and gilteritinib.
• the RET inhibitors include sunitinib, cabozantinib, sorafenib, lenvatinib, and vandetanib.
• the FLT3 inhibitors include sunitinib, cabozantinib, midostaurin, gilteritinib, and sorafenib.
• the KIT inhibitors include sunitinib, midostaurin, pazopanib, lenvatinib, and sorafenib.
• the CSF1R inhibitors include sunitinib, BLZ-945, and ARRY-382.
• the TIE2 inhibitors include cabozantinib.
• the TRKB inhibitors include cabozantinib and entrectinib.
• the CDK4/6 inhibitors include palbociclib, ribociclib, and abemaciclib.
• the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
• a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
• the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.
• different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent.
• Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves.
• the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
• a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
• the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
• the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
• dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth.
• the compound provided herein when co-administered with a second therapeutic agent, is administered either simultaneously with the second therapeutic agent, or sequentially.
• the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
• the compounds described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as well as combination therapies, are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
• the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
• the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
• a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
• the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
• a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
• the compound of described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in combination with an adjuvant.
• the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
• an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
• Step 1 Synthesis of 6-fluoro-2,3-dimethylbenzaldehyde [00149] Into a 1L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-6-fluoro-3-methylbenzaldehyde (50 g, 230 mmol, 1.0 equiv), methylboronic acid (23.4 g, 392 mmol, 1.7equiv), K 3 PO 4 (117.4 g, 553 mmol, 2.4 equiv), Pd(dppf)Cl 2 .CH 2 Cl 2 (5.63 g, 6.91 mmol, 0.03equiv), H 2 O (50 mL), Dioxane (450 mL).
• Step 2.1-(6-fluoro-2,3-dimethylphenyl) ethan-1-ol Into a 1L 3-necked round-bottom flask, the mixture of 6-fluoro-2,3-dimethylbenzaldehyde (27 g, 177.4 mmol, 1 equiv) in THF was added bromo(methyl)magnesium (42.3 g, 355 mmol, 2 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50mL).
• Step 3.2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene [00151] Into a 500 mL 3-necked round-bottom flask were added 1-(6-fluoro-2,3-dimethylphenyl) ethanol (25 g, 148.6 mmol, 1.0 equiv) and CHCl3 (250 mL) at room temperature.
• (2S)-2-((tert-butoxycarbonyl) amino)-3-(6-fluoro-2,3-dimethylphenyl) butanoic acid [00153] Into a 250 mL round-bottom flask were added (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl) butanoic acid (5 g, 22.2 mmol, 1.0 equiv), Et3N (6.74 g, 66.6 mmol, 3.0 equiv), H 2 O (25 mL) and Dioxane (25 mL) at room temperature.
• Step 6 synthesis of 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)- one, HCl
• (2S)-2-[(tert-butoxycarbonyl) amino]-3-(6-fluoro- 2,3-dimethylphenyl) butanoic acid 9 g, 27.7 mmol, 1.0 equiv
• CDI (11.2 g, 69.2 mmol, 2.5equiv)and THF (60 mL)
• THF 60 mL
• Example 1 and 2 5-((1S,2R)-1-(5-chloro-1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro- 2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2S)-1-(5-chloro-1,1-dioxido-3- oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one Step 1.
• Step 4.5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)sulfamoyl)benzoic acid [00161] Into a 8 mL vial were added 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl) propyl)sulfamoyl)benzoic acid (50 mg, 0.100mmol, 1equiv), THF (3 mL) and LiOH.H 2 O (16.85 mg, 0.400mmol, 4equiv) at room temperature.
• Example 3 and 4 5-((1S,2R)-1-(5-chloro-7-methoxy-1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-2- (6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2S)-1-(5-chloro-7- methoxy-1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4- oxadiazol-2(3H)-one Step 1.
• methyl 2-amino-5-chloro-3-methoxybenzoate [00165] Into a 100mL round-bottom flask were added methyl 2-amino-3-methoxybenzoate (2 g, 11.038mmol, 1.00equiv) in DMF (20 mL) and N-chloro succinimide (1.62 g, 12.142mmol, 1.1equiv) at room temperature. The resulting mixture was stirred for 2h at 50 degrees C. The resulting mixture was extracted with EtOAc (3 x 15mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) propyl) sulfamoyl)-3-methoxybenzoate 100 mg, 0.189mmol, 1.00equiv
• THF 3 mL
• water 1 mL
• LiOH.H 2 O 15.90 mg, 0.378mmol, 2.0 equiv
• Example 5 and 6 5-((1S,2S)-1-(5-chloro-7-methoxy-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6- fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(5-chloro-7-methoxy- 1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)- one Step 1.4-chloro-N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl)-2-(hydroxymethyl
• 4-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H- 1,3,4-oxadiazol-2-yl) propyl]-2-(hydroxymethyl)-6-methoxybenzenesulfonamide 100 mg, 0.200mmol, 1.00equiv
• DCM (3 mL)
• TEA 83.41uL, 0.600mmol, 3equiv
• Example 7 and 8 Synthesis of 5-((1S,2S)-1-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2]thiazin- 2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(6-chloro- 1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4- oxadiazol-2(3H)-one Step 1.
• methyl 2-[(diphenylmethylidene)amino]acetate [00179] To a stirred mixture of methyl 2-aminoacetate hydrochloride (12.6 g, 100.358 mmol, 1 equiv) in toluene was added benzophenone (36.58 g, 200.716 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 30 min at 120°C. To the above mixture was added DIPEA (25.94 g, 200.716 mmol, 2 equiv) dropwise over 3h at 120°C. The resulting mixture was stirred for additional 3 h at 120°C. The resulting mixture was concentrated under vacuum.
• tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate Into a 40 mL vial were added tert-butyl 2-(2-bromo-5-chlorophenyl)acetate (2 g, 6.545 mmol, 1.00 equiv) and dioxane (6 mL, 82.636 mmol) , DIEA (2.54 g, 19.635 mmol, 3 equiv) ,benzyl mercaptan (0.98 g, 7.854 mmol, 1.2 equiv), XantPhos (378.68 mg, 0.655 mmol, 0.1 equiv) ,Pd 2 (dba) 3 (299.65 mg, 0.327 mmol, 0.05 equiv).
• tert-butyl 2-[5-chloro-2-(chlorosulfonyl)phenyl] acetate Into a 50 mL round-bottom flask were added tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl] acetate (5.5 g, 15.850 mmol, 1.00 equiv), MECN (30 mL, 76.099 mmol), CH 3 COOH (3.6 mL, 21.093 mmol), H 2 O (1.8 mL, 21.093 mmol).
• methyl 2-((2-(2-(tert-butoxy)-2-oxoethyl)-4-chlorophenyl) sulfonamido)-3- (6-fluoro-2,3-dimethylphenyl)butanoate (4.3 g, 8.143 mmol, 1 equiv) is added HCl 4N in 1,4-dioxane (40 mL, 819.919 mmol, 100.69 equiv) at room temperature.
• 2-(5-chloro-2-(N-(3- (6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)acetic acid (1.15 g, 2.437 mmol, 1 equiv) in THF (10 ml) dropwise at room temperature under nitrogen atmosphere.
• Example 9 and 10 5-((1S,2S)-1-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2- (6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(7-chloro-1,1- dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4- oxadiazol-2(3H)-one Step 1.
• (2S)-3-(6-fluoro-2,3-dimethylphenyl)-2-[N-(prop-2-en-1-yl)4-chloro-2- ethenylbenzenesulfonamido] butanoate Into a 100 mL round-bottom flask were added methyl (2S)-2-(4-chloro-2- ethenylbenzenesulfonamido)-3-(6-fluoro- 2,3-dimethylphenyl) butanoate (1.5 g, 3.410 mmol, 1 equiv) , allyl bromide (412.49 mg, 3.410 mmol, 1 equiv) , Cs 2 CO 3 (3.33 g, 10.230 mmol, 3 equiv) and DMF (15 mL) at room temperature.
• methyl (2S)-2-(7-chloro-1,1-dioxidobenzo[f][1,2] thiazepin-2(3H)- yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate 300 mg, 0.664 mmol, 1 equiv)
• THF 9 mL
• H 2 O 3 mL
• (2S)-2-(7-chloro-1,1-dioxidobenzo[f][1,2] thiazepin-2(3H)-yl)-3-(6- fluoro-2,3-dimethylphenyl)butanoic acid (380 mg, 0.868 mmol, 1 equiv)
• CDI 365.84 mg, 2.257 mmol, 2.6 equiv
• THF 7.6 mL
• Example 11 and 12 Synthesis of 5-((1S,2S)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H- benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5- ((1S,2R)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3- dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one Step 1.
• tert-butyl 2-[2-(benzylsulfanyl)-4-chlorophenyl] acetate Into a 250 mL round-bottom flask were added tert-butyl 2-(2-bromo-4-chlorophenyl)acetate (6 g, 19.634 mmol, 1 equiv) and dioxane (50 mL, 590.198 mmol) at room temperature.
• tert-butyl 2-[4-chloro-2-(chlorosulfonyl)phenyl] acetate [00209] Into a 50 mL 3-necked round-bottom flask were added tert-butyl 2-[2-(benzylsulfanyl)-4- chlorophenyl] acetate (3 g, 8.599 mmol, 1 equiv) and CH 3 CN (20 mL) at room temperature.
• Example 13 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)-3,4- dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide Step 1.
• tert ⁇ butyl N ⁇ [(1S,2R) ⁇ 1 ⁇ cyano ⁇ 2 ⁇ (6 ⁇ fluoro ⁇ 2,3 ⁇ dimethylphenyl)propyl]carbamate Trifluoroacetic anhydride (354 ⁇ L, 2.547 mmol, 1.502 eq) was added dropwise at 0°C to a solution of tert-butyl N-[(1S,2R)-1-carbamoyl-2-(6-fluoro-2,3-dimethylphenyl) propyl]carbamate (550 mg, 1.695 mmol, 1.0 eq) in pyridine (16.5 mL). The reaction was continued at RT overnight. Solvent was removed in vacuo.
• the mixture was thoroughly degassed and purged with argon with constant stirring for 15 min. Afterwards, the reaction vessel was immersed in a preheated oil bath to 110°C and benzyl mercaptan (0.817 mL, 6.96 mmol, 0.96 eq) was added via a syringe. The reaction vessel was sealed, and the reaction was continued for 20 h. Upon completion, the mixture was allowed to cool to room temperature. The volatiles were removed in vacuo. The residue was redissolved in EtOAc and filtered through a pad of silica gel.
• Step 10 4-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl) propyl]-2-(2- hydroxyethyl)benzene-1-sulfonamide [00231] To a solution of 2-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl) propyl) sulfamoyl)phenyl)acetic acid (125 mg, 0.259 mmol, 1.0 eq) in THF (6.25 mL) was added borane dimethyl sulfide complex (0.246 mL, 2.594 mmol, 10 eq).
• Example 14 synthesis of 5-((1S,2R)-1-(5-chloro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro- 2,3-dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2- yl) propyl]-2-(hydroxymethyl)benzenesulfonamide
• [00234] Into a 50 mL round-bottom flask were added methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl
• Step 2 Synthesis of 2-(bromomethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H- 1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide
• 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4- oxadiazol-2-yl)propyl]-2-(hydroxymethyl)benzenesulfonamide (128 mg, 0.27 mmol, 1 equiv) and carbon tetrabromide (135 mg, 0.41 mmol, 1.5 equiv) in DCM was added triphenylphosphine (143 mg, 0.54 mmol, 2 equiv) in portions at 0°C.The resulting mixture was stirred overnight at 40
• Step 3 Synthesis of 5-((1S)-1-(5-chloro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3- dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)-one
• 2-(bromomethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H- 1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide (87 mg, 0.16 mmol, 1 equiv) in DMF was added Cs 2 CO 3 (106.4 mg, 0.33 mmol, 2 equiv) in portions at room temperature.
• Step 4 Synthesis of 5-((1S,2R)-1-(5-chloro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3- dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)-one [00236]
• the crude product (50 mg) was purified by Chiral-Prep-HPLC.
• Example 15 5-((1R,2S)-1-(5-chloro-7-methoxy-1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6- fluoro-2,3-dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of methyl 2-amino-5-chloro-3-methoxybenzoate [00237] Into a 100mL round-bottom flask were added methyl 2-amino-3-methoxybenzoate (2 g, 11 mmol, 1 equiv) in DMF (20 mL) and NCS (1.62 g, 12.1 mmol, 1.1equiv) at room temperature. The resulting mixture was stirred for 2h at 50 degrees C. The resulting mixture was extracted with EtOAc (3 x 15mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• Step 2 Synthesis of methyl 2-bromo-5-chloro-3-methoxybenzoate [00238] Into a 100 mL round-bottom flask were added methyl 2-amino-5-chloro-3-methoxybenzoate (1 g, 4.6 mmol, 1equiv), CuBr 2 (2.07 g, 9.3 mmol, 2 equiv) and CH 3 CN (10 mL) at room temperature. The resulting mixture was stirred 20 min at room temperature.
• Step 3 Synthesis of methyl 2-(benzylsulfanyl)-5-chloro-3-methoxybenzoate [00239] Into a 100 mL round-bottom flask, was placed methyl 2-bromo-5-chloro-3-methoxybenzoate (1.6 g, 5.7 mmol, 1 equiv), benzyl mercaptan (0.85 g, 6.9 mmol, 1.2 equiv), DIEA (2.2 g, 17.2 mmol, 3 equiv), Xantphos (0.66 g, 1.15 mmol, 0.2 equiv), Pd 2 (dba) 3 (0.52 g, 0.57 mmol, 0.1 equiv), dioxane (15 mL).
• Step 4 Synthesis of methyl 5-chloro-2-(chlorosulfonyl)-3-methoxybenzoate
• a 250 mL round-bottom flask the mixture of methyl 2-(benzylsulfanyl)-5-chloro-3- methoxybenzoate (1.3 g, 4 mmol, 1 equiv) in MeCN were added 1,3-dichloro-5,5-dimethylimidazolidine- 2,4-dione (1.6 g, 8 mmol, 2 equiv), AcOH (0.90 mL, 15.7 mmol, 3.9 equiv) and H 2 O (0.70 mL) in portions at 0 degrees C.
• Step 5 Synthesis of methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl) propyl) sulfamoyl)-3-methoxybenzoate [00241]
• the mixture of 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl) propyl]-3H-1,3,4-oxadiazol-2-one hydrochloride (200 mg, 0.66 mmol, 1 equiv) in pyridine (5 mL) was added methyl 5-chloro-2-(chlorosulfonyl)-3-methoxybenzoate (400 mg, 1.33 mmol, 2 equiv) dropwise at 0 degrees C.
• Step 6 Synthesis of 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl) propyl) sulfamoyl)-3-methoxybenzoic acid [00242] Into a 8 mL round-bottom flask were added methyl 5-chloro-2- ⁇ [(1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]sulfamoyl ⁇ -3-methoxybenzoate (100 mg, 0.19mmol, 1 equiv) in THF (3 mL),water (1 mL) and LiOH.H 2 O (15.9 mg, 0.38 mmol, 2.0equiv) at room temperature.
• Step 7 Synthesis of 5-((1S,2R)-1-(5-chloro-7-methoxy-1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)- 2-(6-fluoro-2,3-dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)-one [00243] Into a 20 mL round-bottom flask were added 5-chloro-2- ⁇ [(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]sulfamoyl ⁇ -3-methoxybenzoic acid (120 mg, 0.23 mmol, 1.00 equiv), EDCI (89.5 mg, 0.47 mmol, 2.0 equiv),DMAP (2.85 mg, 0.023 mmol, 0.1 equiv) and DCM (3
• Step 2 Synthesis of methyl 2-(benzyloxy)-2-(2-bromo-5-chlorophenyl) acetate methyl 2-(benzyloxy)-2- (2-bromo-5-chlorophenyl)acetate
• methyl 2-(2-bromo-5-chlorophenyl)-2-diazoacetate 11 g, 38 mmol, 1 equiv
• phenylmethanol 41.1 g, 380 mmol, 10 equiv
• HClO 4 700 ⁇ L, 12.2 mmol, 0.32 equiv
• Step 3 Synthesis of methyl 2-(benzyloxy)-2-[2-(benzylsulfanyl)-5-chlorophenyl] acetate
• Pd2(dba)3 2.3 g, 2.52 mmol, 0.1 equiv
• XantPhos 2.54 g, 4.38 mmol, 0.2 equiv
• DIEA 9.76 g, 75.5 mmol, 3 equiv
• benzyl mercaptan (3.75 g, 30.2 mmol, 1.2 equiv) at room temperature.
• Step 4 Synthesis afford methyl 2-(benzyloxy)-2-[5-chloro-2-(chlorosulfonyl)phenyl] acetate
• methyl 2-(benzyloxy)-2-[2-(benzylsulfanyl)-5-chlorophenyl] acetate 8.83 g, 21.4 mmol, 1 equiv
• H 2 O 3.47 mL
• AcOH 6 mL
• Step 5 Synthesis of methyl 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) propyl) sulfamoyl) phenyl) acetate
• Step 6 Synthesis of 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl) propyl) sulfamoyl) phenyl) acetic acid [00249] To a stirred solution/mixture of methyl 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl) phenyl)acetate (6.4 g, 10.4 mmol, 1 equiv) and H 2 O (32 mL) in MeOH (32 mL) was added LiOH.H 2 O (2172 mg
• the resulting mixture was stirred for 1h at room temperature.
• the resulting mixture was diluted with water (20 mL).
• the mixture was acidified to pH 6 with HCl (2M).
• the resulting mixture was extracted with EtOAc (3 x 100mL).
• the combined organic layers were washed with brine (1x200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• the crude resulting product was used in the next step directly without further purification.
• Step 7 Synthesis of 2-[1-(benzyloxy)-2-hydroxyethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide [00250] To a stirred solution of 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetic acid (6.2 g, 10.3 mmol, 1 equiv) in THF (62 mL) was added BH3-THF 1M (62 mL, 62 mmol, 6 equiv) dropwise at 0°C
• Step 8 Synthesis of 2-[1-(benzyloxy)-2-chloroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)- 1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzene sulfonamide [00251] To a stirred solution of 2-[1-(benzyloxy)-2-hydroxyethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (1.32 g, 0.053 mmol, 1equiv) and PPh 3 (1173 mg, 4.47 mmol, 2 equiv) in DCE was added CCl 4 (619 mg, 4.03 mmol, 1.8
• Step 9 Synthesis of 5-((1S)-1-(4-(benzyloxy)-6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00252] To a stirred mixture of 2-[1-(benzyloxy)-2-cholroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide (325 mg, 0.53 mmol, 1 equiv) in DMF was added Cs 2 CO 3 (522 mg, 1.60 mmol, 3 equiv) in portions at room temperature.
• Step 10 Synthesis of 5-((1S)-1-(6-chloro-4-hydroxy-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin- 2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00253] To a stirred solution/mixture of 5-((1S)-1-(4-(benzyloxy)-6-chloro-1,1-dioxido-3,4-dihydro-2H- benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (225 mg, 0.39 mmol, 1 equiv) in DCM (1.9 mL) was added boron trichloride (1.57 mL, 1.57
• Step 11 Synthesis of 5-((1S)-1-(6-chloro-1,1-dioxido-4-oxo-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)- 2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00254] To a stirred solution/mixture of 5-((1S)-1-(6-chloro-4-hydroxy-1,1-dioxido-3,4-dihydro-2H- benzo[e][1,2] thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (130 mg, 0.27 mmol, 1 equiv) in DCM was added Dess-Martin (228 mg, 0.54 mmol, 2 equiv) in portions at room temperature
• Example 17 5-((1S)-1-(6-chloro-1,1-dioxido-3-oxo-3,4-dihydro-2H-benzo[e] [1,2] thiazin-2-yl)-2-(6- fluoro-2,3-dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl] acetate
• methyl 2-(2-bromo-5-chlorophenyl) acetate (1 g, 3.80 mmol, 1 equiv)
• dioxane 10 mL, 118 mmol
• benzyl mercaptan (0.57 g, 4.55 mmol, 1.2equiv)
• DIEA (1.47 g, 11.4 mmol, 3equiv).
• Step 2 Synthesis of methyl 2-[5-chloro-2-(chlorosulfonyl) phenyl] acetate [00257] Into a 50 mL 3-necked round-bottom flask were added methyl 2-[2-(benzylsulfanyl)-5- chlorophenyl] acetate (400 mg, 1.30 mmol, 1 equiv) and CH 3 CN (4 mL).
• Step 3 Synthesis of methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl) propyl) sulfamoyl) phenyl) acetate [00258] Into an 8 mL vial were added 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl) propyl]-3H-1,3,4- oxadiazol-2-one hydrochloride (50 mg, 0.17 mmol, 1 equiv) and Pyridine (2 mL, 25 mmol, 152 equiv).
• Step 4 Synthesis of 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl) propyl) sulfamoyl) phenyl) acetic acid [00259] Into a 8mL vial were added methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) propyl) sulfamoyl) phenyl) acetate (20 mg, 0.039mmol, 1 equiv), THF (1 mL), lithium hydrate (4.92 mg, 0.12mmol, 3 equiv), H 2 O (0.3 mL).
• Step 5 Synthesis of 5-((1S)-1-(6-chloro-1,1-dioxido-3-oxo-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)- 2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00260] Into an 8 mL vial were added 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetic acid (40 mg, 0.080mmol, 1 equi
• Example 18 5-((1S,2R)-1-(1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)-2-(6-fluoro-2,3- dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00261] Into a 50 mL round-bottom flask were added 5-((1S)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H- benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (120 mg, 0.26 mmol, 1 equiv) and MeOH (5 mL), EtOAc (5 mL) at room temperature.
• Example 19 5-((1S,2R)-1-(6-chloro-4-hydroxy-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)- 2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00262]
• the crude product from example 16 (step 11) (90 mg) was purified by Chiral-Prep-HPLC.
• Example 20 5-((1S)-1-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)-2-(6- fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of tert-butyl 2-(2-bromo-5-chlorophenyl) propanoate
• tert-butyl 2-(2-bromo-5-chlorophenyl) acetate 4 g, 13 mmol, 1 equiv
• THF 40 mL
• NaHMDS 3.60 g, 19.6 mmol, 1.5 equiv
• the resulting mixture was stirred for additional 45 min at room temperature.
• Step 2 Synthesis of tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl] propanoate
• tert-butyl 2-(2-bromo-5-chlorophenyl) propanoate (2 g, 6.3 mmol, 1 equiv)
• dioxane 7 mL
• DIEA 2426 mg, 18.8 mmol, 3 equiv
• benzyl mercaptan (933 mg, 7.5 mmol, 1.2 equiv
• Pd2(dba)3 (286 mg, 0.31 mmol, 0.05 equiv)
• XantPhos (362 mg, 0.63 mmol, 0.10 equiv) at room temperature.
• Step 3 Synthesis of tert-butyl 2-[5-chloro-2-(chlorosulfonyl)phenyl] propanoate [00265] Into a 100 mL round-bottom flask were added tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl] propanoate (1.3 g, 3.6 mmol, 1 equiv) and ACN (20 mL) at room temperature.
• Step 4 Synthesis of methyl (2S)-2-((2-(1-(tert-butoxy)-1-oxopropan-2-yl)-4-chlorophenyl) sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl) butanoate [00266] Into a 40 mL vial were added methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl) butanoate (500 mg, 2.1 mmol, 1 equiv) and Pyridine (5 mL, 0.44 mmol) at room temperature.
• Step 5 Synthesis of 2-(5-chloro-2-(N-((2S)-3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2- yl) sulfamoyl) phenyl) propanoic acid [00267] Into a 100 mL round-bottom flask were added methyl (2S)-2- ⁇ 2-[1-(tert-butoxy)-1-oxopropan-2- yl]-4-chlorobenzenesulfonamido ⁇ -3-(6-fluoro-2,3-dimethylphenyl) butanoate (500 mg, 0.92 mmol, 1 equiv) and HCl(gas)in 1,4-dioxane (5 mL), DCM (2 mL) at room temperature.
• Step 6 Synthesis of methyl (2S)-2-((4-chloro-2-(1-hydroxypropan-2-yl) phenyl) sulfonamido)-3-(6- fluoro-2,3-dimethylphenyl) butanoate
• BH 3 -THF 1.23 mL, 1.2 mmol, 2 equiv
• 2-(5-chloro-2-(N-((2S)- 3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl) sulfamoyl) phenyl) propanoic acid 300 mg, 0.62 mmol, 1 equiv) in tetrahydrofuran (3mL) at room temperature.
• Step 7 Synthesis of methyl (2S)-2-((4-chloro-2-(1-((methylsulfonyl)oxy) propan-2-yl) phenyl) sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl) butanoate [00269] Into a 50 mL round-bottom flask were added methyl (2S)-2-[4-chloro-2-(1-hydroxypropan-2-yl) benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl) butanoate (120 mg, 0.25 mmol, 1 equiv) and DCM (5 mL), TEA (212 ⁇ L, 1.5 mmol, 6 equiv) at room temperature.
• Step 8 Synthesis of (2S)-2-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)- 3-(6-fluoro-2,3-dimethylphenyl)butanoic acid [00270]
• Into a 50 mL 3-necked round-bottom flask were methyl (2S)-2- ⁇ 4-chloro-2-[1- (methanesulfonyloxy) propan-2-yl] benzenesulfonamido ⁇ -3-(6-fluoro-2,3-dimethylphenyl) butanoate (100 mg, 0.18 mmol, 1 equiv) and tetrahydrofuran (10 mL) at room temperature.
• Step 9 Synthesis of tert-butyl 2-((2S)-2-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[e] [1,2] thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate [00271] Into a 50 mL round-bottom flask were added (2S)-2-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro- 2H-benzo[e][1,2] thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (20 mg, 0.045 mmol, 1 equiv) ,DCM (3 mL) ,tert-butoxycarbohydrazide (7.81 mg, 0.06 mmol, 1.3 equiv
• Step 10 Synthesis of (2S)-2-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)- 3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide [00272]
• Into a 20 mL vial were added tert-butyl 2-((2S)-2-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro-2H- benzo[e][1,2] thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (20 mg, 0.04 mmol, 1 equiv) and DCM (2 mL),2,6-lutidine (77.4 mg, 0.72 mmol, 20 equiv) at room temperature.
• Example 21 5-((1S)-1-(6-chloro-4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)- 2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of methyl 2-(2-bromo-5-chlorophenyl)-2-methylpropanoate [00274] To a solution of methyl 2-(2-bromo-5-chlorophenyl) acetate (5 g, 18.9 mmol, 1 equiv) in DMF was added sodium hydride (60% in oil, 3 g) at 0 degrees C.
• Step 2 Synthesis of methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2-methylpropanoate [00275] In a 50 mL round-bottom flask were added methyl 2-(2-bromo-5-chlorophenyl)-2- methylpropanoate (2.54 g, 8.7 mmol, 1 equiv) and dioxane (25 mL) at room temperature.
• Step 3 Synthesis of methyl 2-[5-chloro-2-(chlorosulfonyl) phenyl]-2-methylpropanoate [00276] To a stirred solution of methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2-methylpropanoate (900 mg, 2.7 mmol, 1 equiv) in CH 3 CN (10 mL) were added AcOH(1.5 mL), H 2 O (1 mL) and 1,3-dichloro-5,5- dimethylimidazolidine-2,4-dione (1060 mg, 5.4 mmol, 2.0 equiv) in portions at 0°C.
• Step 4 Synthesis of methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl) propyl)sulfamoyl)phenyl)-2-methylpropanoate [00277] To a stirred solution of 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4- oxadiazol-2-one hydrochloride (620 mg, 2.06 mmol, 1 equiv) in DCM (5 mL, 78.7 mmol) were added pyridine (500 ⁇ L, 6.2 mmol, 3 equiv) and methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]-2-methylpropanoate (767 mg, 2.47
• Step 5 Synthesis of 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2- yl) propyl]-2-(1-hydroxy-2-methylpropan-2-yl) benzenesulfonamide [00278] To a stirred solution of methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)-2-methylpropanoate (210 mg, 0.39 mmol, 1 equiv) in DCM was added DIBAL-H (780 ⁇ L, 1.2 mmol, 3 equiv) dropwise at 0°C under nitrogen atmosphere.
• Step 6 Synthesis of -(1-bromo-2-methylpropan-2-yl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide [00279] To a stirred solution of 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4- oxadiazol-2-yl)propyl]-2-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide (50 mg, 0.098 mmol, 1 equiv) and PPh3 (51 mg, 0.2 mmol, 2 equiv) in DCM was added CBr4 (49 mg, 0.15 mmol, 1.5 equiv) in portions at room
• Step 7 Synthesis of 5-((1S)-1-(6-chloro-4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin- 2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00280] In a 25 mLpropan-2-yl)-4-chloro-N-[(1S)-2- (6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl]benzenesulfonamide (30 mg, 0.052 mmol, 1 equiv) and DMF (500 ⁇ L) at room temperature.
• Example 22 5-((1S,2R)-1-(6-chloro-4,4-difluoro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2- yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of tert-butyl 2-(2-bromo-5-chlorophenyl)-2,2-difluoroacetate [00281] In a 250-mL round bottom flask, to a solution of tert-butyl 2-(2-bromo-5-chlorophenyl) acetate (10 g, 32.7 mmol, 1 equiv) in THF (100 mL) was added dropwise LiHMDS (1 M in THF, 163 mL,) at -78 degrees C under N 2 atmosphere.
• Step 3 Synthesis of 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2,2-difluoroethanol
• a solution of tert-butyl 2-[2- (benzylsulfanyl)-5-chlorophenyl]-2,2-difluoroacetate 3800 mg, 9.9 mmol, 1 equiv) in THF, followed by the addition of LiAlH 4 (2 mol/L in THF) (10 mL, 20 mmol, 2.0 equiv,) dropwise at room temperature.
• LiAlH 4 (2 mol/L in THF
• Step 4 Synthesis of 2-[2-(benzyloxy)-1,1-difluoroethyl]-1-(benzylsulfanyl)-4-chlorobenzene
• 2-[2-(benzyloxy)-1,1-difluoroethyl]-1-(benzylsulfanyl)-4-chlorobenzene Into a 50 mL round-bottom flask were added a solution of 2-[2-(benzylsulfanyl)-5-chlorophenyl]- 2,2-difluoroethanol (1033 mg, 3.3 mmol, 1 equiv) in THF and was treated with NaH 60% (118mg, 4.9 mmol, 1.5 equiv) for 30 min at 0°C under nitrogen atmosphere followed by the addition of (bromomethyl)benzene (674 mg, 3.94 mmol, 1.2 equiv) dropwise at 0°C.
• Step 5 Synthesis of 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chlorobenzenesulfonyl chloride [00285] Into a 50 mL round-bottom flask were added a solution of 2-[2-(benzyloxy)-1,1-difluoroethyl]-1- (benzylsulfanyl)-4-chlorobenzene (1069 mg, 2.6 mmol, 1 equiv) in MeCN .To the mixture was added H 2 O (590 ⁇ L) and AcOH (855 ⁇ L) at 0°C followed by 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1040 mg, 5.3 mmol, 2.0 equiv) in portions at 0°C.
• Step 6 Synthesis of 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide [00286] To a stirred solution of 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl) propyl]-3H-1,3,4- oxadiazol-2-one hydrochloride (237mg, 0.79 mmol, 1 equiv) and pyridine (3 mL) was added 2-[2- (benzyloxy)-1,1-difluoroethyl]-4-chlorobenzenesulfonyl chloride (300 mg, 0.79 mmol, 1 equiv) in DCM dropwise at 0°C
• Step 7 Synthesis of 4-chloro-2-(1,1-difluoro-2-hydroxyethyl)-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)- 1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide
• 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chloro-N-[(1S)- 2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (587 mg, 0.96 mmol, 1 equiv) in DCM (2 mL) followed by the addition of BBr 3 (2900 ⁇ L, 2.9 mmol, 3.0 equi
• Step 8 Synthesis of 2-(2-bromo-1,1-difluoroethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide
• benzenesulfonamide 232 mg, 0.45 mmol, 1 equiv) in DCE (3 mL) and CBr 4 (222 mg, 0.67 mmol, 1.5 equiv).To the mixture was added
• Step 9 Synthesis of 5-((1S,2R)-1-(6-chloro-4,4-difluoro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00289] To a stirred solution of 2-(2-bromo-1,1-difluoroethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide (185 mg, 0.32 mmol, 1 equiv) in DMF (2 mL, 1.29 mmol) was added Cs 2 CO 3 (207 mg, 0.63 mmol,
• Example 23 5-((1S,2R)-1-(5-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)-2-(6-fluoro- 2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of methyl 2-(2-bromo-6-chlorophenyl) acetate [00291] In a 40 mL round-bottom flask were added (2-bromo-6-chlorophenyl) acetic acid (3 g, 12.
• Step 2 Synthesis of methyl 2-[2-(benzylsulfanyl)-6-chlorophenyl] acetate
• methyl 2-(2-bromo-6-chlorophenyl)acetate 3.2 g, 12.1 mmol, 1 equiv
• benzyl mercaptan 1809 mg, 14.6 mmol, 1.2 equiv
• DIEA 4708 mg, 36 mmol, 3.0 equiv
• Xantphos 1405 mg, 2.4 mmol, 0.2 equiv
• Pd2(dba)3 1112 mg, 1.2 mmol, 0.1 equiv
• dioxane 20 mL
• Step 3 Synthesis of methyl 2-[2-chloro-6-(chlorosulfonyl)phenyl] acetate
• methyl 2-[2-(benzylsulfanyl)-6-chlorophenyl] acetate 1000 mg, 3.26 mmol, 1 equiv
• CH 3 CN 10 mL
• H 2 O 500 ⁇ L
• AcOH 700 ⁇ L
• 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1284 mg, 6.5 mmol, 2 equiv
• Step 4 Synthesis of methyl 2-(2-chloro-6-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl) propyl) sulfamoyl) phenyl) acetate
• Pyridine (2 mL)
• DCM 10 mL
• Step 5 Synthesis of 3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2- yl)propyl]-2-(2-hydroxyethyl)benzenesulfonamide
• Step 6 Synthesis of 2-(2-bromoethyl)-3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H- 1,3,4-oxadiazol-2-yl) propyl]benzenesulfonamide [00295] In a 40 mL vial were added 3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4- oxadiazol-2-yl) propyl]-2-(2-hydroxyethyl) benzenesulfonamide (400 mg, 0.83 mmol, 1 equiv), DCE (10 mL), PPh 3 (433 mg, 1.65 mmol, 2.0 equiv) and CBr4 (411mg, 1.24 mmol, 1.5 equiv).
• Step 7 Synthesis of 5-((1S,2R)-1-(5-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)-2-(6- fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00296] In a 8mL vial were added 2-(2-bromoethyl)-3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] benzenesulfonamide (90 mg, 19.9%)
• Step 7 Synthesis of 5-((1S,2R)-1-(5-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thi
• Example 24 5-((1S,2R)-1-(6-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-e] [1,2]thiazin-2-yl)-2-(6- fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of methyl 2-(3-bromo-6-chloropyridin-2-yl) acetate [00297] A solution of 3-bromo-6-chloro-2-methylpyridine (5 g, 24.2 mmol, 1 equiv) and LiHMDS (36.3 mL, 36.3 mmol, 1.5 equiv) in THF was stirred for 1h at 0 °C under nitrogen atmosphere.
• Step 3 Synthesis of 3-bromo-2- ⁇ 2-[(tert-butyldiphenylsilyl) oxy] ethyl ⁇ -6-chloropyridine
• 2-(3-bromo-6-chloropyridin-2-yl) ethanol (3.36 g, 14.2 mmol, 1 equiv)
• DMF 33 mL
• imidazole (3.87 g, 56.8 mmol, 4 equiv)
• TBDPSCl 5.54 mL, 21.3 mmol, 1.5 equiv
• Step 4 Synthesis of 3-(benzylsulfanyl)-2- ⁇ 2-[(tert-butyldiphenylsilyl) oxy] ethyl ⁇ -6-chloropyridine
• 3-bromo-2- ⁇ 2-[(tert-butyldiphenylsilyl) oxy] ethyl ⁇ -6-chloropyridine 520 mg, 1.1 mmol, 1 equiv)
• dioxane 3 mL
• DIEA 381 ⁇ L, 2.19 mmol, 2 equiv)
• xantphos 63 mg, 0.11 mmol, 0.1 equiv)
• Pd 2 (dba) 3 50 mg, 0.06mmol, 0.05 equiv
• benzyl mercaptan 166 ⁇ L, 1.42 mmol, 1.3 equiv
• Step 5 Synthesis of 2-(2-((tert-butyldiphenylsilyl) oxy) ethyl)-6-chloropyridine-3-sulfonyl chloride
• 3-(benzylsulfanyl)-2- ⁇ 2-[(tert-butyldiphenylsilyl) oxy] ethyl ⁇ -6-chloropyridine 1.5 g, 2.90 mmol, 1 equiv
• AcOH (13.5 mL)
• H 2 O (4.50 mL)
• Step 6 Synthesis of 2-(2-((tert-butyldiphenylsilyl) oxy) ethyl)-6-chloro-N-((1S)-2-(6-fluoro-2,3- dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) propyl)pyridine-3-sulfonamide
• Step 7 Synthesis of 6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2- yl) propyl]-2-(2-hydroxyethyl) pyridine-3-sulfonamide
• 2-(2-((tert-butyldiphenylsilyl) oxy) ethyl)-6-chloro-N- ((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) propyl)pyridine-3- sulfonamide (848 mg, 1.17 mmol, 1 equiv) in THF (17 mL) and TBAF (367 mg, 1.41 mmol, 1.2 equiv) at room
• Step 8 Synthesis of 6-chloro-2-(2-chloroethyl)-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H- 1,3,4-oxadiazol-2-yl) propyl] pyridine-3-sulfonamide
• 6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5- oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(2-hydroxyethyl)pyridine-3-sulfonamide (464 mg, 0.96 mmol, 1 equiv) , DCE (2 mL) , CBr 4 (470mg, 1.44 mmol, 1.5 equiv) and PPh 3 (501 mg, 1.91 mmol, 2 equiv) at
• Step 9 Synthesis of 5-((1S,2R)-1-(6-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-e] [1,2] thiazin-2- yl)-2-(6-fluoro-2,3-dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)-one [00305] In a 10 mL vial were added 2-(2-bromoethyl)-6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1- (5-oxo-4H-1,3,4-oxadiazol-2-yl) propyl] pyridine-3-sulfonamide (136 mg, 0.25 mmol, 1 equiv), Cs 2 CO 3 (360 mg, 1.10 mmol, 2 equiv), DMF (4.1 mL) at room temperature.
• Example 25 5-((1S,2R)-1-(6-chloro-4-hydroxy-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2] thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00306] To a stirred mixture of Example 16 (20 mg, 0.042 mmol, 1 equiv) and Lanthanum (III) chloride bis (lithium chloride) complex solution(81 uL,0.042 mmol, 1 equiv) in THF (0.80 mL) were added iodo(methyl)magnesium (417 ⁇ L, 0.42 mmol, 10 equiv) dropwise at 0°C under nitrogen atmosphere.
• Lanthanum (III) chloride bis (lithium chloride) complex solution (81 uL,0.042 mmol, 1 equi
• Example 26 5-((1S)-1-((4S,5R)-7-chloro-4,5-dihydroxy-1,1-dioxido-4,5-dihydrobenzo[f][1,2] thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00307] Into a 100 mL round-bottom flask were added 5-((1S)-1-(7-chloro-1,1- dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (100 mg, 0.21 mmol, 1 equiv) , Acetone (2 mL , NMO (73.5 mg, 0.63 mmol, 3 equiv)
• Example 27 5-((1S,2R)-1-(6-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-e] [1,2] thiazin-2-yl)-2-(6- fluoro-2,3-dimethylphenyl) propyl)-1,3,4-oxadiazol-2(3H)-one
• Step 1 Synthesis of methyl 2-(5-bromo-2-chloropyridin-4-yl) acetate
• a solution of 3-bromo-6-chloro-2-methylpyridine (5 g, 24.2 mmol, 1 equiv) and LiHMDS (51 mL, 51 mmol, 1.5 equiv) in THF was stirred for 1h at 0 °C under nitrogen atmosphere.
• dimethyl carbonate 4.3 mL, 51 mmol, 1.5 equiv
• the resulting mixture was stirred 1 h at 0 °C.
• the reaction was quenched by the addition of sat.
• Step 2 Synthesis of 5-bromo-4-(2-((tert-butyldiphenylsilyl) oxy) ethyl)-2-chloropyridine
• 2-(5-bromo-2-chloropyridin-4-yl) ethanol (1.91 g, 8.1 mmol, 1 equiv)
• DMF 38 mL
• imidazole 2.20 g, 32.3 mmol, 4 equiv
• TBDPSCl 4.20 mL, 16.2 mmol, 2 equiv
• Step 3 Synthesis of 5-(benzylthio)-4-(2-((tert-butyldiphenylsilyl) oxy) ethyl)-2-chloropyridine
• 5-bromo-4- ⁇ 2-[(tert-butyldiphenylsilyl) oxy] ethyl ⁇ -2-chloropyridine (3.7 g, 7.8 mmol, 1 equiv)
• dioxane 37 mL
• Xantphos 450 mg, 0.8 mmol, 0.1 equiv)
• Pd2(dba)3 356 mg, 0.39 mmol, 0.05 equiv
• benzyl mercaptan 1.1 mL, 9.3 mmol, 1.2 equiv
• Step 4 Synthesis of 4-(2-((tert-butyldiphenylsilyl) oxy) ethyl)-6-chloropyridine-3-sulfonyl chloride [00311] Into a 100 mL round-bottom flask were added 5-(benzylthio)-4-(2-((tert-butyldiphenylsilyl) oxy) ethyl)-2-chloropyridine (1.55 g, 3 mmol, 1 equiv) , AcOH (15 mL) and H 2 O (5 mL) at room temperature.
• Step 5 Synthesis of tert-butyl (2S)-2-((4-(2-((tert-butyldiphenylsilyl) oxy) ethyl)-6-chloropyridine)-3- sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl) butanoate [00312] Into a 8 mL vial were added intermediate III 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl) propyl]-3H-1,3,4-oxadiazol-2-one (500 mg, 1.8 mmol, 1.00 equiv) and Pyridine (719 ⁇ L, 8.9 mmol, 5 equiv) at room temperature.
• Step 6 Synthesis of tert-butyl (2S)-2-[6-chloro-4-(2-hydroxyethyl) pyridine-3-sulfonamido]-3-(6- fluoro-2,3-dimethylphenyl) butanoate [00313] Into a 100 mL round-bottom flask were added tert-butyl (2S)-2-(4- ⁇ 2-[(tert-butyldiphenylsilyl) oxy] ethyl ⁇ -6-chloropyridine-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl) butanoate (530 mg, 0.72 mmol, 1 equiv) , THF (10.
• Step 7 Synthesis of tert-butyl (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-e] [1,2] thiazin- 2-yl)-3-(6-fluoro-2,3-dimethylphenyl) butanoate [00314] Into a 10 mL vial were added in tert-butyl (2S)-2-[6-chloro-4-(2-hydroxyethyl) pyridine-3- sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl) butanoate (20 mg, 0.04 mmol, 1 equiv) , THF (1.6 mL) and PPh 3 (83.8 mg, 0.32 mmol, 2 equiv) at room temperature.
• Step 8 Synthesis of (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-3-(6- fluoro-2,3-dimethylphenyl)butanoic acid [00315]
• Step 9 Synthesis of 5-((1S,2R)-1-(6-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)- 2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one [00316] Into a 10mL vial were added 2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-e] [1,2] thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl) butanoic acid (70 mg, 0.16 mmol, 1 equiv) , CDI (79.8 mg, 0.49 mmol, 3 equiv) and THF (1.4 mL) at room temperature.
• Example A RNR Enzyme Activity
• RF/MS rapid-fire mass spectrometry
• Colo320 DM cells (ATCC # CCL-220, derived from human colorectal adenocarcinoma, Dukes’ type C) were seeded on a 96-well, cell culture treated assay plate at a density of 50,000 cells/well in 200 ⁇ L of RPMI-1640 media supplemented with 10% Fetal Bovine Serum and incubated at 37 degrees Celsius overnight.
• test compound dilutions were added directly to the plated cells by a Tecan digital dispenser to a final DMSO concentration of ⁇ 0.5%. and incubated at 37 degrees Celsius overnight (approximately 16 hours). The following day all cull culture media was removed from the cells.75 ⁇ L of 1x AlphaLisa lysis buffer was added to each well and plates were agitated on a shaker for 30 minutes at room temperature. The lysis of cells and detection of pCHK1 (S345) were performed with regents contained within the AlphaLisa Sure Fire assay kit (Perkin Elmer # ALSU-PCHK1-A) according to the manufacturer’s instructions.
• Example C Pharmaceutical Compositions
• Example C1 Parenteral Composition [00324] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.
• Example C2 Oral Composition
• 100 mg of a compound described herein is mixed with 750 mg of starch.
• the mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.
• Example C3 Sublingual (Hard Lozenge) Composition
• To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge mix 100 mg of a compound described herein, with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.
• the examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

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