WO2020247804A1 - Heterocycle substituted pyridine derivative antifungal agents - Google Patents

Heterocycle substituted pyridine derivative antifungal agents Download PDF

Info

Publication number
WO2020247804A1
WO2020247804A1 PCT/US2020/036400 US2020036400W WO2020247804A1 WO 2020247804 A1 WO2020247804 A1 WO 2020247804A1 US 2020036400 W US2020036400 W US 2020036400W WO 2020247804 A1 WO2020247804 A1 WO 2020247804A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
pyridin
ring
methyl
Prior art date
Application number
PCT/US2020/036400
Other languages
French (fr)
Inventor
Michael Trzoss
Jonathan COVEL
Karen Joy Shaw
Peter Webb
Original Assignee
Amplyx Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amplyx Pharmaceuticals, Inc. filed Critical Amplyx Pharmaceuticals, Inc.
Publication of WO2020247804A1 publication Critical patent/WO2020247804A1/en

Links

Classifications

    • 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
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • compositions are useful for the treatment of cryptococcosis.
  • one of X 1 and X 2 is N while the other is O;
  • X 13 and X 14 are independently N or C(R 1B );
  • X 15 is a bond,–NH–,–O–,–S–, or–SO 2 –;
  • L is a bond or substituted or unsubstituted C 1-6 alkylene
  • W is N or N + – CH 2 OPO 3 H – ;
  • Ring Q is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 2 is independently hydrogen,–NH 2 , or halogen
  • R 29 and R 30 are independently hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • R a is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
  • R b is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R c and R d is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 1A is , R 2 is– NH 2 ,, Ring Q is 2-pyridinyl, L is methylene, R 10A is hydrogen, X 1 is O, X 2 is N, X 13 is CH, X 14 is CH, n is 1, and z1 is 0, then X 15 is a bond,–NH–,–S–, or–SO 2 –.
  • R 1A is , R 2 is 2-amino, Ring Q is 2-pyridinyl, L is methylene, R 10A is hydrogen, X 1 is O, X 2 is N, X 13 is CH, X 14 is CH, n is 1, and z1 is 0, then X 15 is a bond,–NH–,–S–, or–SO 2 –.
  • the compound of Formula (III) is of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: Formula (IIIa).
  • one of X 11 and X 12 is N while the other is O;
  • one of Y 11 and Y 12 is -NH- or -O- while the other is -CH 2 -;
  • one of Y 13 and Y 14 is -S- while the other is -CH 2 -;
  • one of x' y' and z' is -O- while the others are -CH 2 -;
  • Ring A' is heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring B' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring C' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring D' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring E' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring F' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring G' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring H' is bicyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
  • Ring J' is aryl
  • R 22 is hydrogen, -NH 2 , or halogen
  • R 29 and R 30 are independently hydrogen, halogen, C 1 -C 6 alkyl, aryl, heteroaryl, cycloalkyl,
  • R a is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R b is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • each R c and R d is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R c and R d together with the nitrogen atom to which they are attached, form an substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • f is 1; h is 1-3; i is 1-3; j is 1-3; k is 1-3; l is 1-3; m is 1-3; o is 1-3; w is 1-3; and e is 1-3.
  • one of X 11 and X 12 is N while the other is O;
  • one of Y 11 and Y 12 is -NH- or -O- while the other is -CH 2 -;
  • one of Y 13 and Y 14 is -S- while the other is -CH 2 -;
  • one of x' y' and z' is -O- while the others are -CH 2 -;
  • Ring A' is heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring B' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring C' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring D' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring E' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring F' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring G' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring H' is bicyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
  • Ring I' is aryl
  • Ring J' is aryl
  • R 22 is hydrogen, -NH 2 , or halogen
  • each R 29 and R 30 is independently hydrogen, halogen, C 1 -C 6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl;
  • R a is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R b is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R c and R d is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or
  • R c and R d together with the nitrogen atom to which they are attached, form an substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • f is 1; h is 1-3; i is 1-3; j is 1-3; k is 1-3; l is 1-3; m is 1-3; o is 1-3; w is 1-3; z is 1-3; and e is 1-3.
  • the compound of Formula (II) is of Formula (IIa), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: Formula (IIa).
  • the compound of Formula (II) is of Formula (IIb), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: Formula (IIb).
  • the compound of Formula (II) is of Formula (IIc), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
  • FIG.1 shows the efficacy of certain compounds of the present disclosure in a murine model of cryptococcal meningitis when dosed in the presence of the pan-CYP inhibitor 1-aminobenzotriazole (ABT).
  • ABT pan-CYP inhibitor 1-aminobenzotriazole
  • FIG.2 shows a dose response study with (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (Example 172) and (2- amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (Example 173).
  • FIG.3 shows the efficacy of (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (Example 172) and amphotericin B (AMB) in a delayed model of cryptococcal meningitis.
  • AMB amphotericin B
  • Immunocompromised individuals include, for example, elderly individuals, individuals with HIV/AIDS, or individuals undergoing chemotherapy treatment or immunosuppressive therapy after a transplant.
  • Alkyl refers to an substituted or unsubstituted straight-chain, or substituted or unsubstituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • 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,
  • a numerical range such as“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, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a methyl.
  • an alkyl group is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, or–OMe.
  • alkenyl refers to a7 substituted or unsubstituted straight-chain, or substituted or unsubstituted 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, wherein an sp2- hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • 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 substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkenyl is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, or–OMe.
  • Alkynyl refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted 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.
  • a numerical range such as“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 the occurrence of the term“alkynyl” where no numerical range is designated.
  • the 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 substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is substituted or
  • an alkynyl is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, or–OMe.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, an alkylene is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, or–OMe.
  • Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, an alkoxy is substituted or unsubstituted with oxo, halogen, -CN, -CF 3 , -OH, or–OMe.
  • 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.
  • 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 substituted or unsubstituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,
  • an aryl is substituted or unsubstituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an aryl is substituted or unsubstituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • “Cycloalkyl” refers to a stable, 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
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 ,, or -NO 2 . In some embodiments, a cycloalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Halo or“halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated 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.
  • 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.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl.
  • the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring.
  • 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 substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 ,, or -NO 2 .
  • a heterocycloalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • 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, 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.
  • a Heteroalkyl is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, or -OMe.
  • 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.
  • 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. In some embodiments, 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,
  • a heteroaryl is substituted or unsubstituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is substituted or unsubstituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH 2 ,, or -NO 2 .
  • a heteroaryl is substituted or unsubstituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • All the above groups may be either substituted or unsubstituted.
  • substituted as used herein means any of the above groups (e.g., alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl and/or heteroaryl) may be further functionalized wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom substituent.
  • a substituted group may include one or more substituents selected from: oxo, amino, -CO2H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, trialkylammonium (-N + R3), N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups, perfluoroalkyl, or perfluoroalkoxy, for example, trifluoromethyl or trifluoromethoxy.
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a higher-order bond e.g., a double- or triple-bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
  • each of the foregoing substituents may also be substituted or unsubstituted with one or more of the above substituents.
  • any of the above groups may be substituted to include one or more internal oxygen, sulfur, or nitrogen atoms.
  • an alkyl group may be substituted with one or more internal oxygen atoms to form an ether or polyether group.
  • an alkyl group may be substituted with one or more internal sulfur atoms to form a thioether, disulfide, etc.
  • optional substituents are independently selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • “inhibition” refers to a decrease of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100% in biological activity.
  • compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • one of X 1 and X 2 is N while the other is O;
  • X 13 and X 14 are independently N or C(R 1B );
  • X 15 is a bond,–NH–,–O–,–S–, or–SO 2 –;
  • L is a bond or substituted or unsubstituted C 1-6 alkylene
  • W is N or N + –CH 2 OPO 3 H – ;
  • Ring Q is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 2 is independently hydrogen,–NH 2 , or halogen
  • R 29 and R 30 are independently hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • R a is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
  • R b is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R c and R d is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 1A is , R 2 is– NH 2 ,, Ring Q is 2-pyridinyl, L is methylene, R 10A is hydrogen, X 1 is O, X 2 is N, X 13 is CH, X 14 is CH, n is 1, and z1 is 0, and then X 15 is a bond,–NH–,–S–, or–SO 2 –.
  • R 1A i R 2 is 2-amino
  • Ring Q is 2-pyridinyl
  • L is methylene
  • R 10A is hydrogen
  • X 1 is O
  • X 2 is N
  • X 13 is CH
  • X 14 is CH
  • n is 1
  • z1 is 0, then X 15 is a bond,–NH–,–S–, or–SO 2 –.
  • R 2 is 2-amino and R 2 is–NH 2 are synonymous and refer to an amino group (i.e.,–NH 2 group) on the 2-position of the pyridinyl or pyridinium ring of a compound of Formula (III) as shown in Formula (IV):
  • the compound of Formula (III) is of Formula (III '), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: wherein:
  • R 2 , W, X 1 , X 2 , R 1B , X 13 , X 14 , R 1A , z1, z2, z3, and n are as described herein, including embodiments.
  • L A and L B are independently a bond or substituted or unsubstituted C 1-6 alkylene;
  • X A is a bond,–NH–,–O–,–S–, or–SO 2 –.
  • the compound is not (2-amino-3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate or 3-(3-(4-((pyridin- 2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine.
  • W is N. In some embodiments, N + – CH 2 OPO 3 H – .
  • X 1 is -O-; and X 2 is N.
  • R 2 is–NH 2 .
  • R 10A is hydrogen or halogen.
  • z3 is 0. In some embodiments, z3 is 1. In some embodiments, z3 is 2. In some embodiments, z3 is 3.
  • z3 is 1-2.
  • z2 is 0. In some embodiments, z2 is 1. In some embodiments, z2 is 2. In some embodiments, z2 is 3.
  • z1 is 0. In some embodiments, z1 is 1. In some embodiments, z1 is 2.
  • the compound of Formula (III) is of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: Formula (IIIa).
  • R 1A is ; and Ring Q is bicyclic aryl, bicyclic heteroaryl, monocyclic heteroaryl containing at least 2 N atoms in the ring, or oxazolyl.
  • R 1A is ; and Ring Q is bicyclic aryl, bicyclic heteroaryl, monocyclic 5-membered heteroaryl, or cycloalkyl.
  • X 15 is–O–.
  • Ring Q is bicyclic aryl or bicyclic heteroaryl.
  • Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
  • Ring Q is quinolinyl or quinoxalinyl.
  • Ring Q is monocyclic heteroaryl containing at least 2 N atoms in the ring.
  • Ring Q is monocyclic heteroaryl containing at least 2 N atoms in the ring is selected from the group consisting of pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • Ring Q is pyrimidinyl
  • Ring Q is monocyclic 5-membered heteroaryl.
  • Ring Q is monocyclic 5-membered heteroaryl selected from the group consisting of imidazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, and thiadiazolyl.
  • Ring Q is imidazolyl or oxazolyl.
  • Ring Q is cycloalkyl
  • Ring Q is cyclohexyl
  • X 15 is–NH–.
  • Ring Q is heteroaryl or cycloalkyl.
  • Ring Q is heteroaryl selected from the group consisting of azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
  • benzothiazolyl benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
  • Ring Q is pyridinyl, thiadiazolyl, pyrimidinyl, azaindolyl,
  • R 1A is ; and Ring Q is heteroaryl or cycloalkyl.
  • Ring Q is heteroaryl
  • Ring Q is heteroaryl selected from the group consisting of azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
  • benzothiazolyl benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
  • Ring Q is pyridinyl, thiadiazolyl, pyrimidinyl, azaindolyl,
  • Ring Q is cycloalkyl.
  • R 1A is ; and Ring Q is aryl, bicyclic heteroaryl, or cycloalkyl.
  • Ring Q is aryl selected from phenyl and naphthyl.
  • Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
  • Ring Q is C 3 -C 6 cycloalkyl.
  • z3 is 1. In some embodiments, z3 is 2.
  • R 10A is hydrogen,–CF 3 , halogen, or methyl.
  • R 1A is ; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
  • R 1A is ; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
  • R 1A is ; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
  • R 1A is ; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
  • R 1A is ; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
  • R 1A is ; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
  • Ring Q is aryl selected from phenyl and naphthyl. In some embodiments, Ring Q is substituted or unsubstituted phenyl. In some embodiments, Ring Q is substituted or unsubstituted heteroaryl. In some embodiments, Ring Q is substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, Ring Q is substituted or unsubstituted pyridinyl. In some embodiments, Ring Q is substituted or unsubstituted furanyl.
  • Ring Q is heteroaryl containing at least 1 N atom in the ring.
  • Ring Q is selected from
  • R 10A is selected from the group consisting of hydrogen, -CN, halogen, - CH 2 -OH, -CF 3, methyl, ethyl, isobutyl, and butyl.
  • R 10A is -F, isobutyl, or -CH 2 -OH.
  • R 10A is–F. and Ring Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
  • R 1A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl. In some embodiments, R 1A is substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered heteroaryl, or substituted or unsubstituted 6-membered heteroaryl. In some embodiments, R 1A is heteroaryl selected from pyridinyl and furanyl.
  • Ring Q is heteroaryl selected from the group consisting of azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
  • benzothiazolyl benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
  • Ring Q is heteroaryl selected from furyl and benzofuranyl.
  • Ring Q is cycloalkyl selected from C 3 -C 6 cycloalkyl.
  • Ring Q is heterocycloalkyl wherein the heterocycloalkyl contains at least one O atom.
  • Ring Q is heterocycloalkyl that contains at least one O atom selected from the group consisting of
  • R 10A is hydrogen, methyl, -CF 3 , or halogen.
  • R 1A is–CClR 5 R 6 ; and R 5 and R 6 are is independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • R 5 and R 6 are hydrogen.
  • R 29 and R 30 are hydrogen.
  • R 29 is hydrogen and R 30 is cyclohexyl.
  • L is–CH 2 –; and Ring Q is bicyclic aryl, bicyclic heteroaryl, monocyclic heteroaryl containing at least 2 N atoms in the ring, or oxazolyl.
  • X 15 is a bond; L is–CH 2 –; and Ring Q is aryl, heteroaryl containing at least 1 N atom in the ring, or cycloalkyl.
  • X 15 is a bond
  • L is–(CH 2 ) 2 –
  • Ring Q is aryl, bicyclic heteroaryl, or cycloalkyl.
  • X 15 is a bond; L is–CH(OH)–; and Ring Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
  • X 15 is a bond; L is–NH–; and Ring Q is heteroaryl or cycloalkyl.
  • X 15 is–NH–; L is–CH 2 –; and Ring Q is heteroaryl or cycloalkyl.
  • X 15 is–O– or–S–; L is–CH 2 –; and Ring Q is bicyclic aryl, bicyclic heteroaryl, monocyclic 5-membered heteroaryl, or cycloalkyl.
  • X 13 is CH. In some embodiments, X 13 is N. In some embodiments, X 14 is CH. In some embodiments, X 14 is N.
  • X 13 and X 14 are CH. In some embodiments, X 13 is CH; and X 14 is N.
  • X 14 is N or CH; X 15 is a bond,–NH– or–O–; L is a bond or unsubstituted C 1-2 alkylene; Ring Q is cycloalkyl, aryl, or heteroaryl; R 10A is hydrogen or halogen; and z3 is 1-2.
  • X 14 is N.
  • X 14 is CH.
  • X 15 is a bond; and L is–CH 2 –.
  • X 15 is a bond; and L is–(CH 2 ) 2 –.
  • X 15 is–O– or–NH–; and L is a bond.
  • X 15 –L– is– #– X 15 –L–* or #– X 15 –L–*, wherein # is the attachment point to Ring Q and * is the attachment point to the rest of the molecule.
  • X 15 –L is–CH 2 –O– or–CH 2 –NH–. In some embodiments, X 15 –L is #– CH 2 –O–* or #–CH 2 –NH–*, wherein # is the attachment point to Ring Q and * is the attachment point to the rest of the molecule. In other embodiments, X 15 –L is *–CH 2 –O–# or *–CH 2 –NH–#, wherein # is the attachment point to Ring Q and * is the attachment point to the rest of the molecule.
  • X 15 –L is–(CH 2 )2–O– or–(CH 2 )2–NH—.
  • one of X 1 and X 2 is N while the other is O;
  • Y 1 is -O- or -S-;
  • one of Y 2 and Y 3 is -NH- while the other is -CH 2 -;
  • Ring A is bicyclic aryl, bicyclic heteroaryl, monocyclic heteroaryl containing at least 2 N atoms in the ring, or oxazolyl;
  • Ring B is bicyclic aryl, bicyclic heteroaryl, monocyclic 5-membered heteroaryl, or cycloalkyl;
  • Ring C is heteroaryl or cycloalkyl
  • Ring D is aryl, heteroaryl containing at least 1 N atom in the ring, or cycloalkyl;
  • Ring E is aryl, bicyclic heteroaryl, or cycloalkyl
  • Ring F is aryl, heteroaryl, cycloalkyl, heterocycloalkyl;
  • each R 2 is independently hydrogen, -NH 2 ,, or halogen
  • each R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, or C 1 -C 6 alkyl;
  • each R 29 and R 30 is independently hydrogen, halogen, C 1 -C 6 alkyl, aryl, heteroaryl, cycloalkyl,
  • R a is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R b is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each R c and R d is independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • X 1 is O and X 2 is N. In some embodiments, X 1 is N and X 2 is O. In some embodiments, R 2 is -NH 2 . In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -F, -Cl, or -Br.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • the compound of Formula (I) is of Formula (Ia), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
  • R 1 is . In some embodiments, R 1 is . In some embodiments, R 3 is hydrogen and R 4 is hydrogen. In some embodiments, R 3 is hydrogen and R 4 is halogen. In some embodiments, R 3 is halogen and R 4 is hydrogen. In some embodiments, R 3 is C 1 -C 6 alkyl and R 4 is hydrogen. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is hexyl.
  • R 3 is hydrogen and R 4 is C 1 -C 6 alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is pentyl. In some embodiments, R 4 is hexyl.
  • R 1 is .
  • R 5 is hydrogen and R 6 is hydrogen.
  • R 5 is C 1 -C 6 alkyl and R 6 is hydrogen.
  • R 5 is C 1 -C 6 alkyl and R 6 is C 1 -C 6 alkyl.
  • R 5 is hydrogen and R 6 is C 1 -C 6 alkyl.
  • R 5 is methyl.
  • R 5 is ethyl.
  • R 5 is propyl.
  • R 5 is butyl.
  • R 5 is pentyl.
  • R 5 is hexyl.
  • R 6 is methyl.
  • R 6 is ethyl.
  • R 6 is propyl.
  • R 6 is butyl.
  • R 6 is pentyl.
  • R 6 is hexyl.
  • R 1 is .
  • R 29 is hydrogen and R 30 is hydrogen.
  • R 29 is C 1 -C 6 alkyl and R 30 is hydrogen.
  • R 29 is C 1 -C 6 alkyl and R 30 is C 1 -C 6 alkyl.
  • R 29 is hydrogen and R 30 is C 1 -C 6 alkyl.
  • R 29 is hydrogen and R 30 is cycloalkyl.
  • R 29 is hydrogen and R 30 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 30 is hydrogen and R 29 is cycloalkyl.
  • R 30 is hydrogen and R 29 is hydrogen and R 29 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 1 is–(CH 2 ) 2 S(CH 2 ) 2 OC(O)H .
  • R 1 is In some embodiments of a compound of Formula (I) or (Ia), R 1 is In some embodiments, Y 1 is -O-. In some embodiments, Y 1 is -S-.
  • Ring A is bicyclic aryl. In some embodiments, Ring A is naphthyl.
  • Ring A is bicyclic heteroaryl.
  • Ring A is bicyclic heteroaryl selected from indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
  • Ring A is quinolinyl.
  • Ring A is quinoxalinyl.
  • Ring A is monocyclic heteroaryl containing at least 2 N atoms in the ring. In some embodiments, Ring A is pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. In some embodiments, Ring A is pyrimidinyl. [0136] In some embodiments of a compound of Formula (I) or (Ia), Ring A is oxazolyl.
  • p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, R 7 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 7 is hydrogen, -CF 3 , or methyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is -CF 3 . In some embodiments, R 7 is methyl. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -F. In some embodiments, R 7 is -Cl. In some embodiments, R 7 is -Br.
  • R 1 is .
  • Y 1 is -O-
  • Y 1 is -S- .
  • Ring B is bicyclic aryl. In some embodiments, Ring B is naphthyl.
  • Ring B is bicyclic heteroaryl.
  • Ring B is bicyclic heteroaryl selected from indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
  • Ring B is bicyclic heteroaryl selected from indolyl, indazolyl, benzimidazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, and pteridinyl. In some embodiments, Ring B is quinolinyl. In some embodiments, Ring B is quinoxalinyl.
  • Ring B is monocyclic heteroaryl containing at least 2 N atoms in the ring. In some embodiments, Ring B is monocyclic heteroaryl containing at least 2 N atoms in the ring selected from pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. In some embodiments, Ring B is pyrimidinyl.
  • Ring B is oxazolyl
  • Ring B is cycloalkyl. In some embodiments, Ring B is cyclopropyl, cyclobutyl, cycolopentyl, or cyclohexyl. In some embodiments, Ring B is cyclohexyl. In some embodiments, Ring B is cyclopropyl. In some embodiments, Ring B is cyclobutyl. In some embodiments, Ring B is cyclopentyl.
  • q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, R 8 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 8 is hydrogen, methyl, -CF 3 , or halogen. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl. In some embodiments, R 8 is -CF 3 . In some embodiments, R 8 is halogen. In some embodiments, R 8 is -Cl. In some embodiments, R 8 is -F.
  • R 1 is In some embodiments, Y 2 is -CH 2 - and Y 3 is -NH-. In some embodiments, Y 2 is -NH- and Y 3 is -CH 2 -.
  • Ring C is heteroaryl.
  • Ring C is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazany
  • Ring C is pyridinyl, thiadiazolyl, pyrimidinyl, azaindolyl, or thiazolyl. In some embodiments, Ring C is pyridinyl. In some embodiments, Ring C is thiadiazolyl. In some embodiments, Ring C is pyrimidinyl. In some embodiments, Ring C is azaindolyl. In some embodiments, Ring C is thiazolyl.
  • Ring C is cycloalkyl. In some embodiments, Ring C is cyclopropyl, cyclobutyl, cycolopentyl, or cyclohexyl. In some embodiments, Ring C is cyclohexyl. In some embodiments, Ring C is cyclopropyl. In some embodiments, Ring C is cyclobutyl. In some embodiments, Ring C is cyclopentyl.
  • s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, R 9 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 9 is hydrogen, methyl, -CF 3 , or halogen. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is methyl. In some embodiments, R 9 is -CF 3. In some embodiments, R 9 is halogen. In some embodiments, R 9 is -Cl. In some embodiments, R 9 is -F.
  • R 1 is .
  • Ring D is aryl. In some embodiments, Ring D is phenyl. In some embodiments, Ring D is naphthyl.
  • Ring D is heteroaryl containing at least 1 N atom in the ring.
  • Ring D is heteroaryl containing at least 1 N atom in the ring including but not limited to azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,
  • Ring D is selected from, , , , [0152] In some embodiments of a compound of Formula (I) or (Ia), Ring D is . In
  • Ring D is . In some embodiments, Ring D is
  • Ring D is . In some embodiments, Ring .
  • Ring D is cycloalkyl.
  • Ring D is cyclopropyl, cyclobutyl, cycolopentyl, or cyclohexyl.
  • Ring D is cyclohexyl.
  • Ring D is cyclopropyl.
  • Ring D is cyclobutyl.
  • Ring D is cyclopentyl.
  • Ring D is partially saturated.
  • Ring D is .
  • t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, R 10 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 10 is hydrogen, -CN, halogen, -CF 3, methyl, ethyl, and butyl. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -CN. In some embodiments, R 10 is -F. In some embodiments, R 10 is -CF 3. In some embodiments, R 10 is methyl. In some embodiments, R 10 is ethyl. In some embodiments, R 10 is propyl. In some embodiments, R 10 is butyl. In some embodiments, R 10 is pentyl. In some embodiments, R 10 is hexyl. In some embodiments, R 10 is heptyl. In some embodiments, R 10 is octyl.
  • R 10 is nonyl. In some embodiments, R 10 is decyl. In some embodiments, R 10 is isobutyl. In some embodiments, R 10 is isopentyl. [0155] In some embodiments of a compound of Formula (I) or (Ia), R 1 is
  • Ring E is aryl.
  • Ring E is phenyl. In some embodiments, Ring E is naphthyl.
  • Ring E is bicyclic heteroaryl.
  • Ring E is bicyclic heteroaryl selected from indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
  • Ring E is indolyl, indazolyl, benzimidazolyl, quinazolinyl, or quinolinyl. In some embodiments, Ring E is indolyl. In some embodiments, Ring E is indazolyl. In some embodiments, Ring E is benzimidazolyl. In some embodiments, Ring E is quinazolinyl. In some embodiments, Ring E is quinolinyl.
  • Ring E is cycloalkyl. In some embodiments, Ring E is cyclopropyl, cyclobutyl, cycolopentyl, or cyclohexyl. In some embodiments, Ring E is cyclohexyl. In some embodiments, Ring E is cyclopropyl. In some embodiments, Ring E is cyclobutyl. In some embodiments, Ring E is cyclopentyl.
  • u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, R 11 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 11 is hydrogen or -CF 3. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -CF 3 . In some embodiments, R 11 is halogen. In some embodiments, R 11 is -F. In some embodiments, R 11 is -Cl. In some embodiments, R 11 is -Br.
  • R 1 is .
  • Ring F is aryl.
  • Ring F is phenyl. In some embodiments, Ring F is naphthyl.
  • Ring F is heteroaryl
  • Ring F is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzo
  • Ring F is imidazolyl, triazolyl, pyrazinyl furyl, quinolinyl, benzofuranyl, quinazolinyl, or pyridazinyl. In some embodiments, Ring F is furyl. In some embodiments, Ring F is benzofuranyl.
  • Ring F is cycloalkyl. In some embodiments, Ring F is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Ring F is cyclohexyl. In some embodiments, Ring F is cyclopropyl. In some embodiments, Ring F is cyclobutyl. In some embodiments, Ring F is cyclopentyl.
  • Ring F is heterocycloalkyl.
  • Ring F is a 5-membered heterocycloalkyl.
  • Ring F is a 6-membered heterocycloalkyl.
  • Ring F is heterocycloalkyl that contains at least one O atom.
  • Ring F is heterocycloalkyl that contains at least one O atom selected from
  • Ring F is In some embodiments, Ring F is . In some embodiments, Ring F is In some embodiments, Ring F is . In some embodiments, Ring F is . In some embodiments, Ring F is
  • Ring F is . In some embodiments, Ring F i s . In some
  • Ring F is . In some embodiments, Ring F is In some
  • Ring F is In some embodiments, Ring F is . In some embodiments, Ring F is .
  • v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, R 12 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 12 is hydrogen, -CF 3 , methyl, or halogen. In some embodiments, R 12 is hydrogen or -CF 3 . In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is -CF 3 . In some embodiments, R 12 is methyl. In some embodiments, R 12 is halogen. In some embodiments, R 12 is -F.
  • one of X11 and X12 is N while the other is O;
  • one of Y 11 and Y 12 is -NH- or -O- while the other is -CH 2 -;
  • one of Y 13 and Y 14 is -S- while the other is -CH 2 -;
  • one of x' y' and z' is -O- while the others are -CH 2 -;
  • Ring A' is heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring B' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring C' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring D' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring E' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring F' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring G' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring H' is bicyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
  • Ring J' is aryl
  • R 22 is hydrogen, -NH 2 , or halogen; each R 29 and R 30 is independently hydrogen, halogen, C 1 -C 6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl;
  • R a is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R b is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • each R c and R d is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R c and R d together with the nitrogen atom to which they are attached, form an substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • f is 1; h is 1-3; i is 1-3; j is 1-3; k is 1-3; l is 1-3; m is 1-3; o is 1-3; w is 1-3; and e is 1-3.
  • R 21 is halogen, , , , , ,
  • one of X11 and X12 is N while the other is O;
  • one of Y 11 and Y 12 is -NH- or -O- while the other is -CH 2 -;
  • one of Y 13 and Y 14 is -S- while the other is -CH 2 -;
  • one of x' y' and z' is -O- while the others are -CH 2 -;
  • Ring A' is heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring B' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring C' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring D' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring E' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring F' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring G' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Ring H' is bicyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
  • Ring I' is aryl
  • Ring J' is aryl
  • R 22 is hydrogen, -NH 2 , or halogen
  • R 29 and R 30 are independently hydrogen, halogen, C 1 -C 6 alkyl, aryl, heteroaryl, cycloalkyl,
  • R a is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R b is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstit
  • each R c and R d is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R c and R d together with the nitrogen atom to which they are attached, form an substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • f is 1; h is 1-3; i is 1-3; j is 1-3; k is 1-3; l is 1-3; m is 1-3; o is 1-3; w is 1-3; z is 1-3; and e is 1-3.
  • X 11 is O and X 12 is N.
  • X 11 is N and X 12 is O.
  • R 22 is -NH 2 .
  • R 22 is hydrogen.
  • R 22 is a halogen.
  • R 22 is -F, - Cl, or -Br.
  • f is 1.
  • the compound of Formula (II) is of Formula (IIa) , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: Formula (IIa).
  • the compound of Formula (II) is of Formula (IIb) , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: Formula (IIb).
  • the compound of Formula (II) is of Formula (IIc) , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: Formula (IIc).
  • R 21 is .
  • Y 11 is -O- and Y 12 is -CH 2 - .
  • Y 11 is -NH- and Y 12 is -CH 2 - .
  • Y 12 is -O- and Y 11 is -CH 2 - .
  • Y 12 is -NH- and Y 11 is -CH 2 - .
  • Ring I' is aryl. In some embodiments, Ring I' is phenyl. In some embodiments, Ring I' is naphthyl.
  • z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, R 33 is hydrogen, methyl, or–F. In some embodiments, R 33 is hydrogen. In some embodiments, R 33 is methyl. In some
  • R 33 is a halogen. In some embodiments, R 33 is -Cl. In some embodiments, R 33 is -F. In some embodiments, R 33 is -Br.
  • R 21 is -F. In some embodiments, R 21 is -Cl. In some embodiments, R 21 is -Br.
  • R 21 is
  • Y 11 is -O- and Y 12 is -CH 2 -. In some embodiments, Y 11 is -NH- and Y 12 is -CH 2 -. In some embodiments, Y 12 is -O- and Y 11 is -CH 2 -. In some embodiments, Y 12 is -NH- and Y 11 is -CH 2 -.
  • Ring A' is heteroaryl.
  • Ring A' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridin
  • Ring A' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl.
  • Ring A' is pyridinyl.
  • Ring A' is isoxazolyl.
  • Ring A' is thienyl.
  • Ring A' is thiazolyl.
  • Ring A' is pyrazolyl.
  • Ring A' is pyrimidinyl.
  • Ring A' is furyl.
  • Ring A' is oxazolyl.
  • Ring A' is cycloalkyl.
  • Ring A' is C 3 -C 6 cycloalkyl.
  • Ring A' is cyclopropyl or cyclobutyl.
  • Ring A' is cyclohexyl.
  • Ring A' is cyclopropyl.
  • Ring A' is cyclobutyl.
  • Ring A' is cyclopentyl.
  • Ring A' is heterocycloalkyl.
  • Ring A' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thia
  • Ring A' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring A' is oxetanyl.
  • h is 1. In some embodiments, h is 2. In some embodiments, h is 3.
  • R 23 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 23 is hydrogen, methyl, or–F.
  • R 23 is hydrogen.
  • R 23 is methyl.
  • R 23 is a halogen.
  • R 23 is -Cl.
  • R 23 is -F.
  • R 23 is -Br.
  • R 21 is
  • Ring B' is aryl. In some embodiments, Ring B' is phenyl. In some embodiments, Ring B' is naphthyl.
  • Ring B' is heteroaryl.
  • Ring B' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteri
  • Ring B' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl.
  • Ring B' is pyridinyl.
  • Ring B' is isoxazolyl.
  • Ring B' is thienyl.
  • Ring B' is thiazolyl.
  • Ring B' is pyrazolyl.
  • Ring B' is pyrimidinyl.
  • Ring B' is furyl.
  • Ring B' is cycloalkyl.
  • Ring B' is C 3 -C 6 cycloalkyl.
  • Ring B' is cyclopropyl.
  • Ring B' is cyclobutyl.
  • Ring B' is cyclopentyl.
  • Ring B' is cyclohexyl.
  • Ring B' is heterocycloalkyl.
  • Ring B' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiaze
  • Ring B' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring B' is oxetanyl.
  • i is 1. In some embodiments, i is 2. In some embodiments, i is 3.
  • R 24 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 24 is hydrogen, methyl, or–F.
  • R 24 is hydrogen.
  • R 24 is methyl.
  • R 24 is a halogen.
  • R 24 is -Cl.
  • R 24 is -F.
  • R 24 is -Br.
  • R 21 is
  • Ring C' is aryl. In some embodiments, Ring C' is phenyl. In some embodiments, Ring C' is naphthyl. [0193] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring C' is heteroaryl.
  • Ring C' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzox
  • Ring C' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl.
  • Ring C' is pyridinyl.
  • Ring C' is isoxazolyl.
  • Ring C' is thienyl.
  • Ring C' is thiazolyl.
  • Ring C' is pyrazolyl.
  • Ring C' is pyrimidinyl.
  • Ring C' is furyl.
  • Ring C' is cycloalkyl.
  • Ring C' is C 3 -C 6 cycloalkyl.
  • Ring C' is cyclopropyl.
  • Ring C' is cyclobutyl.
  • Ring C' is cyclopentyl.
  • Ring C' is cyclohexyl.
  • Ring C' is heterocycloalkyl.
  • Ring C' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiaze
  • Ring C' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring C' is oxetanyl.
  • j is 1. In some embodiments, j is 2. In some embodiments, j is 3.
  • R 25 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 25 is hydrogen, methyl, or -F.
  • R 25 is hydrogen.
  • R 25 is methyl.
  • R 25 is a halogen.
  • R 25 is -Cl.
  • R 25 is -F.
  • R 25 is -Br.
  • k is 1. In some embodiments, k is 2. In some embodiments, k is 3.
  • R 26 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 26 is hydrogen, methyl, or -F.
  • R 26 is hydrogen.
  • R 26 is methyl.
  • R 26 is a halogen.
  • R 26 is -Cl.
  • R 26 is -F.
  • R 26 is -Br.
  • R 21 is
  • x' is O; y' is -CH 2 -; and z' is -CH 2 - . In some embodiments, x' is -CH 2 -; y' is -O-; and z' is -CH 2 - . In some embodiments, x' is -CH 2 -; y' is -CH 2 -; and z' is -O- .
  • Ring E' is aryl. In some embodiments, Ring E' is phenyl. In some embodiments, Ring E' is naphthyl.
  • Ring E' is heteroaryl.
  • Ring E' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridin
  • Ring E' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl.
  • Ring E' is pyridinyl.
  • Ring E' is isoxazolyl.
  • Ring E' is thienyl.
  • Ring E' is thiazolyl.
  • Ring E' is pyrazolyl.
  • Ring E' is pyrimidinyl.
  • Ring E' is furyl.
  • Ring E' is cycloalkyl.
  • Ring E' is C 3 -C 6 cycloalkyl.
  • Ring E' is cyclopropyl.
  • Ring E' is cyclobutyl.
  • Ring E' is cyclopentyl.
  • Ring E' is cyclohexyl.
  • Ring E' is heterocycloalkyl.
  • Ring E' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiaze
  • Ring E' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring E' is oxetanyl.
  • l is 1. In some embodiments, l is 2. In some embodiments, l is 3.
  • R 27 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 27 is hydrogen, methyl, or -F.
  • R 27 is hydrogen.
  • R 27 is methyl.
  • R 27 is a halogen.
  • R 27 is -Cl.
  • R 27 is -F.
  • R 27 is -Br.
  • R 21 is
  • Ring F' is aryl. In some embodiments, phenyl. In some embodiments, Ring F' is naphthyl.
  • Ring F' is heteroaryl.
  • Ring F' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridin
  • Ring F' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl.
  • Ring F' is pyridinyl.
  • Ring F' is isoxazolyl.
  • Ring F' is thienyl.
  • Ring F' is thiazolyl.
  • Ring F' is pyrazolyl.
  • Ring F' is pyrimidinyl.
  • Ring F' is furyl.
  • Ring F' is cycloalkyl.
  • Ring F' is C 3 -C 6 cycloalkyl.
  • Ring F' is cyclopropyl.
  • Ring F' is cyclobutyl.
  • Ring F' is cyclopentyl.
  • Ring F' is cyclohexyl.
  • Ring F' is heterocycloalkyl.
  • Ring F' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thia
  • Ring F' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring F' is oxetanyl.
  • m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • R 28 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 28 is hydrogen, methyl, or -F.
  • R 28 is hydrogen.
  • R 28 is methyl.
  • R 28 is a halogen.
  • R 28 is -Cl.
  • R 28 is -F.
  • R 28 is -Br.
  • R 21 is
  • Ring G' is aryl. In some embodiments, Ring G' is phenyl. In some embodiments, Ring G' is naphthyl.
  • Ring G' is heteroaryl.
  • Ring G' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteri
  • Ring G' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl.
  • Ring G' is pyridinyl.
  • Ring G' is isoxazolyl.
  • Ring G' is thienyl.
  • Ring G' is thiazolyl.
  • Ring G' is pyrazolyl.
  • Ring G' is pyrimidinyl.
  • Ring G' is furyl.
  • Ring G' is cycloalkyl. In some embodiments, Ring G' is C 3 -C 6 cycloalkyl. In some embodiments, Ring G' is cyclopropyl. In some embodiments, Ring G' is cyclobutyl. In some embodiments, Ring G' is cyclopentyl. In some embodiments, Ring G' is cyclohexyl.
  • Ring G' is heterocycloalkyl.
  • Ring G' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thia
  • Ring G' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring G' is oxetanyl.
  • o is 1. In some embodiments, o is 2. In some embodiments, o is 3.
  • R 31 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 31 is hydrogen, methyl, or -F.
  • R 31 is hydrogen.
  • R 31 is methyl.
  • R 31 is a halogen.
  • R 31 is -Cl.
  • R 31 is -F.
  • R 31 is -Br.
  • R 21 is
  • Ring H' is bicyclic aryl. In some embodiments, Ring H' is naphthyl.
  • Ring H' is heteroaryl.
  • Ring H' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteri
  • Ring H' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl.
  • Ring H' is pyridinyl.
  • Ring H' is isoxazolyl.
  • Ring H' is thienyl.
  • Ring H' is thiazolyl.
  • Ring H' is pyrazolyl.
  • Ring H' is pyrimidinyl.
  • Ring H' is furyl.
  • Ring H' is cycloalkyl. In some embodiments, Ring H' is C 3 -C 6 cycloalkyl. In some embodiments, Ring H' is cyclopropyl. In some embodiments, Ring H' is cyclobutyl. In some embodiments, Ring H' is cyclopentyl. In some embodiments, Ring H' is cyclohexyl.
  • Ring H' is heterocycloalkyl.
  • Ring H' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thia
  • Ring H' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring H' is oxetanyl.
  • w is 1. In some embodiments, w is 2. In some embodiments, w is 3.
  • R 32 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 32 is hydrogen, methyl, or -F.
  • R 32 is hydrogen.
  • R 32 is methyl.
  • R 32 is a halogen.
  • R 32 is -Cl.
  • R 32 is -F.
  • R 32 is -Br.
  • R 21 is .
  • R 29 is hydrogen and R 30 is hydrogen.
  • R 29 is hydrogen and R 30 is hydrogen.
  • R 29 is C 1 -C 6 alkyl and R 30 is hydrogen.
  • R 29 is C 1 -C 6 alkyl and R 30 is C 1 -C 6 alkyl.
  • R 29 is hydrogen and R 30 is C 1 -C 6 alkyl.
  • R 29 is hydrogen and R 30 is cycloalkyl.
  • R 29 is hydrogen and R 30 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 30 is hydrogen and R 29 is cycloalkyl. In some embodiments, R 30 is hydrogen and R 29 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 21 is a compound of Formula (II), (IIa), (IIb), (IIc), (II’) or (II”), R 21 is
  • Ring J' is aryl. In some embodiments, Ring J' is phenyl. In some embodiments, Ring J' is naphthyl.
  • e is 1. In some embodiments, e is 2. In some embodiments, e is 3. In some embodiments, R 34 is hydrogen, methyl, or–F. In some embodiments, R 34 is hydrogen. In some embodiments, R 34 is methyl. In some embodiments, R 33 is a halogen. In some embodiments, R 34 is -Cl. In some embodiments, R 34 is -F. In some embodiments, R 34 is -Br.
  • X 15 is–O–,–NH–,–S–,–SO 2 –, or a bond
  • L is a bond or substituted or unsubstituted C 1-6 alkylene
  • Ring Q is monocyclic 6-membered heteroaryl, monocyclic 5-membered heteroaryl, bicyclic heteroaryl, phenyl, naphthyl, monocyclic cycloalkyl, bicyclic cycloalkyl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl;
  • X 13 is C(R 1B ) or N;
  • X 14 is C(R 1B ) or N;
  • R a is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6
  • R b is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl,
  • substituted or unsubstituted C 2 -C 6 alkynyl substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R c and R d is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
  • z3 is 1, 2, or 3
  • a pharmaceutically acceptable salt of a compound of Formula (III-C), or a solvate, hydrate, or a deuterated variant thereof is prepared by reacting a compound of Formula (III-C) with ammonia, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, sodium hydroxide, sodium hydroxide followed by calcium acetate, calcium hydroxide, potassium hydroxide, or phosphoric acid.
  • ammonia hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, sodium hydroxide, sodium hydroxide followed by calcium acetate, calcium hydroxide, potassium hydroxide, or phosphoric acid.
  • Other pharmaceutically acceptable salts of a compound of Formula (III-C), or a solvate, hydrate, or a deuterated variant thereof are described herein.
  • X 13 is CH, CF or N; and X 14 is CH, CF or N.
  • the compound of Formula (III-C) has the following structure:
  • the compound of Formula (III-C) has the following structure:
  • the compound of Formula (III-C) has the following structure:
  • R 1B is hydrogen of F; and X 14 is CH, CF, or N.
  • R 1A i s ; X 15 is–O–,–NH–,–S–,–SO 2 –, or a bond; and L is a bond, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, - CH(CH 3 )CH 2 -, -C(CH 3 )2CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • R 1A is ; and X 15 is–O–,–NH–,–S–,–SO 2 –, or a bond; and L is a bond, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, - CH(CH 3 )CH 2 -, -C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • X 15 is–O–,–NH–, or a bond; and L is a bond, -CH 2 -, or -CH 2 CH 2 -.
  • X 15 is–O–,–NH–, or a bond; and L is a bond or -CH 2 -.
  • X 15 is–O–.
  • X 15 is–NH-.
  • X 15 is a bond.
  • Ring Q is monocyclic 6-membered heteroaryl, monocyclic 5-membered heteroaryl, bicyclic heteroaryl, phenyl, naphthyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered
  • Ring Q is monocyclic 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; or Ring Q is monocyclic 5- membered heteroaryl selected from the group consisting of imidazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, and thiadiazolyl; or Ring Q is phenyl or naphthyl; or Ring Q is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or Ring Q is aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, imidazolinyl, imidazolidinyl,
  • Ring Q is pyridinyl
  • Ring Q is phenyl
  • Ring Q is monocyclic 5-membered heteroaryl selected from the group consisting of imidazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, and thiadiazolyl.
  • Ring Q is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Ring Q is azetidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydropyranyl, and thiomorpholinyl.
  • Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
  • R 10A is selected from the group consisting of hydrogen, F, Cl, Br, -CF 3 , - CN, -CH 2 -OH, -OH, -OCH 3 , -OCH 2 CH 3 -OCH(CH 3 ) 2 , -OC(CH 3 )3, -OCF 3 , methyl, ethyl, isopropyl, isobutyl, and butyl; z3 is 1 or 2.
  • the compound of Formula (III) is not (2-amino-3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate or a compound having structural formula:
  • the compound of Formula (III) is not 3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine or a compound having structural formula:
  • the compounds described herein exist as geometric isomers.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration.
  • 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.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by
  • 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 of Formula (I), (II), or (III), or a solvate, 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 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • 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, 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.
  • “Prodrug” is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein.
  • the term“prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam).
  • Prodrugs are delivered through any known methods described herein, including but not limited to orally, intravenously, intraperitoneal, or other method of administration known by those skilled in the art.
  • prodrugs are provided in Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs include any group bound to a heteroatom, such as the nitrogen of a pyridine which is cleaved in-vivo to form the active compound or metabolite thereof.
  • examples of prodrugs include, but are not limited to, acetate, formate phosphate, and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
  • a prodrug of a pyridine compound described herein is a phosphate prodrug.
  • a prodrug of a pyridine compound described herein is an alkyl phosphate prodrug.
  • an alkyl phosphate prodrug of a pyridine compound described herein is formed with the nitrogen atom of the pyridine ring.
  • described herein are methyl hydrogen phosphate prodrugs of pyridine antifungal compounds.
  • described herein are pyridin-1-ium-1-ylmethyl hydrogen phosphate prodrugs.
  • the pyridin-1- ium-1-ylmethyl hydrogen phosphate prodrugs are substituted pyridin-1-ium-1-yl)methyl hydrogen phosphate.
  • prodrugs described herein are substituted (2-amino-3-(3-benzylisoxazol- 5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds. In some embodiments, prodrugs described herein are substituted (2-amino-3-(3-benzylisoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds, wherein the (2-amino-3-(3-benzylisoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds are substituted at the 4-position of the benzyl group with R 1A .
  • prodrugs described herein are substituted (2-amino-3-(3-((pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds.
  • prodrugs described herein are substituted (2-amino-3-(3-((pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds, wherein the (2-amino-3-(3-((pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds are substituted at the 6-position of the (pyridin-3-yl) with with R 1A .
  • Formula (III) describes both parent compounds (when W is N) and methyl hydrogen phosphate prodrugs (when W is -N + – CH 2 OPO3H – ).
  • an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen- 15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine
  • an“isotopic variant” of a compound is in a stable form, that is, non-radioactive.
  • an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon- 12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), and iodine- 127 ( 127 I).
  • an“isotopic variant” of a compound is in an unstable form, that is, radioactive.
  • an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus- 33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 Cl), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I), and iodine-131 ( 131 I).
  • any hydrogen can be 2 H, for example, or any carbon can be 13 C, for example, or any nitrogen can be 15 N, for example, or any oxygen can be 18 O, for example, where feasible according to the judgment of one of skill.
  • an“isotopic variant” of a compound contains unnatural proportions of deuterium (D).
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • 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, 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, 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 + (C1-4 alkyl)4, and the like.
  • 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.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents 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. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol.
  • 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.
  • the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) as described herein is administered as a pure chemical.
  • the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a
  • pharmaceutically suitable (or acceptable) excipient 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 at least one compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, together with one or more
  • the carrier(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) 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.
  • 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, sex, age, renal status, hepatic status, or blood volume of the patient.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day, or one to four times per week
  • the compounds contemplated by the present disclosure may be administered (e.g., orally) at dosage levels of about 0.01 mg/kg to about 1000 mg/kg, or about 1 mg/kg to about 50 mg/kg, of subject body weight per day, one, two, three, four or more times a day, to obtain the desired therapeutic effect.
  • compositions can be provided in the form of tablets, capsules and the like containing from 0.05 to 1000 milligrams of the active ingredient, particularly 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0, 175.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient.
  • Pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s) may be present in an amount of from about 0.1 g to about 2.0 g.
  • a fungal disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • a fungal disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, comprising compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B), and at least one pharmaceutically acceptable excipient, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • a pharmaceutical composition comprising compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B), and at least one pharmaceutically acceptable excipient, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • the fungal disease is selected from the group consisting of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (Valley Fever), cryptococcosis, fungal eye infection, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), ringworm, sporotrichosis, and talaromycosis.
  • the fungal disease is aspergillosis.
  • aspergillosis is allergic bronchopulmonary aspergillosis (abpa), allergic aspergillus sinusitis, chronic pulmonary aspergillosis, invasive aspergillosis or cutaneous (skin) aspergillosis.
  • the subject has an aspergilloma.
  • the fungal disease is blastomycosis. [0291] In some embodiments, the fungal disease is candidiasis. In some embodiments, candidiasis is oropharyngeal candidiasis (thrush), vulvovaginal candidiasis (vaginal candidiasis), fungemia, or invasive candidiasis.
  • the fungal disease is coccidioidomycosis (Valley Fever). In some embodiments, coccidioidomycosis is acute coccidioidomycosis (primary pulmonary
  • coccidioidomycosis chronic coccidioidomycosis
  • disseminated coccidioidomycosis including primary cutaneous coccidioidomycosis.
  • the fungal disease is cryptococcosis. In some embodiments,
  • cryptococcosis is wound or cutaneous cryptococcosis, pulmonary cryptococcosis, or cryptococcal meningitis.
  • the fungal disease is a fungal eye infection.
  • the fungal eye infection is fungal keratitis, fungal exogenous endophthalmitis, or fungal endogenous endophthalmitis.
  • the fungal disease is histoplasmosis. In some embodiments,
  • histoplasmosis is acute histoplamosis. In some embodiments, histoplamosis is chronic histoplamosis.
  • the fungal disease is mucormycosis. In some embodiments,
  • mucormycosis is rhinocerebral (sinus and brain) mucormycosis, pulmonary (lung) mucormycosis, gastrointestinal mucormycosis, cutaneous (skin) mucormycosis, or disseminated mucormycosis.
  • the fungal disease is Pneumocystis pneumonia (PCP).
  • the fungal disease is ringworm.
  • the ringworm is tinea pedis, tinea cruris, tinea capitis, tinea barbae, tinea manuum, tinea unguium, or tinum corporis.
  • the ringworm is caused by a type of fungi including Trichophyton, Microsporum, or Epidermophyton.
  • the fungal disease is sporotrichosis.
  • sporotrichosis is cutaneous (skin) sporotrichosis, pulmonary (lung) sporotrichosis, or disseminated sporotrichosis.
  • the fungal disease is talaromycosis.
  • the fungal disease is caused by a fungal species including, but not limited to, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Blastomyces dermatitidis, Ajellomyces dermatitidis, Candida albicans, Candida auris, Candida glabrata, Candida parapsilosis, Candida rugosa, Candida tropicalis, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species,
  • the fungal disease is caused by the fungal species Aspergillus fumigatus. In some embodiments, the fungal disease is caused by the fungal species Candida albicans. In some embodiments, the fungal disease is caused by the fungal species Fusarium solani. In some embodiments, the fungal disease is caused by the fungal species Mucor indicus. In some embodiments, the fungal disease is caused by the fungal species Scedosporium apiospermum. In some embodiments, the fungal disease is caused by the fungal species Cryptococcus neoformans. In some embodiments, the fungal disease is caused by the fungal species Cryptococcus gattii. In some embodiments, the fungal disease is caused by the fungal species Candida auris.
  • a method of treating a fungal disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B).
  • a method of treating a fungal disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) and at least one pharmaceutically acceptable excipient.
  • the fungal disease is selected from the group consisting of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (Valley Fever), cryptococcosis, fungal eye infection, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), ringworm, sporotrichosis, and talaromycosis.
  • the fungal disease is caused by a fungal species selected the group consisting of Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatitidis, Ajellomyces dermatitidis, Candida albicans, Candida glabrata, Candida rugosa, Candida auris, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species, Basidiobolus species, Sporothrix schenckii, Pneumocysti
  • the subject is immunocompromised.
  • the subject has received chemotherapy treatment.
  • the subject is infected with HIV/AIDS.
  • the fungal disease is caused by
  • Cryptococcus neoformans or Cryptococcus gattii are known as Cryptococcus neoformans or Cryptococcus gattii.
  • the compound is selected from the compounds in Table 1. In some embodiments of the methods disclosed herein, the compound is selected from the compounds in Table 2.
  • the compound is selected from:
  • a compound described herein is active against the fungal Gwt1 protein.
  • This conserved enzyme catalyzes the glycosylphosphatidyl inositol (GPI) post-translational modification that anchors eukaryotic cell surface proteins to the cell membrane.
  • GPI glycosylphosphatidyl inositol
  • yeasts GPI mediates cross-linking of cell wall mannoproteins to b-1,6-glucan.
  • the subject is immunocompromised. In some embodiments, the subject is an immunocompromised human subject. In some embodiments, the human subject is under the age of 1 year. In some embodiments, the human subject is an infant under 1 month old. In some embodiments, the human subject is over the age of 70 years. In some embodiments, the subject is infected with HIV/AIDS. In some embodiments, the subject is undergoing or has undergone cancer chemotherapy treatment. In some embodiments, the subject is undergoing or has undergone corticosteroid treatment. In some embodiments, the subject is undergoing or has undergone TNF inhibitor treatment. In some
  • the subject is a transplant recipient.
  • the subject is a recipient of a hematopoietic stem-cell transplant, bone marrow transplant, lung transplant, liver transplant, heart transplant, kidney transplant, pancreas transplant or a combination thereof.
  • the subject is a recipient of a hematopoietic stem-cell transplant.
  • the subject is a recipient of a bone marrow transplant.
  • the subject is a recipient of a lung transplant.
  • the subject is a recipient of a liver transplant.
  • the subject is a recipient of a heart transplant.
  • the subject is a recipient of a kidney transplant.
  • the subject is a recipient of a pancreas transplant.
  • the subject is a vertebrate.
  • the vertebrate is a fish, an amphibian, a reptile, a bird, a marsupial, or a mammal.
  • the subject is a fish.
  • the subject is a mammal.
  • the mammal is a human.
  • the mammal is a dog.
  • the mammal is a cat.
  • the mammal is livestock.
  • the livestock is selected from the group consisting of cattle, sheep, goats, swine, poultry, bovine, and equine animals.
  • the subject is an invertebrate.
  • the invertebrate is an insect.
  • the invertebrate is a plant.
  • the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent.
  • the benefit experienced by a subject 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 of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' ), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is co- administered with a second therapeutic agent, wherein the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, 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.
  • 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 of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, 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.
  • a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, 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.
  • 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).
  • 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 of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ⁇ ), (II ⁇ ⁇ ), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, 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 second therapeutic agent is antifungal agent.
  • the second therapeutic agent is an antifungal agent selected from the group consisting of: a polyene antifungal agent, an azole antifungal agent, an allylamine antifungal agent, and an echinocandin antifungal agent.
  • the polyene antifungal agent is selected from the group consisting of: Amphotericin B, Candicidin, Filipin, Hamycin, Natamycin, Nystatin, and Rimocidin.
  • the azole antifungal agent is selected from the group consisting of: an imidazole, a triazole, and a thiazole.
  • the imidazole is selected from the group consisting of: Bifonazole, Butoconazole, Clotrimazole, Econazole, Fenticonazole, Isoconazole,
  • the triazole is selected from the group consisting of: Albaconazole, Efinaconazole, Epoxiconazole, Fluconazole, Isavuconazole, Itraconazole, Posaconazole, Propiconazole, Ravuconazole, Terconazole, and Voriconazole.
  • the thiazole is Abafungin.
  • the allylamine antifungal agent is selected from the group consisting of: Amorolfin, Butenafine, Naftifine, and Terbinafine.
  • the echinocandin antifungal agent is selected from the group consisting of: Anidulafungin, Caspofungin, Micafungin and Rezafungin.
  • are methods for treating a subject with a fungal disease comprising administering to the subject a combination treatment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and fluconazole, wherein the subject is selected from the group consisting of cattle, sheep, goats, swine, poultry, bovine, and equine animals.
  • are methods for treating a subject with a fungal disease comprising administering to the subject a combination treatment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' ), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and ketoconazole, wherein the subject is selected from the group consisting of cattle, sheep, goats, swine, poultry, bovine, and equine animals.
  • a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and ketoconazole wherein the subject is selected from the group consisting of cattle, sheep, goats, swine, poultry, bo
  • are methods for treating a subject with a fungal disease comprising administering to the subject a combination treatment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and itraconazole, wherein the subject is selected from the group consisting of cattle, sheep, goats, swine, poultry, bovine, and equine animals.
  • a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and itraconazole wherein the subject is selected from the group consisting of cattle, sheep, goats, swine,
  • the acidic solution (pH 3) was stirred for 10 min, then basified to pH 9 with aqueous 5N NaOH solution.
  • the basic mixture was extracted three times with ethyl acetate.
  • the combined organic phase was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give the title compound as a yellow solid (0.32 g, 77%). This material was taken forward without further purification.
  • Step 5 Di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate:
  • the mixture was heated under reflux for 2h.
  • the cooled mixture was poured into an ice-cold pH7 phosphate buffer solution (0.5M, 100mL) containing an additional amount of NaOH (480mg, 12mmol) to neutralize the excess of HCl.
  • the resulting mixture was extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • N-benzyl-N,N-diethylethanaminium chloride (237mg, 1.04mmol) and phosphoryl trichloride (0.58mL, 6.24mmol) were added, followed by the addition of N-ethyl-N- isopropylpropan-2-amine (0.71mL, 4.16mmol).
  • the mixture was heated in a sealed tube at 90°C for 20h and then slowly added to a stirred solution of NaHCO3 in water. Some ice was added to maintain a temperature around 30°C. After quenching was complete, the mixture was extracted with EtOAc.
  • Example 1 Synthesis of 3-(3-(4-((1H-pyrazol-1-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
  • Diisopropylethylamine (0.14 mL, 0.80 mmol) was added and the homogeneous amber-colored solution was stirred at room temperature. After 3 hours an additional 2 equivalents of 1,2,4-thiadiazol-5-amine (0.070 g, 0.66 mmol) and another 1.2 equivalents of diisopropylethylamine (0.070 mL, 0.40 mmol) were added. The mixture was heated at 60 ⁇ C for 72 hours. The mixture was cooled to room temperature and extracted three times with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure.
  • Example 8 Synthesis of 3-(3-(4-benzylbenzyl)isoxazol-5-yl)pyridin-2-amine [0363] Phenylboronic acid (61mg, 0.50mmol) and 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin- 2-amine (Intermediate B, 100mg, 0.33mmol) were mixed in DME (4mL) in a sealable tube.
  • Example 11 Synthesis of 3-(3-(4-((1-methyl-1H-pyrazol-4-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
  • Example 12 Synthesis of 3-(3-(4-((1-ethyl-1H-pyrazol-4-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
  • Example 13 Synthesis of 3-(3-(4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)benzyl)isoxazol-5- yl)pyridin-2-amine
  • Example 15 Synthesis of 3-(3-(4-((6-fluoropyridin-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
  • Example 16 Synthesis if 3-(3-(4-((1-isobutyl-1H-pyrazol-4-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
  • Example 17 Synthesis of 3-(3-(4-(cyclopent-1-en-1-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2- amine
  • Example 19 Synthesis of 3-(3-(4-((2-fluoropyridin-4-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
  • Example 22 Synthesis of (4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenyl)(phenyl)methanol
  • the vial was sealed and heated at 90 ⁇ C for 40 min under microwave irradiation.
  • the mixture was filtered through Celite with ethyl acetate.
  • the solvents were evaporated under reduced pressure and the residue was purified using Biotage flash chromatography (50g SNAP, 2-75% acetone/hexane). Like fractions were combined and evaporated to give the desired di- BOC-protected intermediate.
  • This material was dissolved in dichloromethane (10 mL) and treated with 4M hydrogen chloride in dioxane (3 mL). After stirring for 16 hours at room temperature, the mixture was diluted with water and basified with 5M aqueous sodium hydroxide solution to pH 13.
  • Example 24 Synthesis of 3-(3-(4-((naphthalen-1-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
  • Example 25 Synthesis of 3-(3-(4-(((4-chloronaphthalen-1-yl)oxy)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
  • Example 29 Synthesis of 3-(3-(4-((5-methylpyrimidin-2-yl)methoxy)benzyl)isoxazol-5- yl)pyridin-2-amine
  • Example 30 Synthesis of 3-(3-(4-(quinoxalin-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridin-2- amine
  • Example 35 Synthesis of 3-(3-((6-(pyridin-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 36 Synthesis of 3-(3-((6-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 37 Synthesis of 3-(3-((6-(pyridin-4-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 38 Synthesis of 3-(3-((6-((5-methylisoxazol-3-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
  • Example 39 Synthesis of 3-(3-((6-(2-(pyridin-2-yl)ethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 40 Synthesis of 3-(3-((6-(thiophen-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 41 Synthesis of 3-(3-((6-(thiazol-4-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 42 Synthesis of 3-(3-((6-(thiazol-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine [0429] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
  • Example 43 Synthesis of 3-(3-((6-(cyclopropylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(cyclopropylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (38mg, 0.097mmol, 64%) as a white solid.
  • Example 44 Synthesis of 3-(3-((6-(oxetan-3-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 46 Synthesis of 3-(3-((6-(pyrimidin-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 48 Synthesis of 3-(3-((6-(furan-3-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 49 Synthesis of 3-(3-((6-((1-methyl-1H-pyrazol-4-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
  • Example 50 Synthesis of 3-(3-((6-((2-methylthiazol-4-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
  • Example 51 Synthesis of 3-(3-((6-((5-fluoropyridin-2-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
  • Example 53 Synthesis of 3-(3-((6-(oxazol-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine [0451] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
  • Example 54 Synthesis of 3-(3-((6-((3-fluoropyridin-4-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
  • Example 55 Synthesis of 3-(3-((6-(1-(pyridin-2-yl)ethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 58 Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-phenylpyridin-2- amine
  • Example 60 Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2- fluorophenyl)pyridin-2-amine
  • Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(3- fluorophenyl)pyridin-2-amine (18mg, 0.048mmol, 26%) as a pink solid.
  • 1,4-phenylenedimethanol (7.50g, 54.3mmol) and 2-fluoropyridine (1.76g, 18.09mmol) were dissolved in DMF (40mL) and sodium hydride (60% w/mineral oil, 2.171g, 54.3mmol) was added at 0°C in 10 portions over the course of 20min.
  • the resulting mixture was allowed to warm to 21-25°C within 30min and then warmed to 70°C and stirred for 30min at this temperature.
  • the cooled reaction mixture was poured into a stirring mixture of ice-water (300mL) and ethyl acetate (500mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3 ⁇ 100mL).
  • Step 3 2-((4-((4-bromo-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridine
  • Sodium hydride (60% w/mineral oil, 48.3mg, 1.21mmol) was suspended in DMF (2mL) and a solution of 4-bromo-1H-pyrazole (165 mg, 1.12mmol) in DMF (1.5mL) was added at 0°C. The mixture was allowed to warm to 23°C and stirred for 15min.
  • Step 4 2-((4-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridine
  • Fractions containing the product also contained a small amount of inseparable impurities and were re-purified using RP flash chromatography (Biotage). Fractions containing the product were lyophilized to obtain 2-((4-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridine (53mg, 0.16mmol, 49%) as a white solid.
  • Example 63 Synthesis of 3-(1-((6-phenoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2- amine Step 1: 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2-fluoropyridine
  • Phenylmethanol (845mg, 7.81mmol) was added to a suspension of sodium hydride (60% w/mineral oil, 312mg, 7.81mmol) in DMF (4mL). After no more gases evolved, a solution of 5-((4- bromo-1H-pyrazol-1-yl)methyl)-2-fluoropyridine (500mg, 1.95mmol) in DMF (2mL) was added and the mixture was stirred at 21-25°C for 1h. The reaction mixture was poured into a stirring mixture of ice- water (50mL) and ethyl acetate (150mL).
  • Example 71 Synthesis of 4-((5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)pyridin-2- yl)oxy)-2,5-dimethylfuran-3(2H)-one
  • Example 72 Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,3- difluorophenyl)pyridin-2-amine
  • Example 74 Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2- fluorobenzyl)pyridin-2-amine
  • Example 75 Synthesis of 3-(3-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 76 Synthesis of 4-(((5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)pyridin-2- yl)oxy)methyl)benzonitrile
  • Example 77 Synthesis of 3-(3-((6-(2-fluorophenethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
  • Example 78 Synthesis of 3-(3-((6-phenethoxypyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2- amine
  • Example 80 Synthesis of 3-(3-((6-((3-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine

Abstract

Described herein are heterocycle substituted pyridine derivative antifungal agents and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of fungal diseases and infections.

Description

HETEROCYCLE SUBSTITUTED PYRIDINE DERIVATIVE ANTIFUNGAL AGENTS RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/858,897 filed on June 7, 2019, which is incoporated by reference in its entirety. BACKGROUND
[0002] A need exists in the art for an effective treatment of fungal diseases. BRIEF SUMMARY OF THE INVENTION
[0003] Provided herein are compounds of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof, and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for treating fungal diseases.
Furthermore, the subject compounds and compositions are useful for the treatment of cryptococcosis.
[0004] Provided herein are compounds having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000003_0001
( );
wherein:
R1A is–OH, substituted or unsubstituted C1-6 alkyl,–(CH2)2S(CH2) 2OC(O)H,–X15–L–CºN,–L– X15– (CH2)z2CºN,–X15–L–CH=CR29R30,
Figure imgf000003_0002
one of X1 and X2 is N while the other is O;
X13 and X14 are independently N or C(R1B);
X15 is a bond,–NH–,–O–,–S–, or–SO2–;
L is a bond or substituted or unsubstituted C1-6 alkylene;
W is N or N+– CH2OPO3H–;
Ring Q is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R2 is independently hydrogen,–NH2, or halogen;
each R1B and R10A is independently hydrogen, halogen, -CF3, -CN, -CH2-OH, -ORa, -SRa, -S(=O)Rb, - NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R29 and R30 are independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
Ra is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rb is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rc and Rd is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or
unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
n is 0-3; z1 is 0-2; z2 is 0-3; and z3 is 1-3.
[0005] In some embodiments of a compound of Formula (III), if R1A is
Figure imgf000004_0001
, R2 is– NH2,, Ring Q is 2-pyridinyl, L is methylene, R10A is hydrogen, X1 is O, X2 is N, X13 is CH, X14 is CH, n is 1, and z1 is 0, then X15 is a bond,–NH–,–S–, or–SO2–.
[0006] In some embodiments of a compound of Formula (III), if R1A is
Figure imgf000004_0002
, R2 is 2-amino, Ring Q is 2-pyridinyl, L is methylene, R10A is hydrogen, X1 is O, X2 is N, X13 is CH, X14 is CH, n is 1, and z1 is 0, then X15 is a bond,–NH–,–S–, or–SO2–.
[0007] In some embodiments, the compound of Formula (III) is of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000004_0003
Formula (IIIa).
[0008] Provided herein are compounds having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000005_0001
wherein:
Figure imgf000005_0002
one of X11 and X12 is N while the other is O;
one of Y11 and Y12 is -NH- or -O- while the other is -CH2-;
one of Y13 and Y14 is -S- while the other is -CH2-;
one of x' y' and z' is -O- while the others are -CH2-;
Ring A' is heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring B' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring C' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring D' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring E' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring F' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring G' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring H' is bicyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring J' is aryl;
R22 is hydrogen, -NH2, or halogen;
R29 and R30 are independently hydrogen, halogen, C1-C6 alkyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl;
each R23, R24, R25, R26, R27, R28, R31, and R32 is independently hydrogen, halogen, -CF3, -CN, -ORa, - SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ra is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rb is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each Rc and Rd is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or Rc and Rd, together with the nitrogen atom to which they are attached, form an substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
f is 1; h is 1-3; i is 1-3; j is 1-3; k is 1-3; l is 1-3; m is 1-3; o is 1-3; w is 1-3; and e is 1-3.
[0009] In some embodiments provided herein are compounds compound having the structure of Formula (II') or Formula (II''), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000006_0001
Formula (II'') wherein:
Figure imgf000006_0002
Figure imgf000007_0001
, ;
one of X11 and X12 is N while the other is O;
one of Y11 and Y12 is -NH- or -O- while the other is -CH2-;
one of Y13 and Y14 is -S- while the other is -CH2-;
one of x' y' and z' is -O- while the others are -CH2-;
Ring A' is heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring B' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring C' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring D' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring E' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring F' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring G' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring H' is bicyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring I' is aryl,
Ring J' is aryl,
R22 is hydrogen, -NH2, or halogen;
each R29 and R30 is independently hydrogen, halogen, C1-C6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl;
each R23, R24, R25, R26, R27, R28, R31, R32 , R33, R34 is independently hydrogen, halogen, -CF3, -CN, - ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, - OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, - NRaC(=O)Rb, -NRaC(=O)ORa, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ra is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rb is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rc and Rd is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or Rc and Rd, together with the nitrogen atom to which they are attached, form an substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
f is 1; h is 1-3; i is 1-3; j is 1-3; k is 1-3; l is 1-3; m is 1-3; o is 1-3; w is 1-3; z is 1-3; and e is 1-3.
[0010] In some embodiments, the compound of Formula (II) is of Formula (IIa), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000008_0001
Formula (IIa).
[0011] In some embodiments, the compound of Formula (II) is of Formula (IIb), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000008_0002
Formula (IIb).
[0012] In some embodiments, the compound of Formula (II) is of Formula (IIc), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000008_0003
Formula (IIc). BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG.1 shows the efficacy of certain compounds of the present disclosure in a murine model of cryptococcal meningitis when dosed in the presence of the pan-CYP inhibitor 1-aminobenzotriazole (ABT).
[0014] FIG.2 shows a dose response study with (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (Example 172) and (2- amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (Example 173). [0015] FIG.3 shows the efficacy of (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (Example 172) and amphotericin B (AMB) in a delayed model of cryptococcal meningitis. DETAILED DESCRIPTION OF THE INVENTION
[0016] The incidence of fungal infections has increased over the last few decades. Such infections have risen in the last few decades in part due to an increase in individuals that are immunocompromised. Immunocompromised individuals include, for example, elderly individuals, individuals with HIV/AIDS, or individuals undergoing chemotherapy treatment or immunosuppressive therapy after a transplant.
[0017] Current antifungal therapies exploit differences between mammalian cells and fungal cells to kill the fungi. However, because fungi and mammals are both eukaryotes, many antifungal therapies cause side effects in the host mammal. Additionally, many fungal organisms have developed resistance to front line antifungal treatments. Thus, there exists a need for new compositions and methods for treating fungal diseases.
Definitions
[0018] As used herein and in the appended claims, the singular forms“a,”“and,” and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to“an agent” includes a plurality of such agents, and reference to“the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term“about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term“comprising” (and related terms such as“comprise” or“comprises” or“having” or“including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein,“consist of” or“consist essentially of” the described features.
[0019] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0020]“Alkyl” refers to an substituted or unsubstituted straight-chain, or substituted or unsubstituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. 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, and the like. Whenever it appears herein, a numerical range such as“C1-C6 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. In some embodiments, the alkyl is a C1-C10 alkyl, a C1- C9 alkyl, a C1-C8 alkyl, a C1-C7 alkyl, a C1-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a methyl. Unless stated otherwise specifically in the specification, an alkyl group is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, or–OMe.
[0021]“Alkenyl” refers to a7 substituted or unsubstituted straight-chain, or substituted or unsubstituted 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, wherein an sp2- hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as“C2-C6 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. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, or–OMe.
[0022]“Alkynyl” refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted 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. Whenever it appears herein, a numerical range such as“C2-C6 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 the occurrence of the term“alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is substituted or
unsubstituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2,, or -NO2. In some embodiments, an alkynyl is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, or–OMe.
[0023] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, or–OMe.
[0024] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is substituted or unsubstituted with oxo, halogen, -CN, -CF3, -OH, or–OMe.
[0025]“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. In some embodiments, 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. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be substituted or unsubstituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is substituted or unsubstituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is substituted or unsubstituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0026]“Cycloalkyl” refers to a stable, 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 (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, 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. Unless stated otherwise specifically in the specification, a cycloalkyl is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2,, or -NO2. In some embodiments, a cycloalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0027] “Halo” or“halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
[0028]“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
[0029] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such 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, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3- dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. 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). Unless stated otherwise specifically in the specification, a heterocycloalkyl is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2,, or -NO2. In some embodiments, a heterocycloalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0030]“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, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl. Unless stated otherwise specifically in the specification, a Heteroalkyl is substituted or unsubstituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is substituted or unsubstituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe.
[0031]“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. 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. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, 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, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is substituted or unsubstituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is substituted or unsubstituted with halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2,, or -NO2. In some embodiments, a heteroaryl is substituted or unsubstituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0032] All the above groups may be either substituted or unsubstituted. The term“substituted” as used herein means any of the above groups (e.g., alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl and/or heteroaryl) may be further functionalized wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom substituent. Unless stated specifically in the specification, a substituted group may include one or more substituents selected from: oxo, amino, -CO2H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, trialkylammonium (-N+R3), N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups, perfluoroalkyl, or perfluoroalkoxy, for example, trifluoromethyl or trifluoromethoxy. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example,“substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NH2, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, - SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. In addition, each of the foregoing substituents may also be substituted or unsubstituted with one or more of the above substituents. Furthermore, any of the above groups may be substituted to include one or more internal oxygen, sulfur, or nitrogen atoms. For example, an alkyl group may be substituted with one or more internal oxygen atoms to form an ether or polyether group.
Similarly, an alkyl group may be substituted with one or more internal sulfur atoms to form a thioether, disulfide, etc. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups.
[0033] The terms“inhibit,”“block,”“suppress,” and grammatical variants thereof are used
interchangeably herein and refer to any statistically significant decrease in biological activity, including full blocking of the activity. In some embodiments,“inhibition” refers to a decrease of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100% in biological activity.
[0034] As used herein,“treatment” or“treating,” or“palliating” or“ameliorating” are used
interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
Compounds
[0035] Described herein are compounds of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II’), (II”), (III), (IIIa), and (III-B). These compounds, and compositions comprising these compounds, are useful for the treatment of fungal diseases in humans and in animals.
[0036] In an aspect, provided herein is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
wherein:
Figure imgf000015_0001
R1A is–OH, substituted or unsubstituted C1-6 alkyl,–(CH2)2S(CH2) 2OC(O)H,–X15–L–CºN,–L– X15– (CH2)z2CºN,–X15–L–CH=CR29R30,
Figure imgf000015_0002
one of X1 and X2 is N while the other is O;
X13 and X14 are independently N or C(R1B);
X15 is a bond,–NH–,–O–,–S–, or–SO2–;
L is a bond or substituted or unsubstituted C1-6 alkylene;
W is N or N+–CH2OPO3H–;
Ring Q is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R2 is independently hydrogen,–NH2, or halogen;
each R1B and R10A is independently hydrogen, halogen, -CF3, -CN, -CH2-OH, -ORa, -SRa, -S(=O)Rb, - NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, - C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; R29 and R30 are independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
Ra is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rb is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rc and Rd is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or
unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
n is 0-3; z1 is 0-2; z2 is 0-3; and z3 is 1-3.
Figure imgf000016_0001
[0037] In some embodiments of a compound of Formula (III), if R1A is , R2 is– NH2,, Ring Q is 2-pyridinyl, L is methylene, R10A is hydrogen, X1 is O, X2 is N, X13 is CH, X14 is CH, n is 1, and z1 is 0, and then X15 is a bond,–NH–,–S–, or–SO2–.
[0038] In some embodiments of a compound of Formula (III), if R1A i
Figure imgf000016_0002
R2 is 2-amino, Ring Q is 2-pyridinyl, L is methylene, R10A is hydrogen, X1 is O, X2 is N, X13 is CH, X14 is CH, n is 1, and z1 is 0, then X15 is a bond,–NH–,–S–, or–SO2–.
[0039] In some embodiments of a compound of Formula (III), R2 is 2-amino and R2 is–NH2 are synonymous and refer to an amino group (i.e.,–NH2 group) on the 2-position of the pyridinyl or pyridinium ring of a compound of Formula (III) as shown in Formula (IV):
Figure imgf000016_0003
Formula (IV).
[0040] In some embodiments, the compound of Formula (III) is of Formula (III '), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof: wherein:
Figure imgf000017_0004
R2, W, X1, X2, R1B, X13, X14, R1A, z1, z2, z3, and n are as described herein, including embodiments. LA and LB are independently a bond or substituted or unsubstituted C1-6 alkylene; and
XA is a bond,–NH–,–O–,–S–, or–SO2–.
[0041] In some embodiments, the compound is not (2-amino-3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate or 3-(3-(4-((pyridin- 2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine.
[0042] In some embodiments, W is N. In some embodiments, N+– CH2OPO3H–.
[0043] In some embodiments, X1 is -O-; and X2 is N.
[0044] In some embodiments, R2 is–NH2. In some embodiments, R10A is hydrogen or halogen. In some embodiments, z3 is 0. In some embodiments, z3 is 1. In some embodiments, z3 is 2. In some embodiments, z3 is 3.
[0045] In some embodiments, z3 is 1-2.
[0046] In some embodiments, z2 is 0. In some embodiments, z2 is 1. In some embodiments, z2 is 2. In some embodiments, z2 is 3.
[0047] In some embodiments, z1 is 0. In some embodiments, z1 is 1. In some embodiments, z1 is 2.
[0048] In some embodiments, the compound of Formula (III) is of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000017_0001
Formula (IIIa).
[0049] In some embodiments, R1A is
Figure imgf000017_0002
; and Ring Q is bicyclic aryl, bicyclic heteroaryl, monocyclic heteroaryl containing at least 2 N atoms in the ring, or oxazolyl.
[0050] In some embodiments, R1A is
Figure imgf000017_0003
; and Ring Q is bicyclic aryl, bicyclic heteroaryl, monocyclic 5-membered heteroaryl, or cycloalkyl.
[0051] In some embodiments, X15 is–O–.
[0052] In some embodiments, Ring Q is bicyclic aryl or bicyclic heteroaryl. [0053] In some embodiments, Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
[0054] In some embodiments, Ring Q is quinolinyl or quinoxalinyl.
[0055] In some embodiments, Ring Q is monocyclic heteroaryl containing at least 2 N atoms in the ring.
[0056] In some embodiments, Ring Q is monocyclic heteroaryl containing at least 2 N atoms in the ring is selected from the group consisting of pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
[0057] In some embodiments, Ring Q is pyrimidinyl.
[0058] In some embodiments, Ring Q is monocyclic 5-membered heteroaryl.
[0059] In some embodiments, Ring Q is monocyclic 5-membered heteroaryl selected from the group consisting of imidazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, and thiadiazolyl.
[0060] In some embodiments, Ring Q is imidazolyl or oxazolyl.
[0061] In some embodiments, Ring Q is cycloalkyl.
[0062] In some embodiments, Ring Q is cyclohexyl.
[0063] In some embodiments, X15 is–NH–.
[0064] In some embodiments, Ring Q is heteroaryl or cycloalkyl.
[0065] In some embodiments, Ring Q is heteroaryl selected from the group consisting of azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
[0066] In some embodiments, Ring Q is pyridinyl, thiadiazolyl, pyrimidinyl, azaindolyl,
benzimidazolyl, or thiazolyl.
[0067] In some embodiments, R1A is
Figure imgf000018_0001
; and Ring Q is heteroaryl or cycloalkyl.
[0068] In some embodiments, Ring Q is heteroaryl.
[0069] In some embodiments, Ring Q is heteroaryl selected from the group consisting of azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
[0070] In some embodiments, Ring Q is pyridinyl, thiadiazolyl, pyrimidinyl, azaindolyl,
benzimidazolyl, or thiazolyl. [0071] In some embodiments, Ring Q is cycloalkyl.
[0072] In some embodiments, R1A is
Figure imgf000019_0001
; and Ring Q is aryl, bicyclic heteroaryl, or cycloalkyl.
[0073] In some embodiments, Ring Q is aryl selected from phenyl and naphthyl.
[0074] In some embodiments, Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
[0075] In some embodiments, Ring Q is C3-C6 cycloalkyl.
[0076] In some embodiments, z3 is 1. In some embodiments, z3 is 2.
[0077] In some embodiments, R10A is hydrogen,–CF3, halogen, or methyl.
[0078] In some embodiments, R1A is
Figure imgf000019_0002
; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
[0079] In some embodiments, R1A is
Figure imgf000019_0003
; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
[0080] In some embodiments, R1A is
Figure imgf000019_0004
; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
[0081] In some embodiments, R1A is
Figure imgf000019_0005
; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
[0082] In some embodiments, R1A is
Figure imgf000019_0006
; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
[0083] In some embodiments, R1A is
Figure imgf000019_0007
; and Ring Q is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
[0084] In some embodiments, Ring Q is aryl selected from phenyl and naphthyl. In some embodiments, Ring Q is substituted or unsubstituted phenyl. In some embodiments, Ring Q is substituted or unsubstituted heteroaryl. In some embodiments, Ring Q is substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, Ring Q is substituted or unsubstituted pyridinyl. In some embodiments, Ring Q is substituted or unsubstituted furanyl.
[0085] In some embodiments, Ring Q is heteroaryl containing at least 1 N atom in the ring.
[0086] In some embodiments, Ring Q is selected from
Figure imgf000020_0001
[
Figure imgf000020_0002
[0088] In some embodiments, R10A is selected from the group consisting of hydrogen, -CN, halogen, - CH2-OH, -CF3, methyl, ethyl, isobutyl, and butyl.
[0089] In some embodiments, R10A is -F, isobutyl, or -CH2-OH.
[0090] In some embodiments, R10A is–F.
Figure imgf000020_0003
and Ring Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
[0092] In some embodiments, R1A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl. In some embodiments, R1A is substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered heteroaryl, or substituted or unsubstituted 6-membered heteroaryl. In some embodiments, R1A is heteroaryl selected from pyridinyl and furanyl.
[0093] In some embodiments, Ring Q is heteroaryl selected from the group consisting of azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
[0094] In some embodiments, Ring Q is heteroaryl selected from furyl and benzofuranyl.
[0095] In some embodiments, Ring Q is cycloalkyl selected from C3-C6 cycloalkyl.
[0096] In some embodiments, Ring Q is heterocycloalkyl wherein the heterocycloalkyl contains at least one O atom.
[0097] In some embodiments, Ring Q is heterocycloalkyl that contains at least one O atom selected from the group consisting of
Figure imgf000021_0001
[0098] In some embodiments, R10A is hydrogen, methyl, -CF3, or halogen.
[0099] In some embodiments, R1A is–CClR5R6; and R5 and R6 are is independently hydrogen, halogen, or C1-C6 alkyl.
[0100] In some embodiments, R5 and R6 are hydrogen.
Figure imgf000021_0002
[0102] In some embodiments, R29 and R30 are hydrogen.
[0103] In some embodiments, R29 is hydrogen and R30 is cyclohexyl.
[0104] In some embodiments, L is–CH2–; and Ring Q is bicyclic aryl, bicyclic heteroaryl, monocyclic heteroaryl containing at least 2 N atoms in the ring, or oxazolyl.
[0105] In some embodiments, X15 is a bond; L is–CH2–; and Ring Q is aryl, heteroaryl containing at least 1 N atom in the ring, or cycloalkyl.
[0106] In some embodiments, X15 is a bond; L is–(CH2)2–; and Ring Q is aryl, bicyclic heteroaryl, or cycloalkyl.
[0107] In some embodiments, X15 is a bond; L is–CH(OH)–; and Ring Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
[0108] In some embodiments, X15 is a bond; L is–NH–; and Ring Q is heteroaryl or cycloalkyl.
[0109] In some embodiments, X15 is–NH–; L is–CH2–; and Ring Q is heteroaryl or cycloalkyl.
[0110] In some embodiments, X15 is–O– or–S–; L is–CH2–; and Ring Q is bicyclic aryl, bicyclic heteroaryl, monocyclic 5-membered heteroaryl, or cycloalkyl.
[0111] In some embodiments, X13 is CH. In some embodiments, X13 is N. In some embodiments, X14 is CH. In some embodiments, X14 is N.
[0112] In some embodiments, X13 and X14 are CH. In some embodiments, X13 is CH; and X14 is N.
[0113] In an aspect provided herein, is a compound of Formula (III-B), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000021_0003
Formula (III-B);
wherein:
Figure imgf000022_0001
.
[0114] In some embodiments of the compound of Formula (III-B), X14 is N or CH; X15 is a bond,–NH– or–O–; L is a bond or unsubstituted C1-2 alkylene; Ring Q is cycloalkyl, aryl, or heteroaryl; R10A is hydrogen or halogen; and z3 is 1-2.
[0115] In some embodiments of the compound of Formula (III-B), X14 is N.
[0116] In some embodiments of the compound of Formula (III-B), X14 is CH. In some embodiments, X15 is a bond; and L is–CH2–. In some embodiments, X15 is a bond; and L is–(CH2)2–.
[0117] In some embodiments of the compound of Formula (III-B), X15 is–O– or–NH–; and L is a bond.
[0118] In some embodiments,–X15–L– is– #– X15–L–* or #– X15–L–*, wherein # is the attachment point to Ring Q and * is the attachment point to the rest of the molecule.
[0119] In some embodiments, X15–L is–CH2–O– or–CH2–NH–. In some embodiments, X15–L is #– CH2–O–* or #–CH2–NH–*, wherein # is the attachment point to Ring Q and * is the attachment point to the rest of the molecule. In other embodiments, X15–L is *–CH2–O–# or *–CH2–NH–#, wherein # is the attachment point to Ring Q and * is the attachment point to the rest of the molecule.
[0120] In some embodiments, X15–L is–(CH2)2–O– or–(CH2)2–NH–.
[0121] In an aspect provided herein, is a compound selected from the compounds in Table 1.
[0122] In an aspect provided herein, is a compound selected from the compounds in Table 2.
[0123] In an aspect provided herein, is a compound selected from:
3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((6-chloropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((3-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((3,5-difluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(3-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((5-fluorofuran-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-phenoxypyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-((3-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2-fluorophenyl)pyridin-2-amine;
5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,6-difluorophenyl)pyridin-2-amine;
3-(3-(4-benzylbenzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((6-fluoropyridin-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(3,5-difluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(cyclopropylmethoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-(3,5-difluorobenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((2-((3-fluorobenzyl)oxy)pyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-(3-fluorobenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine; and 3-(3-(4-(((3-fluorophenyl)amino)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof.
[0124] In some embodiments provided herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000023_0001
wherein:
Figure imgf000023_0002
one of X1and X2 is N while the other is O;
Y1 is -O- or -S-;
one of Y2 and Y3 is -NH- while the other is -CH2-;
Ring A is bicyclic aryl, bicyclic heteroaryl, monocyclic heteroaryl containing at least 2 N atoms in the ring, or oxazolyl;
Ring B is bicyclic aryl, bicyclic heteroaryl, monocyclic 5-membered heteroaryl, or cycloalkyl;
Ring C is heteroaryl or cycloalkyl;
Ring D is aryl, heteroaryl containing at least 1 N atom in the ring, or cycloalkyl;
Ring E is aryl, bicyclic heteroaryl, or cycloalkyl;
Ring F is aryl, heteroaryl, cycloalkyl, heterocycloalkyl;
each R2 is independently hydrogen, -NH2,, or halogen;
each R3, R4, R5, and R6 are independently hydrogen, halogen, or C1-C6 alkyl;
each R7, R8, R9, R10, R11, and R12 is independently hydrogen, halogen, -CF3, -CN, -CH2-OH, -ORa, - SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R29 and R30 is independently hydrogen, halogen, C1-C6 alkyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl;
Ra is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Rb is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each Rc and Rd is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Rc and Rd, together with the nitrogen atom to which they are attached, form an optionally
substituted heterocycloalkyl or optionally substituted heteroaryl;
n is 1-3; p is 1-3; q is 1-3; s is 1-3; t is 1-3; u is 1-3; and v is 1-3.
[0125] In some embodiments of a compound of Formula (I), X1 is O and X2 is N. In some embodiments, X1 is N and X2 is O. In some embodiments, R2 is -NH2. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogen. In some embodiments, R2 is -F, -Cl, or -Br.
[0126] In some embodiments of a compound of Formula (I), n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
[0127] In some embodiments, the compound of Formula (I) is of Formula (Ia), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000024_0001
Formula (Ia). [0128] In some embodiments of a compound of Formula (I) or (Ia), R1 is
Figure imgf000024_0003
. In some embodiments, R1 is
Figure imgf000024_0002
. In some embodiments, R3 is hydrogen and R4 is hydrogen. In some embodiments, R3 is hydrogen and R4 is halogen. In some embodiments, R3 is halogen and R4 is hydrogen. In some embodiments, R3 is C1-C6 alkyl and R4 is hydrogen. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is butyl. In some embodiments, R3 is pentyl. In some embodiments, R3 is hexyl. In some embodiments, R3 is hydrogen and R4 is C1-C6 alkyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is propyl. In some embodiments, R4 is butyl. In some embodiments, R4 is pentyl. In some embodiments, R4 is hexyl.
[0129] In some embodiments of a compound of Formula (I) or (Ia), R1 is
Figure imgf000025_0001
. In some embodiments, R5 is hydrogen and R6 is hydrogen. In some embodiments, R5 is C1-C6 alkyl and R6 is hydrogen. In some embodiments, R5 is C1-C6 alkyl and R6 is C1-C6 alkyl. In some embodiments, R5 is hydrogen and R6 is C1-C6 alkyl. In some embodiments, R5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is propyl. In some embodiments, R5 is butyl. In some embodiments, R5 is pentyl. In some embodiments, R5 is hexyl. In some embodiments, R6 is methyl. In some embodiments, R6 is ethyl. In some embodiments, R6 is propyl. In some embodiments, R6 is butyl. In some embodiments, R6 is pentyl. In some embodiments, R6 is hexyl.
Figure imgf000025_0002
[0130] In some embodiments of a compound of Formula (I) or (Ia), R1 is . In some embodiments, R29 is hydrogen and R30 is hydrogen. In some embodiments, R29 is C1-C6 alkyl and R30 is hydrogen. In some embodiments, R29 is C1-C6 alkyl and R30 is C1-C6 alkyl. In some embodiments, R29 is hydrogen and R30 is C1-C6 alkyl. In some embodiments, R29 is hydrogen and R30 is cycloalkyl. In some embodiments, R29 is hydrogen and R30 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R30 is hydrogen and R29 is cycloalkyl. In some embodiments, R30 is hydrogen and R29 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0131] In some embodiments of a compound of Formula (I) or (Ia), R1 is–(CH2)2S(CH2) 2OC(O)H .
[0132] In some embodiments of a compound of Formula (I) or (Ia), R1 is In some embodiments, Y1 is -O-. In some embodiments, Y1 is -S-.
Figure imgf000025_0003
[0133] In some embodiments of a compound of Formula (I) or (Ia), Ring A is bicyclic aryl. In some embodiments, Ring A is naphthyl.
[0134] In some embodiments of a compound of Formula (I) or (Ia), Ring A is bicyclic heteroaryl. In some embodiments, Ring A is bicyclic heteroaryl selected from indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl. In some embodiments, Ring A is quinolinyl. In some embodiments, Ring A is quinoxalinyl.
[0135] In some embodiments of a compound of Formula (I) or (Ia), Ring A is monocyclic heteroaryl containing at least 2 N atoms in the ring. In some embodiments, Ring A is pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. In some embodiments, Ring A is pyrimidinyl. [0136] In some embodiments of a compound of Formula (I) or (Ia), Ring A is oxazolyl.
[0137] In some embodiments of a compound of Formula (I) or (Ia), p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, R7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R7 is hydrogen, -CF3, or methyl. In some embodiments, R7 is hydrogen. In some embodiments, R7 is -CF3. In some embodiments, R7 is methyl. In some embodiments, R7 is a halogen. In some embodiments, R7 is -F. In some embodiments, R7 is -Cl. In some embodiments, R7 is -Br.
[0138] In some embodiments of a compound of Formula (I) or (Ia), R1 is . In some embodiments, Y1 is -O-
Figure imgf000026_0001
. In some embodiments, Y1 is -S-.
[0139] In some embodiments of a compound of Formula (I) or (Ia), Ring B is bicyclic aryl. In some embodiments, Ring B is naphthyl.
[0140] In some embodiments of a compound of Formula (I) or (Ia), Ring B is bicyclic heteroaryl. In some embodiments, Ring B is bicyclic heteroaryl selected from indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl. In some embodiments, Ring B is bicyclic heteroaryl selected from indolyl, indazolyl, benzimidazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, and pteridinyl. In some embodiments, Ring B is quinolinyl. In some embodiments, Ring B is quinoxalinyl.
[0141] In some embodiments of a compound of Formula (I) or (Ia), Ring B is monocyclic heteroaryl containing at least 2 N atoms in the ring. In some embodiments, Ring B is monocyclic heteroaryl containing at least 2 N atoms in the ring selected from pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. In some embodiments, Ring B is pyrimidinyl.
[0142] In some embodiments of a compound of Formula (I) or (Ia), Ring B is oxazolyl.
[0143] In some embodiments of a compound of Formula (I) or (Ia), Ring B is cycloalkyl. In some embodiments, Ring B is cyclopropyl, cyclobutyl, cycolopentyl, or cyclohexyl. In some embodiments, Ring B is cyclohexyl. In some embodiments, Ring B is cyclopropyl. In some embodiments, Ring B is cyclobutyl. In some embodiments, Ring B is cyclopentyl.
[0144] In some embodiments of a compound of Formula (I) or (Ia), q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, R8 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R8 is hydrogen, methyl, -CF3, or halogen. In some embodiments, R8 is hydrogen. In some embodiments, R8 is methyl. In some embodiments, R8 is -CF3. In some embodiments, R8 is halogen. In some embodiments, R8 is -Cl. In some embodiments, R8 is -F.
[0145] In some embodiments of a compound of Formula (I) or (Ia), R1 is
Figure imgf000027_0001
In some embodiments, Y2 is -CH2- and Y3 is -NH-. In some embodiments, Y2 is -NH- and Y3 is -CH2-.
[0146] In some embodiments of a compound of Formula (I) or (Ia), Ring C is heteroaryl. In some embodiments, Ring C is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring C is pyridinyl, thiadiazolyl, pyrimidinyl, azaindolyl, or thiazolyl. In some embodiments, Ring C is pyridinyl. In some embodiments, Ring C is thiadiazolyl. In some embodiments, Ring C is pyrimidinyl. In some embodiments, Ring C is azaindolyl. In some embodiments, Ring C is thiazolyl.
[0147] In some embodiments of a compound of Formula (I) or (Ia), Ring C is cycloalkyl. In some embodiments, Ring C is cyclopropyl, cyclobutyl, cycolopentyl, or cyclohexyl. In some embodiments, Ring C is cyclohexyl. In some embodiments, Ring C is cyclopropyl. In some embodiments, Ring C is cyclobutyl. In some embodiments, Ring C is cyclopentyl.
[0148] In some embodiments of a compound of Formula (I) or (Ia), s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, R9 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R9 is hydrogen, methyl, -CF3, or halogen. In some embodiments, R9 is hydrogen. In some embodiments, R9 is methyl. In some embodiments, R9 is -CF3. In some embodiments, R9 is halogen. In some embodiments, R9 is -Cl. In some embodiments, R9 is -F.
[0149] In some embodiments of a compound of Formula (I) or (Ia), R1 is
Figure imgf000027_0002
.
[0150] In some embodiments of a compound of Formula (I) or (Ia), Ring D is aryl. In some embodiments, Ring D is phenyl. In some embodiments, Ring D is naphthyl.
[0151] In some embodiments of a compound of Formula (I) or (Ia), Ring D is heteroaryl containing at least 1 N atom in the ring. In some embodiments, Ring D is heteroaryl containing at least 1 N atom in the ring including but not limited to azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some
embodiments, Ring D is selected from,
Figure imgf000028_0001
, , ,
Figure imgf000028_0002
[0152] In some embodiments of a compound of Formula (I) or (Ia), Ring D is
Figure imgf000028_0003
. In
some embodiments, Ring D is
Figure imgf000028_0005
. In some embodiments, Ring D is
Figure imgf000028_0004
. In some embodiments, Ring D is
Figure imgf000028_0007
. In some embodiments, Ring
Figure imgf000028_0006
.
[0153] In some embodiments of a compound of Formula (I) or (Ia), Ring D is cycloalkyl. In some embodiments, Ring D is cyclopropyl, cyclobutyl, cycolopentyl, or cyclohexyl. In some embodiments, Ring D is cyclohexyl. In some embodiments, Ring D is cyclopropyl. In some embodiments, Ring D is cyclobutyl. In some embodiments, Ring D is cyclopentyl. In some embodiments, Ring D is partially saturated. In some embodiments, Ring D is
Figure imgf000028_0008
.
[0154] In some embodiments of a compound of Formula (I) or (Ia), t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, R10 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R10 is hydrogen, -CN, halogen, -CF3, methyl, ethyl, and butyl. In some embodiments, R10 is hydrogen. In some embodiments, R10 is -CN. In some embodiments, R10 is -F. In some embodiments, R10 is -CF3. In some embodiments, R10 is methyl. In some embodiments, R10 is ethyl. In some embodiments, R10 is propyl. In some embodiments, R10 is butyl. In some embodiments, R10 is pentyl. In some embodiments, R10 is hexyl. In some embodiments, R10 is heptyl. In some embodiments, R10 is octyl. In some embodiments, R10 is nonyl. In some embodiments, R10 is decyl. In some embodiments, R10 is isobutyl. In some embodiments, R10 is isopentyl. [0155] In some embodiments of a compound of Formula (I) or (Ia), R1 is
Figure imgf000029_0001
[0156] In some embodiments of a compound of Formula (I) or (Ia), Ring E is aryl. In some
embodiments, Ring E is phenyl. In some embodiments, Ring E is naphthyl.
[0157] In some embodiments of a compound of Formula (I) or (Ia), Ring E is bicyclic heteroaryl. In some embodiments, Ring E is bicyclic heteroaryl selected from indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl. In some embodiments, Ring E is indolyl, indazolyl, benzimidazolyl, quinazolinyl, or quinolinyl. In some embodiments, Ring E is indolyl. In some embodiments, Ring E is indazolyl. In some embodiments, Ring E is benzimidazolyl. In some embodiments, Ring E is quinazolinyl. In some embodiments, Ring E is quinolinyl.
[0158] In some embodiments of a compound of Formula (I) or (Ia), Ring E is cycloalkyl. In some embodiments, Ring E is cyclopropyl, cyclobutyl, cycolopentyl, or cyclohexyl. In some embodiments, Ring E is cyclohexyl. In some embodiments, Ring E is cyclopropyl. In some embodiments, Ring E is cyclobutyl. In some embodiments, Ring E is cyclopentyl.
[0159] In some embodiments of a compound of Formula (I) or (Ia), u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, R11 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R11 is hydrogen or -CF3. In some embodiments, R11 is hydrogen. In some embodiments, R11 is -CF3. In some embodiments, R11 is halogen. In some embodiments, R11 is -F. In some embodiments, R11 is -Cl. In some embodiments, R11 is -Br.
[0160] In some embodiments of a compound of Formula (I) or (Ia), R1 is
Figure imgf000029_0002
.
[0161] In some embodiments of a compound of Formula (I) or (Ia), Ring F is aryl. In some
embodiments, Ring F is phenyl. In some embodiments, Ring F is naphthyl.
[0162] In some embodiments of a compound of Formula (I) or (Ia), Ring F is heteroaryl.
[0163] In some embodiments of a compound of Formula (I) or (Ia), Ring F is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring F is imidazolyl, triazolyl, pyrazinyl furyl, quinolinyl, benzofuranyl, quinazolinyl, or pyridazinyl. In some embodiments, Ring F is furyl. In some embodiments, Ring F is benzofuranyl.
[0164] In some embodiments of a compound of Formula (I) or (Ia), Ring F is cycloalkyl. In some embodiments, Ring F is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Ring F is cyclohexyl. In some embodiments, Ring F is cyclopropyl. In some embodiments, Ring F is cyclobutyl. In some embodiments, Ring F is cyclopentyl.
[0165] In some embodiments of a compound of Formula (I) or (Ia), Ring F is heterocycloalkyl. In some embodiments, Ring F is a 5-membered heterocycloalkyl. In some embodiments, Ring F is a 6-membered heterocycloalkyl. In some embodiments, Ring F is heterocycloalkyl that contains at least one O atom. In some embodiments, Ring F is heterocycloalkyl that contains at least one O atom selected from
Figure imgf000030_0001
Ring
F is
Figure imgf000030_0002
In some embodiments, Ring F is
Figure imgf000030_0003
. In some embodiments, Ring F is
Figure imgf000030_0004
In some embodiments, Ring F is . In some embodiments, Ring F is
Figure imgf000030_0005
Figure imgf000030_0006
. In
some embodiments, Ring F is
Figure imgf000030_0007
. In some embodiments, Ring F i
Figure imgf000030_0008
s . In some
embodiments, Ring F is
Figure imgf000030_0009
. In some embodiments, Ring F is
Figure imgf000030_0010
In some
embodiments, Ring F is In some embodiments, Ring F is
Figure imgf000030_0011
. In some embodiments, Ring F is .
Figure imgf000030_0012
[0166] In some embodiments of a compound of Formula (I) or (Ia), v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, R12 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R12 is hydrogen, -CF3, methyl, or halogen. In some embodiments, R12 is hydrogen or -CF3. In some embodiments, R12 is hydrogen. In some embodiments, R12 is -CF3. In some embodiments, R12 is methyl. In some embodiments, R12 is halogen. In some embodiments, R12 is -F.
[0167] In some embodiments provided herein is a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000031_0001
wherein
Figure imgf000031_0002
one of X11 and X12 is N while the other is O;
one of Y11 and Y12 is -NH- or -O- while the other is -CH2-;
one of Y13 and Y14 is -S- while the other is -CH2-;
one of x' y' and z' is -O- while the others are -CH2-;
Ring A' is heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring B' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring C' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring D' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring E' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring F' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring G' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring H' is bicyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring J' is aryl;
R22 is hydrogen, -NH2, or halogen; each R29 and R30 is independently hydrogen, halogen, C1-C6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl;
each R23, R24, R25, R26, R27, R28, R31, R32 is independently hydrogen, halogen, -CF3, -CN, -ORa, -SRa, - S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, - CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ra is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rb is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each Rc and Rd is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or Rc and Rd, together with the nitrogen atom to which they are attached, form an substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
f is 1; h is 1-3; i is 1-3; j is 1-3; k is 1-3; l is 1-3; m is 1-3; o is 1-3; w is 1-3; and e is 1-3.
[0168] In some embodiments provided herein is a compound having the structure of Formula (II') or Formula (II''), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000032_0001
Formula (II'') wherein
R21 is halogen,
Figure imgf000032_0002
, , , ,
Figure imgf000033_0001
one of X11 and X12 is N while the other is O;
one of Y11 and Y12 is -NH- or -O- while the other is -CH2-;
one of Y13 and Y14 is -S- while the other is -CH2-;
one of x' y' and z' is -O- while the others are -CH2-;
Ring A' is heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring B' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring C' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring D' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring E' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring F' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring G' is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring H' is bicyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring I' is aryl,
Ring J' is aryl,
R22 is hydrogen, -NH2, or halogen;
R29 and R30 are independently hydrogen, halogen, C1-C6 alkyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl;
each R23, R24, R25, R26, R27, R28, R31, R32 , R33, R34 is independently hydrogen, halogen, -CF3, -CN, - ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, - OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, - NRaC(=O)Rb, -NRaC(=O)ORa, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ra is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Rb is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each Rc and Rd is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or Rc and Rd, together with the nitrogen atom to which they are attached, form an substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
f is 1; h is 1-3; i is 1-3; j is 1-3; k is 1-3; l is 1-3; m is 1-3; o is 1-3; w is 1-3; z is 1-3; and e is 1-3.
[0169] In some embodiments of a compound of Formula (II), X11 is O and X12 is N.
[0170] In some embodiments of a compound of Formula (II), X11 is N and X12 is O.
[0171] In some embodiments of a compound of Formula (II), (II '), or (II ' '), R22 is -NH2. In some embodiments, R22 is hydrogen. In some embodiments, R22 is a halogen. In some embodiments, R22 is -F, - Cl, or -Br.
[0172] In some embodiments of a compound of Formula (II), (II '), or (II ' '), f is 1.
[0173] In some embodiments, the compound of Formula (II) is of Formula (IIa) , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000034_0001
Formula (IIa).
[0174] In some embodiments, the compound of Formula (II) is of Formula (IIb) , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000034_0002
Formula (IIb).
[0175] In some embodiments, the compound of Formula (II) is of Formula (IIc) , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof:
Figure imgf000034_0003
Formula (IIc). [0176] In some embodiments a compound of Formula (II') or (II''), R21 is
Figure imgf000035_0001
. In some embodiments, Y11 is -O- and Y12 is -CH2-. In some embodiments, Y11 is -NH- and Y12 is -CH2-. In some embodiments, Y12 is -O- and Y11 is -CH2-. In some embodiments, Y12 is -NH- and Y11 is -CH2-.
[0177] In some embodiments of a compound of Formula (II') or (II''), Ring I' is aryl. In some embodiments, Ring I' is phenyl. In some embodiments, Ring I' is naphthyl.
[0178] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, R33 is hydrogen, methyl, or–F. In some embodiments, R33 is hydrogen. In some embodiments, R33 is methyl. In some
embodiments, R33 is a halogen. In some embodiments, R33 is -Cl. In some embodiments, R33 is -F. In some embodiments, R33 is -Br.
[0179] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ') or (II ''), R21 is -F. In some embodiments, R21 is -Cl. In some embodiments, R21 is -Br.
[0180] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), R21 is
Figure imgf000035_0002
. In some embodiments, Y11 is -O- and Y12 is -CH2-. In some embodiments, Y11 is -NH- and Y12 is -CH2-. In some embodiments, Y12 is -O- and Y11 is -CH2-. In some embodiments, Y12 is -NH- and Y11 is -CH2-.
[0181] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring A' is heteroaryl. In some embodiments, Ring A' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring A' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl. In some embodiments, Ring A' is pyridinyl. In some embodiments, Ring A' is isoxazolyl. In some embodiments, Ring A' is thienyl. In some embodiments, Ring A' is thiazolyl. In some embodiments, Ring A' is pyrazolyl. In some embodiments, Ring A' is pyrimidinyl. In some embodiments, Ring A' is furyl. In some embodiments, Ring A' is oxazolyl.
[0182] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring A' is cycloalkyl. In some embodiments, Ring A' is C3-C6 cycloalkyl. In some embodiments, Ring A' is cyclopropyl or cyclobutyl. In some embodiments, Ring A' is cyclohexyl. In some embodiments, Ring A' is cyclopropyl. In some embodiments, Ring A' is cyclobutyl. In some embodiments, Ring A' is cyclopentyl.
[0183] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ^ ^), Ring A' is heterocycloalkyl. In some embodiments, Ring A' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. In some embodiments, Ring A' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring A' is oxetanyl.
[0184] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ^ ^), h is 1. In some embodiments, h is 2. In some embodiments, h is 3. In some embodiments, R23 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R23 is hydrogen, methyl, or–F. In some embodiments, R23 is hydrogen. In some embodiments, R23 is methyl. In some embodiments, R23 is a halogen. In some embodiments, R23 is -Cl. In some embodiments, R23 is -F. In some embodiments, R23 is -Br.
[0185] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ^ ^), R21 is
Figure imgf000036_0001
.
[0186] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ^ ^), Ring B' is aryl. In some embodiments, Ring B' is phenyl. In some embodiments, Ring B' is naphthyl.
[0187] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ^ ^), Ring B' is heteroaryl. In some embodiments, Ring B' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring B' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl. In some embodiments, Ring B' is pyridinyl. In some embodiments, Ring B' is isoxazolyl. In some embodiments, Ring B' is thienyl. In some embodiments, Ring B' is thiazolyl. In some embodiments, Ring B' is pyrazolyl. In some embodiments, Ring B' is pyrimidinyl. In some embodiments, Ring B' is furyl.
[0188] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring B' is cycloalkyl. In some embodiments, Ring B' is C3-C6 cycloalkyl. In some embodiments, Ring B' is cyclopropyl. In some embodiments, Ring B' is cyclobutyl. In some embodiments, Ring B' is cyclopentyl. In some embodiments, Ring B' is cyclohexyl.
[0189] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring B' is heterocycloalkyl. In some embodiments, Ring B' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. In some embodiments, Ring B' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring B' is oxetanyl.
[0190] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), i is 1. In some embodiments, i is 2. In some embodiments, i is 3. In some embodiments, R24 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R24 is hydrogen, methyl, or–F. In some embodiments, R24 is hydrogen. In some embodiments, R24 is methyl. In some embodiments, R24 is a halogen. In some embodiments, R24 is -Cl. In some embodiments, R24 is -F. In some embodiments, R24 is -Br.
[0191] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), R21 is
Figure imgf000037_0001
.
[0192] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring C' is aryl. In some embodiments, Ring C' is phenyl. In some embodiments, Ring C' is naphthyl. [0193] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring C' is heteroaryl. In some embodiments, Ring C' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring C' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl. In some embodiments, Ring C' is pyridinyl. In some embodiments, Ring C' is isoxazolyl. In some embodiments, Ring C' is thienyl. In some embodiments, Ring C' is thiazolyl. In some embodiments, Ring C' is pyrazolyl. In some embodiments, Ring C' is pyrimidinyl. In some embodiments, Ring C' is furyl.
[0194] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring C' is cycloalkyl. In some embodiments, Ring C' is C3-C6 cycloalkyl. In some embodiments, Ring C' is cyclopropyl. In some embodiments, Ring C' is cyclobutyl. In some embodiments, Ring C' is cyclopentyl. In some embodiments, Ring C' is cyclohexyl.
[0195] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring C' is heterocycloalkyl. In some embodiments, Ring C' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. In some embodiments, Ring C' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring C' is oxetanyl.
[0196] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), j is 1. In some embodiments, j is 2. In some embodiments, j is 3. In some embodiments, R25 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R25 is hydrogen, methyl, or -F. In some embodiments, R25 is hydrogen. In some embodiments, R25 is methyl. In some embodiments, R25 is a halogen. In some embodiments, R25 is -Cl. In some embodiments, R25 is -F. In some embodiments, R25 is -Br.
Figure imgf000039_0001
[0202] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, R26 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R26 is hydrogen, methyl, or -F. In some embodiments, R26 is hydrogen. In some embodiments, R26 is methyl. In some embodiments, R26 is a halogen. In some embodiments, R26 is -Cl. In some embodiments, R26 is -F. In some embodiments, R26 is -Br.
[0203] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), R21 is
Figure imgf000040_0001
some embodiments, x' is O; y' is -CH2-; and z' is -CH2-. In some embodiments, x' is -CH2-; y' is -O-; and z' is -CH2-. In some embodiments, x' is -CH2-; y' is -CH2-; and z' is -O-.
[0204] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring E' is aryl. In some embodiments, Ring E' is phenyl. In some embodiments, Ring E' is naphthyl.
[0205] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring E' is heteroaryl. In some embodiments, Ring E' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring E' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl. In some embodiments, Ring E' is pyridinyl. In some embodiments, Ring E' is isoxazolyl. In some embodiments, Ring E' is thienyl. In some embodiments, Ring E' is thiazolyl. In some embodiments, Ring E' is pyrazolyl. In some embodiments, Ring E' is pyrimidinyl. In some embodiments, Ring E' is furyl.
[0206] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring E' is cycloalkyl. In some embodiments, Ring E' is C3-C6 cycloalkyl. In some embodiments, Ring E' is cyclopropyl. In some embodiments, Ring E' is cyclobutyl. In some embodiments, Ring E' is cyclopentyl. In some embodiments, Ring E' is cyclohexyl.
[0207] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring E' is heterocycloalkyl. In some embodiments, Ring E' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. In some embodiments, Ring E' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring E' is oxetanyl.
[0208] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), l is 1. In some embodiments, l is 2. In some embodiments, l is 3. In some embodiments, R27 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R27 is hydrogen, methyl, or -F. In some embodiments, R27 is hydrogen. In some embodiments, R27 is methyl. In some embodiments, R27 is a halogen. In some embodiments, R27 is -Cl. In some embodiments, R27 is -F. In some embodiments, R27 is -Br.
[0209] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), R21 is
Figure imgf000041_0001
.
[0210] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring F' is aryl. In some embodiments, phenyl. In some embodiments, Ring F' is naphthyl.
[0211] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring F' is heteroaryl. In some embodiments, Ring F' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring F' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl. In some embodiments, Ring F' is pyridinyl. In some embodiments, Ring F' is isoxazolyl. In some embodiments, Ring F' is thienyl. In some embodiments, Ring F' is thiazolyl. In some embodiments, Ring F' is pyrazolyl. In some embodiments, Ring F' is pyrimidinyl. In some embodiments, Ring F' is furyl.
[0212] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ''), Ring F' is cycloalkyl. In some embodiments, Ring F' is C3-C6 cycloalkyl. In some embodiments, Ring F' is cyclopropyl. In some embodiments, Ring F' is cyclobutyl. In some embodiments, Ring F' is cyclopentyl. In some embodiments, Ring F' is cyclohexyl. [0213] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ' '), Ring F' is heterocycloalkyl. In some embodiments, Ring F' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. In some embodiments, Ring F' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring F' is oxetanyl.
[0214] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ^ ^), m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, R28 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R28 is hydrogen, methyl, or -F. In some embodiments, R28 is hydrogen. In some embodiments, R28 is methyl. In some embodiments, R28 is a halogen. In some embodiments, R28 is -Cl. In some embodiments, R28 is -F. In some embodiments, R28 is -Br.
[0215] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ' '), R21 is
Figure imgf000042_0001
.
[0216] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ' '), Ring G' is aryl. In some embodiments, Ring G' is phenyl. In some embodiments, Ring G' is naphthyl.
[0217] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ' '), Ring G' is heteroaryl. In some embodiments, Ring G' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring G' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl. In some embodiments, Ring G' is pyridinyl. In some embodiments, Ring G' is isoxazolyl. In some embodiments, Ring G' is thienyl. In some embodiments, Ring G' is thiazolyl. In some embodiments, Ring G' is pyrazolyl. In some embodiments, Ring G' is pyrimidinyl. In some embodiments, Ring G' is furyl.
[0218] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), Ring G' is cycloalkyl. In some embodiments, Ring G' is C3-C6 cycloalkyl. In some embodiments, Ring G' is cyclopropyl. In some embodiments, Ring G' is cyclobutyl. In some embodiments, Ring G' is cyclopentyl. In some embodiments, Ring G' is cyclohexyl.
[0219] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), Ring G' is heterocycloalkyl. In some embodiments, Ring G' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. In some embodiments, Ring G' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring G' is oxetanyl.
[0220] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, R31 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R31 is hydrogen, methyl, or -F. In some embodiments, R31 is hydrogen. In some embodiments, R31 is methyl. In some embodiments, R31 is a halogen. In some embodiments, R31 is -Cl. In some embodiments, R31 is -F. In some embodiments, R31 is -Br.
[0221] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), R21 is
Figure imgf000043_0001
.
[0222] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), Ring H' is bicyclic aryl. In some embodiments, Ring H' is naphthyl.
[0223] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), Ring H' is heteroaryl. In some embodiments, Ring H' is heteroaryl selected from azaindolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, Ring H' is heteroaryl selected from pyridinyl, isoxazolyl, thienyl, thiazolyl, pyrazolyl, pyrimidinyl, furyl, and oxazolyl. In some embodiments, Ring H' is pyridinyl. In some embodiments, Ring H' is isoxazolyl. In some embodiments, Ring H' is thienyl. In some embodiments, Ring H' is thiazolyl. In some embodiments, Ring H' is pyrazolyl. In some embodiments, Ring H' is pyrimidinyl. In some embodiments, Ring H' is furyl.
[0224] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), Ring H' is cycloalkyl. In some embodiments, Ring H' is C3-C6 cycloalkyl. In some embodiments, Ring H' is cyclopropyl. In some embodiments, Ring H' is cyclobutyl. In some embodiments, Ring H' is cyclopentyl. In some embodiments, Ring H' is cyclohexyl.
[0225] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), Ring H' is heterocycloalkyl. In some embodiments, Ring H' is heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. In some embodiments, Ring H' is heterocycloalkyl selected from tetrahydrofuranyl, piperazinyl, oxetanyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, and quinolizinyl. In some embodiments, Ring H' is oxetanyl.
[0226] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II ^), or (II ^ ^), w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, R32 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R32 is hydrogen, methyl, or -F. In some embodiments, R32 is hydrogen. In some embodiments, R32 is methyl. In some embodiments, R32 is a halogen. In some embodiments, R32 is -Cl. In some embodiments, R32 is -F. In some embodiments, R32 is -Br.
[0227] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II’) or (II”), R21 is
Figure imgf000044_0001
. In some embodiments, R29 is hydrogen and R30 is hydrogen. In some embodiments, R29 is hydrogen and R30 is hydrogen. In some embodiments, R29 is C1-C6 alkyl and R30 is hydrogen. In some embodiments, R29 is C1-C6 alkyl and R30 is C1-C6 alkyl. In some embodiments, R29 is hydrogen and R30 is C1-C6 alkyl. In some embodiments, R29 is hydrogen and R30 is cycloalkyl. In some embodiments, R29 is hydrogen and R30 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R30 is hydrogen and R29 is cycloalkyl. In some embodiments, R30 is hydrogen and R29 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0228] In some embodiments a compound of Formula (II), (IIa), (IIb), (IIc), (II’) or (II”), R21 is
Figure imgf000045_0001
.
[0229] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II’) or (II”), Ring J' is aryl. In some embodiments, Ring J' is phenyl. In some embodiments, Ring J' is naphthyl.
[0230] In some embodiments of a compound of Formula (II), (IIa), (IIb), (IIc), (II '), or (II ' '), e is 1. In some embodiments, e is 2. In some embodiments, e is 3. In some embodiments, R34 is hydrogen, methyl, or–F. In some embodiments, R34 is hydrogen. In some embodiments, R34 is methyl. In some embodiments, R33 is a halogen. In some embodiments, R34 is -Cl. In some embodiments, R34 is -F. In some embodiments, R34 is -Br.
[0231] In one aspect, described herein is a compound of Formula (III-C), or a solvate, hydrate, or a deuterated variant thereof:
Figure imgf000045_0002
X15 is–O–,–NH–,–S–,–SO2–, or a bond;
L is a bond or substituted or unsubstituted C1-6 alkylene;
Ring Q is monocyclic 6-membered heteroaryl, monocyclic 5-membered heteroaryl, bicyclic heteroaryl, phenyl, naphthyl, monocyclic cycloalkyl, bicyclic cycloalkyl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl; X13 is C(R1B) or N;
X14 is C(R1B) or N;
each R1B and R10A is independently hydrogen, halogen, -CF3, -CN, -CH2-OH, -ORa, -SRa, - S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, - CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ra is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6
alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Rb is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl,
substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rc and Rd is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
z3 is 1, 2, or 3,
wherein the compound of Formula (III-C) is not (2-amino-3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate.
[0232] In another aspect, described herein is a pharmaceutically acceptable salt of a compound of Formula (III-C), or a solvate, hydrate, or a deuterated variant thereof.
[0233] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (III-C), or a solvate, hydrate, or a deuterated variant thereof is prepared by reacting a compound of Formula (III-C) with ammonia, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, sodium hydroxide, sodium hydroxide followed by calcium acetate, calcium hydroxide, potassium hydroxide, or phosphoric acid. Other pharmaceutically acceptable salts of a compound of Formula (III-C), or a solvate, hydrate, or a deuterated variant thereof are described herein.
[0234] In some embodiments, each R1B is independently hydrogen, halogen, -CF3, -CN, -CH2-OH, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, - CO2Ra, -C(=O)NRcRd, -NRaC(=O)Rb, or substituted or unsubstituted C1-C6 alkyl.
[0235] In some embodiments, X13 is CH, CF or N; and X14 is CH, CF or N. [0236] In some embodiments, the compound of Formula (III-C) has the following structure:
Figure imgf000047_0001
or a solvate, hydrate, or a deuterated variant thereof.
[0237] In some embodiments, the compound of Formula (III-C) has the following structure:
Figure imgf000047_0002
or a solvate, hydrate, or a deuterated variant thereof.
[0238] In some embodiments, the compound of Formula (III-C) has the following structure:
Figure imgf000047_0003
or a solvate, hydrate, or a deuterated variant thereof.
[0239] In some embodiments, R1B is hydrogen of F; and X14 is CH, CF, or N.
[0240] In some embodiments, R1A i
Figure imgf000047_0004
s ; X15 is–O–,–NH–,–S–,–SO2–, or a bond; and L is a bond, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, - CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.
[0241] In some embodiments, R1A is
Figure imgf000047_0005
; and X15 is–O–,–NH–,–S–,–SO2–, or a bond; and L is a bond, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, - CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. [0242] In some embodiments, X15 is–O–,–NH–, or a bond; and L is a bond, -CH2-, or -CH2CH2-.
[0243] In some embodiments, X15 is–O–,–NH–, or a bond; and L is a bond or -CH2-.
[0244] In some embodiments, X15 is–O–.
[0245] In some embodiments, X15 is–NH-.
[0246] In some embodiments, X15 is a bond.
[0247] In some embodiments, Ring Q is monocyclic 6-membered heteroaryl, monocyclic 5-membered heteroaryl, bicyclic heteroaryl, phenyl, naphthyl, C3-C6 cycloalkyl, or 3- to 6-membered
heterocycloalkyl.
[0248] In some embodiments, Ring Q is monocyclic 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; or Ring Q is monocyclic 5- membered heteroaryl selected from the group consisting of imidazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, and thiadiazolyl; or Ring Q is phenyl or naphthyl; or Ring Q is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or Ring Q is aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl; or Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl, and pteridinyl.
[0249] In some embodiments, Ring Q is pyridinyl.
[0250] In some embodiments, Ring Q is phenyl.
[0251] In some embodiments, Ring Q is monocyclic 5-membered heteroaryl selected from the group consisting of imidazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, and thiadiazolyl.
[0252] In some embodiments, Ring Q is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0253] In some embodiments, Ring Q is azetidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydropyranyl, and thiomorpholinyl.
[0254] In some embodiments, Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
[0255] In some embodiments, R10A is selected from the group consisting of hydrogen, F, Cl, Br, -CF3, - CN, -CH2-OH, -OH, -OCH3, -OCH2CH3 -OCH(CH3 )2, -OC(CH3)3, -OCF3, methyl, ethyl, isopropyl, isobutyl, and butyl; z3 is 1 or 2.
In some embodiments, described herein is a [0256] In some embodiments, the compound of Formula (III) is not (2-amino-3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate or a compound having structural formula:
Figure imgf000049_0001
Compound 1.
[0257] In some embodiments, the compound of Formula (III) is not 3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine or a compound having structural formula:
Figure imgf000049_0002
Compound 2.
[0258] In some embodiments, disclosed herein in a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure selected from the compounds in Table 1.
Table 1.
Figure imgf000049_0003
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [0259] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, 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. In some embodiments, dissociable complexes are preferred. In some embodiments, 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
[0260] 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. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, 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. Examples of isotopes that can be incorporated into compounds of Formula (I), (II), or (III), or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, l5N, 180, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method. [0261] In some embodiments, 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.
Prodrugs
[0262]“Prodrug” is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term“prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam). Prodrugs are delivered through any known methods described herein, including but not limited to orally, intravenously, intraperitoneal, or other method of administration known by those skilled in the art.
[0263] A discussion of prodrugs is provided in Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
[0264] The term“prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. In some embodiments, prodrugs include any group bound to a heteroatom, such as the nitrogen of a pyridine which is cleaved in-vivo to form the active compound or metabolite thereof. Examples of prodrugs include, but are not limited to, acetate, formate phosphate, and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
[0265] In some embodiments, a prodrug of a pyridine compound described herein is a phosphate prodrug. In some embodiments, a prodrug of a pyridine compound described herein is an alkyl phosphate prodrug. In some embodiments, an alkyl phosphate prodrug of a pyridine compound described herein is formed with the nitrogen atom of the pyridine ring. In some embodiments, described herein are methyl hydrogen phosphate prodrugs of pyridine antifungal compounds. In some embodiments, described herein are pyridin-1-ium-1-ylmethyl hydrogen phosphate prodrugs. In some embodiments, the pyridin-1- ium-1-ylmethyl hydrogen phosphate prodrugs are substituted pyridin-1-ium-1-yl)methyl hydrogen phosphate.
[0266] In some embodiments, prodrugs described herein are substituted (2-amino-3-(3-benzylisoxazol- 5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds. In some embodiments, prodrugs described herein are substituted (2-amino-3-(3-benzylisoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds, wherein the (2-amino-3-(3-benzylisoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds are substituted at the 4-position of the benzyl group with R1A.
[0267] In some embodiments, prodrugs described herein are substituted (2-amino-3-(3-((pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds. In some embodiments, prodrugs described herein are substituted (2-amino-3-(3-((pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds, wherein the (2-amino-3-(3-((pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate compounds are substituted at the 6-position of the (pyridin-3-yl) with with R1A.
[0268] Formula (III) describes both parent compounds (when W is N) and methyl hydrogen phosphate prodrugs (when W is -N+– CH2OPO3H–).
[0269] The term“isotopic variant” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen- 15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine- 79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an“isotopic variant” of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon- 12 (12C), carbon-13 (13C), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), and iodine- 127 (127I). In certain embodiments, an“isotopic variant” of a compound is in an unstable form, that is, radioactive. In certain embodiments, an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus- 33 (33P), sulfur-35 (35S), chlorine-36 (36Cl), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be 2H, for example, or any carbon can be 13C, for example, or any nitrogen can be 15N, for example, or any oxygen can be 18O, for example, where feasible according to the judgment of one of skill. In certain embodiments, an“isotopic variant” of a compound contains unnatural proportions of deuterium (D). Pharmaceutically Acceptable Salts
[0270] 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.
[0271] In some embodiments, 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. In some embodiments, 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.
[0272] 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, hydroxybenzoate, g-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate,
tosylateundeconate, and xylenesulfonate.
[0273] Further, 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-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
[0274] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, 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. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.
[0275] 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
[0276] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
[0277] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents 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. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, 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
[0278] 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. Some examples of tautomeric interconversions include:
Figure imgf000114_0001
Pharmaceutical Compositions
[0279] In certain embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B) as described herein is administered as a pure chemical. In some embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B) 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
[0280] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B) described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, together with one or more
pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
[0281] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[0282] In certain embodiments, the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B) 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.
[0283] 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. In general, 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, sex, age, renal status, hepatic status, or blood volume of the patient.
[0284] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day, or one to four times per week
[0285] In some embodiments, the compounds contemplated by the present disclosure may be administered (e.g., orally) at dosage levels of about 0.01 mg/kg to about 1000 mg/kg, or about 1 mg/kg to about 50 mg/kg, of subject body weight per day, one, two, three, four or more times a day, to obtain the desired therapeutic effect. For administration of an oral agent, the compositions can be provided in the form of tablets, capsules and the like containing from 0.05 to 1000 milligrams of the active ingredient, particularly 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0, 175.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient. Pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s) may be present in an amount of from about 0.1 g to about 2.0 g.
Methods of Treatment
[0286] Disclosed herein, in certain embodiments, are methods for treating a fungal disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B) at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
[0287] Disclosed herein, in certain embodiments, are methods for treating a fungal disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, comprising compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B), and at least one pharmaceutically acceptable excipient, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
Fungal Diseases
[0288] In some embodiments, the fungal disease is selected from the group consisting of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (Valley Fever), cryptococcosis, fungal eye infection, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), ringworm, sporotrichosis, and talaromycosis.
[0289] In some embodiments, the fungal disease is aspergillosis. In some embodiments, aspergillosis is allergic bronchopulmonary aspergillosis (abpa), allergic aspergillus sinusitis, chronic pulmonary aspergillosis, invasive aspergillosis or cutaneous (skin) aspergillosis. In some embodiments, the subject has an aspergilloma.
[0290] In some embodiments, the fungal disease is blastomycosis. [0291] In some embodiments, the fungal disease is candidiasis. In some embodiments, candidiasis is oropharyngeal candidiasis (thrush), vulvovaginal candidiasis (vaginal candidiasis), fungemia, or invasive candidiasis.
[0292] In some embodiments, the fungal disease is coccidioidomycosis (Valley Fever). In some embodiments, coccidioidomycosis is acute coccidioidomycosis (primary pulmonary
coccidioidomycosis), chronic coccidioidomycosis, or disseminated coccidioidomycosis, including primary cutaneous coccidioidomycosis.
[0293] In some embodiments, the fungal disease is cryptococcosis. In some embodiments,
cryptococcosis is wound or cutaneous cryptococcosis, pulmonary cryptococcosis, or cryptococcal meningitis.
[0294] In some embodiments, the fungal disease is a fungal eye infection. In some embodiments, the fungal eye infection is fungal keratitis, fungal exogenous endophthalmitis, or fungal endogenous endophthalmitis.
[0295] In some embodiments, the fungal disease is histoplasmosis. In some embodiments,
histoplasmosis is acute histoplamosis. In some embodiments, histoplamosis is chronic histoplamosis.
[0296] In some embodiments, the fungal disease is mucormycosis. In some embodiments,
mucormycosis is rhinocerebral (sinus and brain) mucormycosis, pulmonary (lung) mucormycosis, gastrointestinal mucormycosis, cutaneous (skin) mucormycosis, or disseminated mucormycosis.
[0297] In some embodiments, the fungal disease is Pneumocystis pneumonia (PCP).
[0298] In some embodiments, the fungal disease is ringworm. In some embodiments, the ringworm is tinea pedis, tinea cruris, tinea capitis, tinea barbae, tinea manuum, tinea unguium, or tinum corporis. In some embodiments, the ringworm is caused by a type of fungi including Trichophyton, Microsporum, or Epidermophyton.
[0299] In some embodiments, the fungal disease is sporotrichosis. In some embodiments, sporotrichosis is cutaneous (skin) sporotrichosis, pulmonary (lung) sporotrichosis, or disseminated sporotrichosis.
[0300] In some embodiments, the fungal disease is talaromycosis.
[0301] In some embodiments, the fungal disease is caused by a fungal species including, but not limited to, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Blastomyces dermatitidis, Ajellomyces dermatitidis, Candida albicans, Candida auris, Candida glabrata, Candida parapsilosis, Candida rugosa, Candida tropicalis, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species, Basidiobolus species, Sporothrix schenckii, Pneumocystis jirovecii, Talaromyces marneffei, Asclepias albicans, Fusarium solani, Scedosporium apiospermum, and Rhizomucor pusillus.. In some embodiments, the fungal disease is caused by the fungal species Aspergillus fumigatus. In some embodiments, the fungal disease is caused by the fungal species Candida albicans. In some embodiments, the fungal disease is caused by the fungal species Fusarium solani. In some embodiments, the fungal disease is caused by the fungal species Mucor indicus. In some embodiments, the fungal disease is caused by the fungal species Scedosporium apiospermum. In some embodiments, the fungal disease is caused by the fungal species Cryptococcus neoformans. In some embodiments, the fungal disease is caused by the fungal species Cryptococcus gattii. In some embodiments, the fungal disease is caused by the fungal species Candida auris.
[0302] In an aspect provided herein, there is a method of treating a fungal disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B). In an aspect provided herein, there is a method of treating a fungal disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B) and at least one pharmaceutically acceptable excipient.
[0303] In some embodiments of the methods disclosed herein, the fungal disease is selected from the group consisting of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (Valley Fever), cryptococcosis, fungal eye infection, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), ringworm, sporotrichosis, and talaromycosis.
[0304] In some embodiments of the methods disclosed herein, the fungal disease is caused by a fungal species selected the group consisting of Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatitidis, Ajellomyces dermatitidis, Candida albicans, Candida glabrata, Candida rugosa, Candida auris, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species, Basidiobolus species, Sporothrix schenckii, Pneumocystis jirovecii, Talaromyces marneffei, Asclepias albicans, Fusarium solani, Scedosporium apiospermum, and Rhizomucor pusillus.
[0305] In some embodiments of the methods disclosed herein, the subject is immunocompromised.
[0306] In some embodiments of the methods disclosed herein, the subject has received chemotherapy treatment.
[0307] In some embodiments of the methods disclosed herein, the subject is infected with HIV/AIDS.
[0308] In some embodiments of the methods disclosed herein, the fungal disease is caused by
Cryptococcus neoformans or Cryptococcus gattii.
[0309] In some embodiments of the methods disclosed herein, the compound is selected from the compounds in Table 1. In some embodiments of the methods disclosed herein, the compound is selected from the compounds in Table 2.
[0310] In some embodiments of the methods disclosed herein, the compound is selected from:
3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((6-chloropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((3-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine; 3-(3-(4-((3,5-difluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(3-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((5-fluorofuran-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-phenoxypyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-((3-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2-fluorophenyl)pyridin-2-amine;
5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,6-difluorophenyl)pyridin-2-amine;
3-(3-(4-benzylbenzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((6-fluoropyridin-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(3,5-difluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(cyclopropylmethoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-(3,5-difluorobenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((2-((3-fluorobenzyl)oxy)pyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-(3-fluorobenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine; and
3-(3-(4-(((3-fluorophenyl)amino)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, a stereoisomer, mixture of stereoisomers, or an isotopic variant thereof.
[0311] In some embodiments, a compound described herein is active against the fungal Gwt1 protein. This conserved enzyme catalyzes the glycosylphosphatidyl inositol (GPI) post-translational modification that anchors eukaryotic cell surface proteins to the cell membrane. In yeasts, GPI mediates cross-linking of cell wall mannoproteins to b-1,6-glucan. Inhibition of this enzyme in both Candida albicans and Saccharomyces cerevisiae has been shown to result in inhibition of maturation and localization of GPI- anchored mannoproteins thus demonstrating pleiotropic effects that include inhibition of fungal adherence to surfaces, inhibition of biofilm formation, inhibition of germ tube formation, severe growth defects, or lethality.
Subjects
[0312] In some embodiments, the subject is immunocompromised. In some embodiments, the subject is an immunocompromised human subject. In some embodiments, the human subject is under the age of 1 year. In some embodiments, the human subject is an infant under 1 month old. In some embodiments, the human subject is over the age of 70 years. In some embodiments, the subject is infected with HIV/AIDS. In some embodiments, the subject is undergoing or has undergone cancer chemotherapy treatment. In some embodiments, the subject is undergoing or has undergone corticosteroid treatment. In some embodiments, the subject is undergoing or has undergone TNF inhibitor treatment. In some
embodiments, the subject is a transplant recipient. In some embodiments, the subject is a recipient of a hematopoietic stem-cell transplant, bone marrow transplant, lung transplant, liver transplant, heart transplant, kidney transplant, pancreas transplant or a combination thereof. In some embodiments, the subject is a recipient of a hematopoietic stem-cell transplant. In some embodiments, the subject is a recipient of a bone marrow transplant. In some embodiments, the subject is a recipient of a lung transplant. In some embodiments, the subject is a recipient of a liver transplant. In some embodiments, the subject is a recipient of a heart transplant. In some embodiments, the subject is a recipient of a kidney transplant. In some embodiments, the subject is a recipient of a pancreas transplant.
[0313] In some embodiments, the subject is a vertebrate. In some embodiments, the vertebrate is a fish, an amphibian, a reptile, a bird, a marsupial, or a mammal. In some embodiments, the subject is a fish. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the mammal is livestock. In some embodiments, the livestock is selected from the group consisting of cattle, sheep, goats, swine, poultry, bovine, and equine animals. In some embodiments, the subject is an invertebrate. In some embodiments, the invertebrate is an insect. In some embodiments, the invertebrate is a plant.
Combination Therapy
[0314] In certain instances, the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent.
[0315] In some embodiments, the benefit experienced by a subject 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.
[0316] In one specific embodiment, a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is co- administered with a second therapeutic agent, wherein the compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, 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.
[0317] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the subject is simply additive of the two therapeutic agents or the subject experiences a synergistic benefit.
[0318] In certain embodiments, 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. Furthermore, 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. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, 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 of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a
pharmaceutically acceptable salt, solvate, 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.
[0319] It is understood that 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). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
[0320] For combination therapies described 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. In additional embodiments, when co-administered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially.
[0321] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) 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).
[0322] The compounds of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II ^), (II ^ ^), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, 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. Thus, in one embodiment, 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. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, 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. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
[0323] In certain embodiments, the second therapeutic agent is antifungal agent. In some embodiments, the second therapeutic agent is an antifungal agent selected from the group consisting of: a polyene antifungal agent, an azole antifungal agent, an allylamine antifungal agent, and an echinocandin antifungal agent.
[0324] In some embodiments, the polyene antifungal agent is selected from the group consisting of: Amphotericin B, Candicidin, Filipin, Hamycin, Natamycin, Nystatin, and Rimocidin.
[0325] In some embodiments, the azole antifungal agent is selected from the group consisting of: an imidazole, a triazole, and a thiazole. In some embodiments, the imidazole is selected from the group consisting of: Bifonazole, Butoconazole, Clotrimazole, Econazole, Fenticonazole, Isoconazole,
Ketoconazole, Luliconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, and Tioconazole. In some embodiments, the triazole is selected from the group consisting of: Albaconazole, Efinaconazole, Epoxiconazole, Fluconazole, Isavuconazole, Itraconazole, Posaconazole, Propiconazole, Ravuconazole, Terconazole, and Voriconazole. In some embodiments, the thiazole is Abafungin.
[0326] In some embodiments, the allylamine antifungal agent is selected from the group consisting of: Amorolfin, Butenafine, Naftifine, and Terbinafine.
[0327] In some embodiments, the echinocandin antifungal agent is selected from the group consisting of: Anidulafungin, Caspofungin, Micafungin and Rezafungin.
[0328] In some embodiments, are methods for treating a subject with a fungal disease comprising administering to the subject a combination treatment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and fluconazole, wherein the subject is selected from the group consisting of cattle, sheep, goats, swine, poultry, bovine, and equine animals.
[0329] In some embodiments, are methods for treating a subject with a fungal disease comprising administering to the subject a combination treatment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and ketoconazole, wherein the subject is selected from the group consisting of cattle, sheep, goats, swine, poultry, bovine, and equine animals.
[0330] In some embodiments, are methods for treating a subject with a fungal disease comprising administering to the subject a combination treatment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (II '), (II ' '), (III), (IIIa), or (III-B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and itraconazole, wherein the subject is selected from the group consisting of cattle, sheep, goats, swine, poultry, bovine, and equine animals. EXAMPLES
Example I: Chemical Synthesis
[0331] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Intermediate A: Synthesis of di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2- yl]imidodicarbonate
Figure imgf000122_0001
Step 1: tert-butyl (3-acetylpyridin-2-yl)carbamate:
[0332] 1-(2-Aminopyridin-3-yl)ethan-1-one (5 g, 37 mmol) was dissolved in tert-butyl alcohol (20 mL), and then di-tert-butyl dicarbonate (12 g) was added. The mixture was heated to 90◦C for 3 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to give a dark-tan solid. The crude material was washed with a mixture of heptane and hexane, and then filtered. The solid was manually crushed, and again washed with heptane and hexane. The solid was air-dried, then extensively vacuum-dried to give the title compound as a tan solid (7.8 g, 90%). This material was taken forward without further purification.
Step 2: Ethyl 5-(2-aminopyridin-3-yl)isoxazole-3-carboxylate:
[0333] To a solution of tert-butyl (3-acetylpyridin-2-yl)carbamate (7.7 g, 33 mmol) and diethyl oxalate (8.9 mL, 65 mmol) in toluene (65 mL) was added potassium tert-butoxide (7.3 g, 65 mmol) portion-wise at room temperature. The dark-purple heterogeneous mixture was stirred under nitrogen and began to form a thick precipitate. An additional 65 mL of toluene was added, and the mixture was stirred for another 2 hours before adding an additional 3.7 g of potassium tert-butoxide. After stirring another 1 hour, ethanol (130 mL) was added followed by hydroxylamine hydrochloride (6.8 g, 98 mmol). The resulting burnt-orange-colored mixture was stirred for 2 hours, and then water (13 mL) was added. The solution briefly cleared somewhat, and then became a thick caramel-color. The mixture was stirred for 16 hours and gradually became a yellowish color. Another 400 mL of water was added and 500 mL of ethyl acetate. The layers were separated. The organic phase was washed with water (2x150 mL). The combined aqueous phase was extracted with ethyl acetate (2x250 mL). The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give an orange solid. To the solid product was added DMF (65 mL) and triethylamine (4.5 mL, 33 mmol). The solution was stirred at 80◦C for 6 hours, and then allowed to gradually reach room temperature overnight. Water (300 mL) was added and the solution was extracted with ethyl acetate, and then evaporated to give an orange oily solid. The crude material was treated with warm hexane/acetone (15:1) which resulted in a deep orange solution over a solid material. The solid was collected by filtering through a sintered glass funnel and washed with copious amounts of hexane. This gave the title compound as a free-flowing tannish pale-orange solid (4 g, 53%) which was taken forward without further purification.
Step 3: (5-(2-Aminopyridin-3-yl)isoxazol-3-yl)methanol:
[0334] To a suspension of ethyl 5-(2-aminopyridin-3-yl)isoxazole-3-carboxylate (0.50 g, 2.1 mmol) in a 1:1 mixture of THF/ethanol (10 mL) at 0◦C was added sodium borohydride (0.24 g, 6.4 mmol) in portions. The cold bath was removed, and the mixture was stirred at room temperature for 19 hours with occasional monitoring by TLC. Another 0.5 equivalents of sodium borohydride (0.040 g, 1.0 mmol) was added to the mixture. After stirring briefly the mixture was quenched by pouring into ice followed by slow cautious addition of aqueous 5N HCl solution (2 mL)– vigorous reaction. The acidic solution (pH 3) was stirred for 10 min, then basified to pH 9 with aqueous 5N NaOH solution. The basic mixture was extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give the title compound as a yellow solid (0.32 g, 77%). This material was taken forward without further purification.
Step 4: 3-(3-(Chloromethyl)isoxazol-5-yl)pyridin-2-amine:
[0335] To a mixture of (5-(2-aminopyridin-3-yl)isoxazol-3-yl)methanol (0.31 g, 1.6 mmol) in N,N- dimethylacetamide (1.6 mL) at 0◦C was added a cold mixture of thionyl chloride (0.24 mL, 3.3 mmol) and benzotriazole (0.43 g, 3.6 mmol) in tetrahydrofuran. The cold bath was removed, and the mixture was stirred at room temperature. TLC after 30 min indicated complete reaction. The mixture was quenched by pouring into ice followed by basification to pH 8 with aqueous 5N NaOH. The mixture was then extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give the title compound as an oil which will be taken forward without further purification.
Step 5: Di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate:
[0336] To a solution of 3-(3-(chloromethyl)isoxazol-5-yl)pyridin-2-amine (0.34 g, 1.6 mmol, based on theoretical yield of previous reaction) in tetrahydrofuran was added N,N-dimethylaminopyridine (0.020 g, 0.16 mmol) and di-tert-butyl dicarbonate (0.75 g, 3.4 mmol). The homogeneous solution was stirred at room temperature and gradually changed color from orange to red. LCMS and TLC after 2h suggested only partially completed conversion, and there was little improvement after 19h. Another 0.6 equivalents of di-tert-butyl dicarbonate (0.20 g, 0.92 mmol) was added and the mixture stirred for another 2h. The reaction was quenched with water and extracted three times with toluene. The combined organic phase was washed with diluted brine, dried over sodium sulfate, and evaporated under reduced pressure to give a red oil. The oil was further purified using Biotage normal-phase flash chromatography (50 g SNAP Ultra, 2-40% ethyl acetate in hexanes). The desired fractions were combined and evaporated to give the title compound as a white solid (0.53 g, 80% yield over two steps). 400 MHz 1H NMR (CDCl3) d 8.50 (dd, J = 4.8, 1.8 Hz, 1H), 8.18 (dd, J = 7.9, 1.8 Hz, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 6.56 (s, 1H), 4.52 (s, 2H), 1.21 (s, 18H); 125 MHz 13C NMR (CDCl3) d 165.7, 161.6, 150.2, 150.0, 148.5, 136.6, 123.6, 121.5, 102.4, 83.5, 35.2, 27.6 ppm. MS: 410.5 [M+H]+.
Intermediate B: Synthesis of 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000124_0001
[0337] Di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 1.00g, 2.44mmol) and 2-((4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl)oxy)pyridine (0.87g, 2.93mmol) were mixed in DME (15mL) in a sealable tube. A 2M solution of sodium carbonate in water (2.81mL, 5.62mmol) and palladium tetrakis triphenylphosphine (226mg, 0.195mmol) were added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 4h at 100°C. The cooled reaction mixture was poured into ethyl acetate (400ml) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate, to which was added formic acid (10mL). The resulting mixture was stirred for 8h at 21-25°C to complete the di-Boc de-protection. The mixture was poured into ice-water (150mL) containing K3PO4 (37g) and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude residue containing 3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine. The residue was dissolved in dioxane (10mL) and concentrated HCl (12M; 1ml, 12mmol) was added. The mixture was heated under reflux for 2h. The cooled mixture was poured into an ice-cold pH7 phosphate buffer solution (0.5M, 100mL) containing an additional amount of NaOH (480mg, 12mmol) to neutralize the excess of HCl. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-(4-(chloromethyl)benzyl)isoxazol-5- yl)pyridin-2-amine (280mg, 0.93mmol, 38% overall yield) as a white solid.400 MHz 1H NMR (CDCl3) d 8.13 (dd, J = 4.9, 1.8 Hz, 1H), 7.70 (dd, J = 7.7, 1.8 Hz, 1H), 7.40– 7.32 (m, 2H), 7.32– 7.25 (m, 2H), 6.70 (dd, J = 7.7, 4.9 Hz, 1H), 6.25 (s, 1H), 5.44 (s, 3H), 4.57 (s, 2H), 4.06 (s, 2H). MS: 300.4 [M+H]+. Intermediate C: Synthesis of 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol
Figure imgf000125_0001
[0338] (4-((4-methoxybenzyl)oxy)phenyl)boronic acid (4.41g, 17.08mmol) was mixed with DME (70mL) in a sealable tube. A 2M solution of sodium carbonate in water (14.64mL, 29.28mmol) was added followed by a solution of di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2- yl]imidodicarbonate (Intermediate A, 5.00g, 12.20mmol) in DME (10mL). Palladium tetrakis triphenylphosphine (1.27g, 1.10mmol) was added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 3h at 90°C. The cooled reaction mixture was poured into a stirring mixture of water (300mL) and warm ethyl acetate (500mL). The layers were separated the aqueous phase was further extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate (6.00g, 10.21mmol), which was dissolved in dioxane (60mL). To the resulting solution was added HCl (4M; 10mL, 40mmol) and the mixture was stirred for 3h at 50°C. THF (100mL) and toluene (100mL) were added and the pH was adjusted to 6-7 by the addition of an aqueous solution of K3PO4. The layers were separated the aqueous phase was further extracted with a mixture of ethyl
acetate/THF/toluene = 1:1:1 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (2.30g, 8.60mmol, 84%) as a white solid.400 MHz 1H NMR (DMSO-d6) d 9.30 (s, 1H), 8.08 (dd, J = 4.8, 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 1.9 Hz, 1H), 7.15– 7.07 (m, 2H), 6.80– 6.65 (m, 4H), 6.26 (s, 2H), 3.90 (s, 2H). MS: 268.4 [M+H]+.
Intermediate D: Synthesis of 3-(3-(4-(aminomethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000125_0002
[0339] Di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 1.35g, 3.30mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (1.00g, 3.00mmol) were mixed in DME (15mL) in a sealable tube. A 2M solution of sodium carbonate in water (3.75mL, 7.50mmol) and palladium tetrakis triphenylphosphine (277mg, 0.240mmol) were added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 4h at 100°C. The cooled reaction mixture was poured into ethyl acetate (400mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the Boc protected coupling intermediate to which was added formic acid (8mL). The resulting mixture was stirred for 13h at 21-25°C to complete the global Boc de-protection, and then added dropwise to a rapidly stirring mixture of diethyl ether and hexane. The precipitated product in form of its formate salt was collected by filtration and dried under vacuum to yield 3-(3-(4- (aminomethyl)benzyl)isoxazol-5-yl)pyridin-2-amine formate (811mg, 2.49mmol, 83%) as a white solid. 500 MHz 1H NMR (DMSO-d6) d 8.32 (s, 2H), 8.09 (dd, J = 4.8, 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 1.8 Hz, 1H), 7.44– 7.34 (m, 4H), 6.81 (s, 1H), 6.70 (dd, J = 7.7, 4.8 Hz, 1H), 6.26 (s, 2H), 4.05 (s, 2H), 3.96 (s, 2H). MS: 281.4 [M+H]+.
Intermediate E: Synthesis of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000126_0001
[0340] (6-fluoropyridin-3-yl)boronic acid (1.90g, 13.48mmol) was mixed with DME (50mL) in a sealable tube. A 2M solution of sodium carbonate in water (11.24mL, 22.48mmol) was added followed by a solution of di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 3.68g, 8.99mmol) in DME (6mL). Palladium tetrakis triphenylphosphine (0.935g, 0.809mmol) was added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 4h at 90°C. The cooled reaction mixture was poured into ethyl acetate (500mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate (2.10g, 4.46mmol), to which was added formic acid (10mL). The resulting mixture was stirred for 13h at 21-25°C to complete the di-Boc de-protection. Ice-water (100mL) and ethyl acetate (300mL) were added and the pH was adjusted to 8-9 by the addition of 5N aqueous NaOH. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the product was precipitated through the addition of hexane. The product was filtered and dried under vacuum to yield 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (1.06g, 3.92mmol, 44%) as a white solid.500 MHz 1H NMR (DMSO-d6) d 8.27– 8.22 (m, 1H), 8.09 (dd, J = 4.8, 1.9 Hz, 1H), 7.95 (td, J = 8.2, 2.6 Hz, 1H), 7.87 (dd, J = 7.7, 1.8 Hz, 1H), 7.16 (dd, J = 8.4, 2.9 Hz, 1H), 6.85 (s, 1H), 6.70 (dd, J = 7.7, 4.8 Hz, 1H), 6.27 (s, 2H), 4.11 (s, 2H). MS: 271.4 [M+H]+. Intermediate F: Synthesis of 4-((5-(2,6-diaminopyridin-3-yl)isoxazol-3-yl)methyl)phenol
Figure imgf000127_0001
[0341] 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine (0.300 g, 0.806 mmol) and TFA (4.96 ml, 64.4 mmol) was added thioanisole (0.381 ml, 3.22 mmol) at room temperature and stirred for 2 hours. To the mixture was added a saturated sodium hydrogen carbon solution and was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-((5-(2,6-diaminopyridin-3-yl)isoxazol-3- yl)methyl)phenol (0.170 g, 0.602 mmol, 74.8 % yield). MS: 283.3 [M+H]+.
Intermediate G: Synthesis of 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridine-2,6-diamine
Figure imgf000127_0002
[0342] 3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridine-2,6-diamine (0.100 g, 0.268 mmol) was dissolved in dioxane (1mL) and added HCl (0.098 ml, 3.21 mmol). The mixture was heated at reflux for 2 hours. The cooled mixture was poured into ice cold buffer with pH7 and neutralized with NaOH and then extracted with EtOAc. Organic solvents were removed under reduced pressure and the residue was purified using flash chromatography to give 3-(3-(4-(chloromethyl)benzyl)isoxazol-5- yl)pyridine-2,6-diamine (0.075 g, 0.238 mmol, 89 % yield). MS: 315.7 [M+H]+.
Intermediate H: Synthesis of 3-(3-((2-fluoropyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000127_0003
[0343] (2-fluoropyridin-4-yl)boronic acid (0.894g, 6.34mmol) was mixed with DME (25mL) in a sealable tube. A 2M solution of sodium carbonate in water (7.32mL, 14.64mmol) was added followed by a solution of di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate
(Intermediate A, 2.00g, 4.88mmol) in DME (4mL). Palladium tetrakis triphenylphosphine (0.395g, 0.342mmol) was added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 2h at 90°C. The cooled reaction mixture was poured into ethyl acetate (200mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate (1.050g, 2.232mmol), to which was added formic acid (6.1mL). The resulting mixture was stirred for 18h at 21-25°C to complete the di-Boc de-protection. Ice-water (50mL) and ethyl acetate (150mL) were added and the pH was adjusted to 8-9 by the addition of 5N aqueous NaOH. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the product was precipitated through the addition of hexane. The product was filtered and dried under vacuum to yield 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (0.515g, 1.91mmol, 41%) as a white solid.500 MHz 1H NMR (DMSO-d6) d 8.19 (d, J = 5.1 Hz, 1H), 8.10 (dd, J = 4.8, 1.8 Hz, 1H), 7.87 (dd, J = 7.7, 1.8 Hz, 1H), 7.32 (dt, J = 5.1, 1.7 Hz, 1H), 7.17 (s, 1H), 6.87 (s, 1H), 6.71 (dd, J = 7.7, 4.8 Hz, 1H), 6.27 (s, 1H), 4.17 (s, 2H). MS: 271.2 [M+H]+.
Intermediate I: Synthesis of 3-(3-((6-fluoropyridin-2-yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000128_0001
[0344] (6-fluoropyridin-2-yl)boronic acid (0.670g, 4.76mmol) was mixed with DME (20mL) in a sealable tube. A 2M solution of sodium carbonate in water (5.49mL, 10.98mmol) was added followed by a solution of di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate
(Intermediate A, 1.500 g, 3.66mmol) in DME (2mL). Palladium tetrakis triphenylphosphine (0.296 g, 0.256 mmol) was added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 4h at 90 °C. The cooled reaction mixture was poured into ethyl acetate (200mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate (0.900g, 1.91mmol), to which was added formic acid (5.5mL). The resulting mixture was stirred for 18h at 21-25 °C to complete the di-Boc de-protection. Ice-water (50mL) and ethyl acetate (150mL) were added and the pH was adjusted to 8-9 by the addition of 5N aqueous NaOH. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the product was precipitated through the addition of hexane. The product was filtered and dried under vacuum to yield 3-(3-((6-fluoropyridin-2-yl)methyl)isoxazol-5-yl)pyridin-2-amine (0.440g, 1.63mmol, 44%) as a white solid. MS: 271.2 [M+H]+.
Intermediate J: Synthesis of 3-(3-((5,6-difluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000129_0001
[0345] (5,6-difluoropyridin-3-yl)boronic acid (1.06g, 6.65mmol) and di-tert-butyl [3-(3-(chloromethyl)- 1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 3.00g, 7.32mmol) were mixed with DME (25mL) in a sealable tube. A 2M solution of sodium carbonate in water (8.32mL, 16.64mmol) was added followed by palladium tetrakis triphenylphosphine (0.54g, 0.47mmol). The sealable tube was flushed with argon and sealed. The mixture was stirred for 3h at 90 °C. The cooled reaction mixture was poured into ethyl acetate (500mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate to which was added formic acid (8mL). The resulting mixture was stirred for 13h at 21-25°C to complete the di-Boc de-protection. Toluene (100mL) and acetonitrile (50mL) were added and all volatiles were removed under reduced pressure. This addition/evaporation procedure was repeated three times to complete the removal of formic acid. Ethyl acetate was added and the precipitation of the product was completed by the addition of some hexane. The product was filtered off and dried under vacuum to yield 3-(3-((5,6-difluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (0.894g, 3.10mmol, 47% overall yield) as a white solid.500 MHz 1H NMR (DMSO-d6) d 8.12– 8.01 (m, 3H), 7.86 (dd, J = 7.6, 1.9 Hz, 1H), 6.87 (s, 1H), 6.70 (dd, J = 7.7, 4.7 Hz, 1H), 6.28 (s, 2H), 4.15 (s, 2H). MS: 289.4 [M+H]+.
Intermediate K: Synthesis of 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-2-fluorophenol
Figure imgf000129_0002
[0346] 2-(3-fluoro-4-((4-methoxybenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.29g, 17.57mmol) and di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 6.00g, 14.64mmol) were mixed with DME (60mL) in a sealable tube. A 2M solution of sodium carbonate in water (18.30mL, 36.60mmol) and palladium tetrakis triphenylphosphine (1.18g, 1.03mmol) were added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 2h at 90°C. The cooled reaction mixture was poured into a stirring mixture of water (300mL) and warm ethyl acetate (500mL). The layers were separated the aqueous phase was further extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate, which was dissolved in dioxane (90mL). To the resulting solution was added conc. HCl (12M; 6.27mL, 75mmol). The mixture was stirred at 55 °C for 2.5h and then poured into a stirred mixture of a solution of sodium hydroxide (2.82g, 70.6mmol) in water (200mL) and EtOAc (300mL). Layers were separated and the aqueous phase was extracted with EtOAc (2x 50mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Before reaching complete dryness, the product started to precipitate out. At this point, ether (100mL) was added and the product was collected by filtration to obtain 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-2-fluorophenol (2.18g, 7.64 mmol, 52% overall yield) as a white powder.500 MHz 1H NMR (DMSO-d6) d 9.72 (s, 1H), 8.09 (dd, J = 4.8, 1.8 Hz, 1H), 7.87 (dd, J = 7.7, 1.8 Hz, 1H), 7.11 (dd, J = 12.2, 2.0 Hz, 1H), 6.96– 6.85 (m, 2H), 6.79 (s, 1H), 6.69 (dd, J = 7.7, 4.8 Hz, 1H), 6.26 (s, 2H), 3.92 (s, 2H). MS: 286.4 [M+H]+.
Intermediate L: Synthesis of 3-(3-((2-chloropyrimidin-5-yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000130_0001
[0347] 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.00g, 4.44mmol) and di- tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 2.00g, 4.88mmol) were mixed with DME (15mL) in a sealable tube. A 2M solution of sodium carbonate in water (5.55mL, 11.09mmol) and palladium tetrakis triphenylphosphine (0.36g, 0.31mmol) were added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 2h at 95°C. The cooled reaction mixture was poured into ethyl acetate (500mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling intermediate, to which was added formic acid (8mL). The resulting mixture was stirred for 13h at 21-25°C to complete the di-Boc de-protection.
During this step the fluoropyridine also completely hydrolyzed. Toluene (100mL) and acetonitrile (50mL) were added and all volatiles were removed under reduced pressure. This addition/evaporation procedure was repeated three times to complete the removal of formic acid and to obtain a solid residue of (5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)pyrimidin-2-ol (570mg, 2.12mmol). The residue was suspended in acetonitrile (2mL). N-benzyl-N,N-diethylethanaminium chloride (237mg, 1.04mmol) and phosphoryl trichloride (0.58mL, 6.24mmol) were added, followed by the addition of N-ethyl-N- isopropylpropan-2-amine (0.71mL, 4.16mmol). The mixture was heated in a sealed tube at 90°C for 20h and then slowly added to a stirred solution of NaHCO3 in water. Some ice was added to maintain a temperature around 30°C. After quenching was complete, the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated under reduced pressure to obtain the crude product (3-(3-((2-chloropyrimidin-5-yl)methyl)isoxazol-5-yl)pyridin-2-amine (180mg, 0.63mmol, 13% overall yield)) as a solid, which was directly used in the following experiments without further purification. 500 MHz 1H NMR (DMSO-d6) d 8.80 (s, 2H), 8.10 (dd, J = 4.8, 1.9 Hz, 1H), 7.86 (dd, J = 7.7, 1.9 Hz, 1H), 6.89 (s, 1H), 6.71 (dd, J = 7.7, 4.8 Hz, 1H), 6.28 (s, 2H), 4.15 (s, 2H). MS: 287.9 [M+H]+.
[0348] Example 1: Synthesis of 3-(3-(4-((1H-pyrazol-1-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000131_0001
[0349] A solution of 1H-pyrazole (91mg, 1.33mmol) in NMP (0.5mL) was added to a suspension of sodium hydride (60% w/mineral oil, 40mg, 1.00mmol) in NMP (1mL). After stirring for 20min at 21- 25°C, a solution of 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 100mg, 0.33mmol) in NMP (1ml) was added and the mixture was stirred for 4min at 60°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fractions containing the product were concentrated under reduced pressure and further purified by HPLC to yield 3-(3-(4-((1H-pyrazol-1-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (75mg, 0.23mmol, 68%) as a white solid. 400 MHz 1H NMR (CDCl3) d 8.12 (dd, J = 4.9, 1.8 Hz, 1H), 7.68 (dd, J = 7.7, 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 2.3, 0.7 Hz, 1H), 7.29– 7.21 (m, 2H), 7.21– 7.13 (m, 2H), 6.69 (dd, J = 7.7, 4.9 Hz, 1H), 6.31– 6.20 (m, 2H), 5.42 (s, 2H), 5.30 (s, 2H), 4.03 (s, 2H). MS: 332.2
[M+H]+.
[0350] Example 2: Synthesis of 2-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)acetonitrile
Figure imgf000131_0002
[0351] Potassium cyanide (209mg, 3.20mmol) was added to PEG400 (1.5ml) and carefully ground to a fine suspension using a glass rod.3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate B, 120mg, 0.40mmol) was added and the mixture was stirred for 30min at 80°C. To the cooled reaction mixture was added to water (50 mL), and then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 2-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)acetonitrile (102mg, 0.35mmol, 88%) as a white solid.400 MHz 1H NMR (CDCl3) d 8.09 (dd, J = 4.9, 1.8 Hz, 1H), 7.65 (dd, J = 7.7, 1.8 Hz, 1H), 7.26 (m, 4H), 6.66 (dd, J = 7.7, 4.9 Hz, 1H), 6.20 (s, 1H), 5.38 (s, 2H), 4.01 (s, 2H), 3.69 (s, 2H). MS: 291.2 [M+H]+.
[0352] Example 3: Synthesis of 1-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-1H- pyrazole-4-carbonitrile
Figure imgf000132_0001
[0353] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 80mg, 0.27mmol) and 1H-pyrazole-4-carbonitrile (99mg, 1.07mmol) were dissolved in NMP (1ml). Potassium 2- methylpropane-2-olate (1M in THF, 0.80mL, 0.80mmol) was added and the mixture was stirred for 5min at 60°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by HPLC to yield 1-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-1H- pyrazole-4-carbonitrile (66mg, 0.19mmol, 69%) as a white solid. 400 MHz 1H NMR (CDCl3) d 8.13 (dd, J = 5.0, 1.8 Hz, 1H), 7.79 (dd, J = 18.1, 0.7 Hz, 2H), 7.69 (dd, J = 7.7, 1.8 Hz, 1H), 7.35– 7.25 (m, 2H), 7.27– 7.17 (m, 2H), 6.70 (dd, J = 7.7, 4.8 Hz, 1H), 6.25 (s, 1H), 5.43 (s, 2H), 5.30 (s, 2H), 4.05 (s, 2H). MS: 357.3 [M+H]+.
[0354] Example 4: Synthesis of 3-(3-(4-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000132_0002
[0355] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 80mg, 0.27mmol) and 4-fluoro-1H-pyrazole (92mg, 1.07mmol) were dissolved in NMP (1ml). Potassium 2-methylpropane- 2-olate (1M in THF, 0.80mL, 0.80mmol) was added and the mixture was stirred for 5min at 60°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by HPLC to yield 3-(3-(4-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (75mg, 0.22mmol, 80%) as a white solid. 400 MHz 1H NMR (CDCl3) d 8.14 (s, 1H), 7.69 (dd, J = 7.7, 1.7 Hz, 1H), 7.35 (dd, J = 4.3, 0.8 Hz, 1H), 7.31– 7.13 (m, 5H), 6.70 (dd, J = 7.7, 4.7 Hz, 1H), 6.24 (s, 1H), 5.43 (s, 2H), 5.18 (s, 2H), 4.04 (s, 2H). MS: 350.3 [M+H]+.
[0356] Example 5: Synthesis of 3-(3-(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)isoxazol- 5-yl)pyridin-2-amine
Figure imgf000132_0003
[0357] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 80mg, 0.27mmol) and 4-(trifluoromethyl)-1H-pyrazole (145mg, 1.07mmol) were dissolved in NMP (1ml). Potassium 2- methylpropane-2-olate (1M in THF, 0.80mL, 0.80mmol) was added and the mixture was stirred for 5min at 60°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by HPLC to yield 3-(3-(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)isoxazol- 5-yl)pyridin-2-amine (75mg, 0.19mmol, 70%) as a white solid. 400 MHz 1H NMR (CDCl3) d 8.14 (d, J = 3.7 Hz, 1H), 7.73 (s, 1H), 7.69 (dd, J = 7.7, 1.8 Hz, 1H), 7.64 (s, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 6.70 (dd, J = 7.7, 4.9 Hz, 1H), 6.25 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H), 4.05 (s, 2H). MS: 400.3 [M+H]+.
[0358] Example 6: Synthesis of N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-1,2,4- thiadiazol-5-amine
Figure imgf000133_0001
[0359] 3-(3-(4-(Chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 0.10 g, 0.33 mmol) and 1,2,4-thiadiazol-5-amine (0.17 g, 1.7 mmol) were dissolved in tetrahydrofuran.
Diisopropylethylamine (0.14 mL, 0.80 mmol) was added and the homogeneous amber-colored solution was stirred at room temperature. After 3 hours an additional 2 equivalents of 1,2,4-thiadiazol-5-amine (0.070 g, 0.66 mmol) and another 1.2 equivalents of diisopropylethylamine (0.070 mL, 0.40 mmol) were added. The mixture was heated at 60◦C for 72 hours. The mixture was cooled to room temperature and extracted three times with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified using Biotage reverse phase flash chromatography (12g C18 SNAP, 5-95% acetonitrile in water with 0.1% formic acid). The desired fraction was lyophilized to give the title compound as a white solid (2.0 mg, 0.0051 mmol, 2%). MS: 365.2 [M+H]+.
[0360] Example 7: Synthesis of N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-1H- pyrrolo[2,3-b]pyridin-5-amine
Figure imgf000133_0002
[0361] 3-(3-(4-(Chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 0.10 g, 0.33 mmol) and 1H-pyrrolo[2,3-b]pyridin-5-amine (0.22 g, 1.7 mmol), were dissolved in tetrahydrofuran. Diisopropylethylamine (0.14 mL, 0.80 mmol) was added and the heterogenous mixture was stirred at room temperature for 3 hours, and then heated at 60◦C for 72 hours. The mixture was cooled to room temperature and extracted three times with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified using Biotage reverse phase flash chromatography (12g C18 SNAP, 5-95% acetonitrile in water with 0.1% formic acid). The desired fraction was lyophilized to give the title compound as a white solid (20 mg, 0.051 mmol, 15%). MS: 397.3 [M+H]+.
[0362] Example 8: Synthesis of 3-(3-(4-benzylbenzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000133_0003
[0363] Phenylboronic acid (61mg, 0.50mmol) and 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin- 2-amine (Intermediate B, 100mg, 0.33mmol) were mixed in DME (4mL) in a sealable tube. A 2M solution of sodium carbonate in water (0.45mL, 0.90mmol) and palladium tetrakis triphenylphosphine (27mg, 0.023mmol) were added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 2h at 90°C. The cooled reaction mixture was poured into ethyl acetate and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-(4-benzylbenzyl)isoxazol-5-yl)pyridin-2- amine (84mg, 0.25mmol, 74%) as a white solid. 400 MHz 1H NMR (CDCl3) d 8.16– 8.10 (m, 1H), 7.69 (dd, J = 7.7, 1.7 Hz, 1H), 7.33– 7.12 (m, 9H), 6.69 (dd, J = 7.7, 4.8 Hz, 1H), 6.24 (s, 1H), 5.40 (s, 2H), 4.01 (s, 2H), 3.96 (s, 2H). MS: 342.2 [M+H]+.
[0364] Example 9: Synthesis of 3-(3-(4-(pyridin-3-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000134_0001
[0365] The title compound was prepared according to the procedure described in Example 8 using pyridin-3-ylboronic acid (61.5mg, 0.50mmol) to yield 3-(3-(4-(pyridin-3-ylmethyl)benzyl)isoxazol-5- yl)pyridin-2-amine (64mg, 0.19mmol, 56%) as a white solid. 400 MHz 1H NMR (CDCl3) d 8.52 (s, 2H), 8.06 (d, J = 4.1 Hz, 1H), 7.73 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.30– 7.24 (m, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.70 (dd, J = 7.7, 4.9 Hz, 1H), 6.26 (s, 1H), 5.94 (s, 2H), 4.03 (s, 2H), 3.97 (s, 2H). MS: 343.2 [M+H]+.
[0366] Example 10: Synthesis of 3-(3-(4-((1H-pyrazol-4-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000134_0002
[0367] The title compound was prepared according to the procedure described in Example 8 using (1H- pyrazol-4-yl)boronic acid (56.0mg, 0.50mmol) and heating for 14h at 90°C to yield 3-(3-(4-((1H- pyrazol-4-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (40mg, 0.12mmol, 36%) as a white solid. MS: 332.3 [M+H]+.
[0368] Example 11: Synthesis of 3-(3-(4-((1-methyl-1H-pyrazol-4-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000134_0003
[0369] The title compound was prepared according to the procedure described in Example 8 using (1- methyl-1H-pyrazol-4-yl)boronic acid (63.0mg, 0.50mmol) to yield 3-(3-(4-((1-methyl-1H-pyrazol-4- yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (60mg, 0.17mmol, 52%) as a white solid. MS: 346.2 [M+H]+.
[0370] Example 12: Synthesis of 3-(3-(4-((1-ethyl-1H-pyrazol-4-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000135_0001
[0371] The title compound was prepared according to the procedure described in Example 8 using (1- ethyl-1H-pyrazol-4-yl)boronic acid (70.0mg, 0.50mmol) to yield 3-(3-(4-((1-ethyl-1H-pyrazol-4- yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (76mg, 0.21mmol, 63%) as a white solid. MS: 360.3 [M+H]+.
[0372] Example 13: Synthesis of 3-(3-(4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000135_0002
[0373] The title compound was prepared according to the procedure described in Example 8 using 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (180mg, 0.73mmol) to yield 3-(3-(4-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (85mg, 0.22mmol, 61%) as a white solid. MS: 383.3 [M+H]+.
[0374] Example 14: Synthesis of 3-(3-(4-(isoxazol-4-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000135_0003
[0375] The title compound was prepared according to the procedure described in Example 8 using isoxazol-4-ylboronic acid (56.5mg, 0.50mmol) to yield 3-(3-(4-(isoxazol-4-ylmethyl)benzyl)isoxazol-5- yl)pyridin-2-amine (76mg, 0.23mmol, 69%) as a white solid. MS: 333.2 [M+H]+.
[0376] Example 15: Synthesis of 3-(3-(4-((6-fluoropyridin-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000135_0004
[0377] The title compound was prepared according to the procedure described in Example 8 using (6- fluoropyridin-2-yl)boronic acid (70.5mg, 0.50mmol) to yield 3-(3-(4-((6-fluoropyridin-2- yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (82mg, 0.23mmol, 68%) as a white solid. 500 MHz 1H NMR (DMSO-d6) d 8.08 (dd, J = 4.8, 1.8 Hz, 1H), 7.93– 7.83 (m, 2H), 7.29– 7.20 (m, 5H), 6.97 (dd, J = 8.1, 2.6 Hz, 1H), 6.80 (s, 1H), 6.69 (dd, J = 7.7, 4.8 Hz, 1H), 6.24 (s, 2H), 4.01 (s, 2H), 3.99 (s, 2H). MS: 361.4 [M+H]+.
[0378] Example 16: Synthesis if 3-(3-(4-((1-isobutyl-1H-pyrazol-4-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000136_0001
[0379] The title compound was prepared according to the procedure for described in Example 8 using (1-isobutyl-1H-pyrazol-4-yl)boronic acid (95.0mg, 0.57mmol) to yield 3-(3-(4-((1-isobutyl-1H-pyrazol- 4-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (72mg, 0.19mmol, 56%) as a white solid. MS: 388.3 [M+H]+.
[0380] Example 17: Synthesis of 3-(3-(4-(cyclopent-1-en-1-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000136_0002
[0381] The title compound was prepared according to the procedure described in Example 8 using cyclopent-1-en-1-ylboronic acid (63.5mg, 0.57mmol) to yield 3-(3-(4-(cyclopent-1-en-1- ylmethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (72mg, 0.22mmol, 65%) as a white solid. MS: 332.2 [M+H]+.
[0382] Example 18: Synthesis of 3-(3-(4-phenethylbenzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000136_0003
[0383] The title compound was prepared according to the procedure described in Example 8 using 2- benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (124mg, 0.57mmol) to yield 3-(3-(4- phenethylbenzyl)isoxazol-5-yl)pyridin-2-amine (41mg, 0.12mmol, 35%) as a white solid. MS: 356.2 [M+H]+.
[0384] Example 19: Synthesis of 3-(3-(4-((2-fluoropyridin-4-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000136_0004
[0385] The title compound was prepared according to the procedure described in Example 8 using (2- fluoropyridin-4-yl)boronic acid (70.5mg, 0.50mmol) to yield 3-(3-(4-((2-fluoropyridin-4- yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (86mg, 0.24mmol, 72%) as a white solid. MS: 346.2 [M+H]+. [0386] Example 20: Synthesis of 3-(3-(4-((2,3-difluoropyridin-4-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000137_0001
[0387] The title compound was prepared according to the procedure described in Example 8 using (2,3- difluoropyridin-4-yl)boronic acid (106mg, 0.67mmol) to yield 3-(3-(4-((2,3-difluoropyridin-4- yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (85mg, 0.23mmol, 67%) as a white solid. MS: 379.2 [M+H]+.
[0388] Example 21: Synthesis of 3-(3-(4-(pyrimidin-5-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000137_0002
[0389] The title compound was prepared according to the procedure described in Example 8 using pyrimidin-5-ylboronic acid (83.0mg, 0.67mmol) to yield 3-(3-(4-(pyrimidin-5-ylmethyl)benzyl)isoxazol- 5-yl)pyridin-2-amine (78mg, 0.23mmol, 68%) as a white solid. MS: 344.3 [M+H]+.
[0390] Example 22: Synthesis of (4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenyl)(phenyl)methanol
Figure imgf000137_0003
[0391] Di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 200mg, 0.49mmol) and (4-(hydroxy(phenyl)methyl)phenyl)boronic acid (122mg, 0.54mmol) were mixed in DME (4mL) in a sealable tube. A 2M solution of sodium carbonate in water (0.56mL,
1.12mmol) and palladium tetrakis triphenylphosphine (45mg, 0.039mmol) were added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 2h at 100°C. The cooled reaction mixture was poured into ethyl acetate and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di- Boc protected coupling product as a yellow oil to which was added formic acid (4mL). This mixture was stirred for 3h at 21-25°C to complete the di-Boc de-protection. To this mixture was added dioxane (10mL), ice and a 5M solution of NaOH in water until the pH of the resulting mixture was about 10-12. The mixture was stirred for 30min at 21-25°C to complete the hydrolysis of the formate ester on the hydroxyl group, which was formed during the di-Boc de-protection. The mixture was diluted with water (50mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield (4-((5-(2-aminopyridin-3- yl)isoxazol-3-yl)methyl)phenyl)(phenyl)methanol (75mg, 0.21mmol, 43%) as a white solid. MS: 358.2 [M+H]+.
[0392] Example 23: Synthesis of 3-(3-(4-((cyclohexyloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000138_0001
[0393] In a microwave vial was combined di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2- yl]imidodicarbonate (Intermediate A, 0.20 g, 0.48 mmol), (4-((cyclohexyloxy)methyl)phenyl)boronic acid (0.17 g, 0.73 mmol), cesium carbonate (0.48 g, 1.5 mmol), copper(I) iodide (0.0047 g, 0.024 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (0.020 g, 0.024 mmol), and 1,2-dimethoxyethane (3 mL). The vial was sealed and heated at 90◦C for 40 min under microwave irradiation. The mixture was filtered through Celite with ethyl acetate. The solvents were evaporated under reduced pressure and the residue was purified using Biotage flash chromatography (50g SNAP, 2-75% acetone/hexane). Like fractions were combined and evaporated to give the desired di- BOC-protected intermediate. This material was dissolved in dichloromethane (10 mL) and treated with 4M hydrogen chloride in dioxane (3 mL). After stirring for 16 hours at room temperature, the mixture was diluted with water and basified with 5M aqueous sodium hydroxide solution to pH 13. The layers were separated, and the aqueous phase was extracted twice more with dichloromethane. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified using Biotage reverse phase flash chromatography (12g C18 SNAP, 5-95% acetonitrile/water containing 0.1% Formic Acid). The desired fractions were combined and lyophilized to give the title compound as a white solid (0.055 g, 0.15 mmol, 31%). MS: 364.5 [M+H]+.
[0394] Example 24: Synthesis of 3-(3-(4-((naphthalen-1-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000138_0002
[0395] The title compound was prepared according to the procedure described in Example 23 using (4- ((naphthalen-1-yloxy)methyl)phenyl)boronic acid (0.20 g, 0.73 mmol) to yield the title compound as a white solid (0.056 g, 0.14 mmol, 29%). MS: 408.5 [M+H]+.
[0396] Example 25: Synthesis of 3-(3-(4-(((4-chloronaphthalen-1-yl)oxy)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000138_0003
[0397] The title compound was prepared according to the procedure described in Example 23 using (4- (((4-chloronaphthalen-1-yl)oxy)methyl)phenyl)boronic acid (0.23 g, 0.73 mmol) to yield the title compound as a white solid (0.063 g, 0.14 mmol, 29%). MS: 442.4 [M+H]+. [0398] Example 26: Synthesis of 3-(3-(4-((5-methylisoxazol-3-yl)methoxy)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000139_0001
[0399] 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (Intermediate C, 80mg, 0.30mmol) was dissolved in DMF (1mL) and potassium 2-methylpropane-2-olate (1M in THF, 0.33mL, 0.33mmol) was added dropwise. The mixture was stirred for 5min and a solution of 3-(bromomethyl)-5-methylisoxazole (63.2mg, 0.36mmol) in DMF (0.5mL) was added. The resulting mixture was stirred for 30min and directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by reversed phase flash chromatography (C18, acetonitrile/water) to yield 3-(3-(4-((1H-pyrazol-1-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (71mg, 0.20mmol, 66%) as a white solid.400 MHz 1H NMR (CDCl3) d 8.13 (s, 1H), 7.70 (dd, J = 7.7, 1.8 Hz, 1H), 7.24– 7.16 (m, 2H), 6.98– 6.89 (m, 2H), 6.70 (dd, J = 7.7, 4.8 Hz, 1H), 6.23 (s, 1H), 6.10 (d, J = 1.1 Hz, 1H), 5.44 (s, 2H), 5.09 (s, 2H), 3.99 (s, 2H), 2.42 (d, J = 0.9 Hz, 3H). MS: 363.3 [M+H]+.
[0400] Example 27: Synthesis of 3-(3-(4-(quinolin-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000139_0002
[0401] The title compound was prepared according to the procedure described in Example 26 using 2- (chloromethyl)quinoline hydrochloride (83mg, 0.39mmol) and potassium 2-methylpropane-2-olate (1M in THF, 0.72mL, 0.72mmol) to yield 3-(3-(4-(quinolin-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridin-2- amine (80mg, 0.20mmol, 66%) as a white solid. MS: 409.3 [M+H]+.
[0402] Example 28: Synthesis of 3-(3-(4-(pyrimidin-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000139_0003
The title compound was prepared according to the procedure described in Example 26 using 2- (chloromethyl)pyrimidine hydrochloride (69mg, 0.42mmol) and potassium 2-methylpropane-2-olate (1M in THF, 0.75mL, 0.75mmol) to yield 3-(3-(4-(pyrimidin-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridin-2- amine (56mg, 0.16mmol, 52%) as a white solid. MS: 360.3 [M+H]+.
[0403] Example 29: Synthesis of 3-(3-(4-((5-methylpyrimidin-2-yl)methoxy)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000139_0004
The title compound was prepared according to the procedure described in Example 26 using 2- (chloromethyl)-5-methylpyrimidine hydrochloride (75mg, 0.42mmol) and potassium 2-methylpropane-2- olate (1M in THF, 0.75mL, 0.75mmol) to yield 3-(3-(4-((5-methylpyrimidin-2- yl)methoxy)benzyl)isoxazol-5-yl)pyridin-2-amine (79mg, 0.21mmol, 71%) as a white solid. MS: 374.3 [M+H]+.
[0404] Example 30: Synthesis of 3-(3-(4-(quinoxalin-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000140_0001
[0405] The title compound was prepared according to the procedure described in Example 26 using 4- ((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (Intermediate C, 90mg, 0.34mmol), 2- (bromomethyl)quinoxaline (90mg, 0.40mmol) and potassium 2-methylpropane-2-olate (1M in THF, 0.34mL, 0.34mmol) to yield 3-(3-(4-(quinoxalin-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridin-2-amine (73mg, 0.18mmol, 53%) as a white solid. MS: 410.3 [M+H]+.
[0406] Example 31: Synthesis of N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-6- fluoropyridin-2-amine
Figure imgf000140_0002
[0407] 3-(3-(4-(aminomethyl)benzyl)isoxazol-5-yl)pyridin-2-amine diformate (Intermediate D, 80mg, 0.22mmol) was dissolved in DMSO (0.5mL). N-ethyl-N-isopropylpropan-2-amine (83mg, 0.65mmol) and 2,6-difluoropyridine (148mg, 1.29mmol) were added and the mixture was stirred for 2h at 120°C. The mixture was diluted with water (15mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-6-fluoropyridin-2-amine (47mg, 0.13mmol, 58%) as a white solid. 500 MHz 1H NMR (DMSO-d6) d 8.08 (dd, J = 4.8, 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 1.8 Hz, 1H), 7.52– 7.40 (m, 2H), 7.28 (s, 4H), 6.79 (s, 1H), 6.69 (dd, J = 7.7, 4.8 Hz, 1H), 6.35 (dd, J = 8.0, 2.5 Hz, 1H), 6.25 (s, 2H), 6.08 (dd, J = 7.6, 2.2 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.00 (s, 2H). MS: 376.3 [M+H]+.
[0408] Example 32: Synthesis of N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)benzyl)pyrimidin-2-amine
Figure imgf000140_0003
[0409] The title compound was prepared according to the procedure described in Example 31 using 2- chloropyrimidine (148mg, 1.29mmol) to yield N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)benzyl)pyrimidin-2-amine (45mg, 0.17mmol, 58%) as a white solid. MS: 359.2 [M+H]+. [0410] Example 33: Synthesis of N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-2- methylpyrimidin-4-amine
Figure imgf000141_0001
[0411] The title compound was prepared according to the procedure described in Example 31 using 4- chloro-2-methylpyrimidine (166mg, 1.29mmol) to yield N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)benzyl)-2-methylpyrimidin-4-amine (41mg, 0.11mmol, 51%) as a slight yellow oil. MS: 373.2 [M+H]+.
[0412] Example 34: Synthesis of N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-4- chlorothiazol-2-amine
Figure imgf000141_0002
[0413] The title compound was prepared according to the procedure described in Example 31 using 2,4- dichlorothiazole (265mg, 1.72mmol) to yield N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)benzyl)-4-chlorothiazol-2-amine (15mg, 0.04mmol, 18%) as a white solid. MS: 398.1 [M+H]+.
[0414] Example 35: Synthesis of 3-(3-((6-(pyridin-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000141_0003
[0415] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol) and pyridin-2-ylmethanol (121mg, 1.11mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was diluted with ice-water (15mL) and the pH was adjusted to 8 using diluted HCl. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-((6-(pyridin-2-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (38mg, 0.11mmol, 57%) as a white solid. MS: 360.3 [M+H]+.
[0416] Example 36: Synthesis of 3-(3-((6-(pyridin-3-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000141_0004
[0417] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 60 mg, 0.22mmol) and pyridin-3-ylmethanol (242mg, 2.22mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 2.22mL, 2.22mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(pyridin-3-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (19mg, 0.052mmol, 23%) as a white solid. MS: 360.2 [M+H]+.
[0418] Example 37: Synthesis of 3-(3-((6-(pyridin-4-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000142_0001
[0419] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 60 mg, 0.22mmol) and pyridin-3-ylmethanol (242mg, 2.22mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 2.22mL, 2.22mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(pyridin-4-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (31mg, 0.086mmol, 39%) as a white solid. MS: 360.2 [M+H]+.
[0420] Example 38: Synthesis of 3-(3-((6-((5-methylisoxazol-3-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000142_0002
[0421] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 60 mg, 0.22mmol) and 5-methylisoxazol-3-yl)methanol (251mg, 2.22mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 2.22mL, 2.22mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((5-methylisoxazol-3- yl)methoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (62mg, 0.171mmol, 77%) as a white solid. MS: 364.1 [M+H]+.
[0422] Example 39: Synthesis of 3-(3-((6-(2-(pyridin-2-yl)ethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000142_0003
[0423] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 60 mg, 0.22mmol) and 2-(pyridin-2-yl)ethan-1-ol (273mg, 2.22mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 2.22mL, 2.22mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(2-(pyridin-2-yl)ethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (6.4mg, 0.017mmol, 7.7%) as a white solid. MS: 374.1 [M+H]+.
[0424] Example 40: Synthesis of 3-(3-((6-(thiophen-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000143_0001
[0425] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and thiophen-2-ylmethanol (211mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(thiophen-2-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (25mg, 0.069mmol, 37%) as a light yellow solid. MS: 365.1 [M+H]+.
[0426] Example 41: Synthesis of 3-(3-((6-(thiazol-4-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000143_0002
[0427] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and thiazol-4-ylmethanol (213mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(thiazol-4-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (35mg, 0.097mmol, 52%) as a white solid. MS: 366.1 [M+H]+.
[0428] Example 42: Synthesis of 3-(3-((6-(thiazol-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000143_0003
[0429] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and thiazol-2-ylmethanol (213mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(thiazol-2-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (36mg, 0.097mmol, 53%) as a white solid. MS: 366.1 [M+H]+.
[0430] Example 43: Synthesis of 3-(3-((6-(cyclopropylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000144_0001
[0431] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and cyclopropylmethanol (133mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(cyclopropylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (38mg, 0.097mmol, 64%) as a white solid. 500 MHz 1H NMR (DMSO-d6) d 8.12 (dd, J = 2.5, 0.8 Hz, 1H), 8.09 (dd, J = 4.8, 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 1.8 Hz, 1H), 7.64 (dd, J = 8.5, 2.5 Hz, 1H), 6.82 (s, 1H), 6.78 (dd, J = 8.5, 0.7 Hz, 1H), 6.69 (dd, J = 7.7, 4.8 Hz, 1H), 6.26 (s, 2H), 4.06 (d, J = 7.1 Hz, 2H), 3.98 (s, 2H), 1.27– 1.18 (m, 1H), 0.58– 0.48 (m, 2H), 0.35– 0.24 (m, 2H). MS: 323.2 [M+H]+.
[0432] Example 44: Synthesis of 3-(3-((6-(oxetan-3-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000144_0002
[0433] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and oxetan-3-ylmethanol (196mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(oxetan-3-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (11mg, 0.031mmol, 14%) as a white solid. MS: 339.3 [M+H]+. [0434] Example 45: Synthesis of 3-(3-((6-((1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000145_0001
[0435] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 1-methyl-1H-pyrazol-3-yl-methanol (207mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((1-methyl-1H-pyrazol-3- yl)methoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (10mg, 0.028mmol, 15%) as a white solid. MS: 363.2 [M+H]+.
[0436] Example 46: Synthesis of 3-(3-((6-(pyrimidin-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000145_0002
[0437] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and pyrimidin-2-ylmethanol (204mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(pyrimidin-2-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (21mg, 0.058mmol, 31%) as a white solid. MS: 361.2 [M+H]+.
[0438] Example 47: Synthesis of 3-(3-((6-(pyrazin-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000145_0003
[0439] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and pyrazin-2-ylmethanol (204mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(pyrazin-2-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (20mg, 0.055mmol, 30%) as a white solid. MS: 361.2 [M+H]+.
[0440] Example 48: Synthesis of 3-(3-((6-(furan-3-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000146_0001
[0441] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and furan-3-ylmethanol (181mg, 1.85mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(furan-3-ylmethoxy)pyridin-3-yl)methyl)isoxazol- 5-yl)pyridin-2-amine (8.0mg, 0.023mmol, 12%) as a white solid. MS: 349.1 [M+H]+.
[0442] Example 49: Synthesis of 3-(3-((6-((1-methyl-1H-pyrazol-4-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000146_0002
[0443] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 1-methyl-1H-pyrazol-4-yl-methanol (207mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((1-methyl-1H-pyrazol-4- yl)methoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (8.5mg, 0.023mmol, 13%) as a white solid. MS: 363.2 [M+H]+.
[0444] Example 50: Synthesis of 3-(3-((6-((2-methylthiazol-4-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000146_0003
[0445] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 2-methylthiazol-4-ylmethanol (213mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(2-methylthiazol-4-ylmethoxy)pyridin- 3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (25mg, 0.067mmol, 36%) as a white solid. MS: 380.1
[M+H]+.
[0446] Example 51: Synthesis of 3-(3-((6-((5-fluoropyridin-2-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000147_0001
[0447] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 5-fluoropyridin-2-yl)methanol (212mg, 1.67mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((5-fluoropyridin-2- yl)methoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (21mg, 0.056mmol, 30%) as a white solid. MS: 378.0 [M+H]+.
[0448] Example 52: Synthesis of 3-(3-((6-((2-methylfuran-3-yl)methoxy)pyridin-3-yl)methyl)isoxazol- 5-yl)pyridin-2-amine
Figure imgf000147_0002
[0449] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 2-methylfuran-3-ylmethanol (124mg, 1.11mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(2-methylfuran-3-ylmethoxy)pyridin- 3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (15mg, 0.040mmol, 22%) as a white solid. MS: 362.8
[M+H]+.
[0450] Example 53: Synthesis of 3-(3-((6-(oxazol-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000147_0003
[0451] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and oxazol-2-ylmethanol (128mg, 1.30mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(oxazol-2-ylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (25mg, 0.072mmol, 39%) as a white solid. MS: 350.0 [M+H]+.
[0452] Example 54: Synthesis of 3-(3-((6-((3-fluoropyridin-4-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000148_0001
[0453] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 3-fluoropyridin-2-yl)methanol (235mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((3-fluoropyridin-2- yl)methoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (40mg, 0.11mmol, 57%) as a white solid. MS: 378.2 [M+H]+.
[0454] Example 55: Synthesis of 3-(3-((6-(1-(pyridin-2-yl)ethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000148_0002
[0455] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 60 mg, 0.22mmol) and 1-(pyridin-2-yl)ethan-1-ol (164mg, 1.33mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 2.22mL, 2.22mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(1-(pyridin-2-yl)ethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (32mg, 0.086mmol, 39%) as a white solid. MS: 374.1 [M+H]+.
[0456] Example 56: Synthesis of 3-(3-((6-(1-(2-fluorophenyl)ethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000149_0001
[0457] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 1-(2-fluorophenyl)ethan-1-ol (207mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 2.22mL, 2.22mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(1-(2-fluorophenyl)ethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (30mg, 0.078mmol, 42%) as a white solid. MS: 391.3 [M+H]+.
[0458] Example 57: Synthesis of 3-(3-((6-(cyclobutylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000149_0002
[0459] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and cyclobutylmethanol (159mg, 1.85mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(cyclobutylmethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (30mg, 0.089mmol, 48%) as a white solid. MS: 337.4 [M+H]+.
[0460] Example 58: Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-phenylpyridin-2- amine
Figure imgf000149_0003
[0461] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and aniline (172mg, 1.85mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 2 hours. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N- phenylpyridin-2-amine (4.8mg, 0.014mmol, 7.6%) as an orange solid. MS: 344.1 [M+H]+. [0462] Example 59: Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(3- fluorophenyl)pyridin-2-amine
Figure imgf000150_0003
[0463] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 3-fluoroaniline (206mg, 1.85mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 2 hours. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(3- fluorophenyl)pyridin-2-amine (8.0mg, 0.022mmol, 12%) as a light orange solid. MS: 362.3 [M+H]+.
[0464] Example 60: Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2- fluorophenyl)pyridin-2-amine
Figure imgf000150_0001
[0465] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 2-fluoroaniline (206mg, 1.85mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 2 hours. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(3- fluorophenyl)pyridin-2-amine (18mg, 0.048mmol, 26%) as a pink solid. 500 MHz 1H NMR (formic acid- salt, DMSO-d6) d 9.07 (s, 1H), 8.20 (dd, J = 7.7, 1.7 Hz, 1H), 8.13 (dd, J = 5.6, 1.7 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.03 (td, J = 8.3, 1.7 Hz, 1H), 7.64 (dd, J = 8.7, 2.4 Hz, 1H), 7.25 (ddd, J = 11.6, 8.1, 1.4 Hz, 1H), 7.16 (td, J = 7.8, 1.4 Hz, 1H), 7.10– 7.03 (m, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.96 (s, 1H), 6.93 (dd, J = 7.6, 5.7 Hz, 1H), 4.00 (s, 2H) signal for -NH2, not observed. MS: 362.3 [M+H]+.
[0466] Example 61: Synthesis of 3-(3-((6-(benzylthio)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000150_0002
[0467] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 60 mg, 0.22mmol) and phenylmethanethiol (165mg, 1.33mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(benzylthio)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine (5.8mg, 0.015mmol, 7%) as a white solid. MS: 375.2 [M+H]+.
[0468] Example 62: Synthesis of 2-((4-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridine
Figure imgf000151_0001
Step 1: (4-((pyridin-2-yloxy)methyl)phenyl)methanol
Figure imgf000151_0002
[0469] 1,4-phenylenedimethanol (7.50g, 54.3mmol) and 2-fluoropyridine (1.76g, 18.09mmol) were dissolved in DMF (40mL) and sodium hydride (60% w/mineral oil, 2.171g, 54.3mmol) was added at 0°C in 10 portions over the course of 20min. The resulting mixture was allowed to warm to 21-25°C within 30min and then warmed to 70°C and stirred for 30min at this temperature. The cooled reaction mixture was poured into a stirring mixture of ice-water (300mL) and ethyl acetate (500mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine (50mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give (4-((pyridin-2-yloxy)methyl)phenyl)methanol (2.6g, 12.08mmol, 67%).
Step 2: 2-((4- (bromomethyl)benzyl)oxy)pyridine
Figure imgf000151_0003
[0470] (4-((pyridin-2-yloxy)methyl)phenyl)methanol (500 mg, 2.32mmol) and triphenylphosphane (914mg, 3.48mmol) were dissolved in THF (15mL) and 2g of celite were added. To the stirred mixture was added a partial solution/suspension of 1-bromopyrrolidine-2,5-dione (NBS, 558mg, 3.14mmol) in THF at 0°C. The mixture was allowed to warm to 21-25°C and stirred for 30min. All volatiles were removed under reduced pressure and the residue was purified by flash chromatography to obtain 2-((4- (bromomethyl)benzyl)oxy)pyridine (250mg, 0.90mmol, 39%) as a colorless oil.
Step 3: 2-((4-((4-bromo-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridine
Figure imgf000151_0004
[0471] Sodium hydride (60% w/mineral oil, 48.3mg, 1.21mmol) was suspended in DMF (2mL) and a solution of 4-bromo-1H-pyrazole (165 mg, 1.12mmol) in DMF (1.5mL) was added at 0°C. The mixture was allowed to warm to 23°C and stirred for 15min. A solution of 2-((4- (bromomethyl)benzyl)oxy)pyridine (240 mg, 0.86 mmol) in DMF (1.5mL) was added at 0°C and the mixture was stirred at 21-25°C for 10min. The mixture was warmed to 40°C for 2min. The cooled reaction mixture was then directly purified by flash chromatography to obtain 2-((4-((4-bromo-1H- pyrazol-1-yl)methyl)benzyl)oxy)pyridine (220mg, 0.64mmol, 74%) as a white solid.
Step 4: 2-((4-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridine
Figure imgf000152_0001
[0472] 2-((4-((4-bromo-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridine (110mg, 0.32mmol) and pyridin- 3-ylboronic acid (62.8mg, 0.51mmol) were mixed in a sealable tube with dioxane (3.5mL). A 2M solution of sodium carbonate in water (511mL, 1.02mmol) was added followed by Pd(dppf)2Cl2 (CH2Cl2 adduct, 26mg, 0.03mmol) and the tube was flushed with argon and sealed. The mixture was heated in the MW at 100°C for 10 min. The cooled reaction mixture was poured into a stirring mixture of water (30mL) and ethyl acetate (50mL). The layers were separated the aqueous phase was further extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine (10mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate).
[0473] Fractions containing the product also contained a small amount of inseparable impurities and were re-purified using RP flash chromatography (Biotage). Fractions containing the product were lyophilized to obtain 2-((4-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridine (53mg, 0.16mmol, 49%) as a white solid. 400 MHz 1H NMR (TFA-salt, CDCl3) d 9.00 (s, 1H), 8.57 (dd, J = 5.6, 1.4 Hz, 1H), 8.29 (dt, J = 8.2, 1.6 Hz, 1H), 8.23– 8.16 (m, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.77 (dd, J = 8.2, 5.4 Hz, 1H), 7.63 (ddd, J = 8.4, 7.1, 2.0 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 6.93 (ddd, J = 7.2, 5.2, 1.0 Hz, 1H), 6.83 (dt, J = 8.3, 0.9 Hz, 1H), 5.38 (s, 2H), 5.37 (s, 2H). MS: 343.4 [M+H]+.
[0474] The free base (RP chromatography solvent contained 0.05% TFA as modifier) was obtained as followed: The product was dissolved in DCM (2mL) and MP-Carbonate resin from Biotage (600mg) was added. The mixture was stirred for 30min and filtered. The resin was washed multiple times with DCM and all solvents were removed under reduced pressure. The residue was dissolved in a small amount of acetonitrile, water was added and the final product obtained by lyophilization.
[0475] Example 63: Synthesis of 3-(1-((6-phenoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2- amine
Figure imgf000152_0002
Step 1: 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2-fluoropyridine
Figure imgf000153_0001
[0476] 4-bromo-1H-pyrazole (2.02g, 13.74mmol) was dissolved in DMF (9mL) and potassium carbonate (1.90g, 13.74mmol) was added. 5-(chloromethyl)-2-fluoropyridine (1g, 6.87mmol) was dissolved in DMF (1mL) and added to the reaction mixture. The mixture was stirred for 4h at 21-25°C and directly purified by flash chromatography to give 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2- fluoropyridine (1.66g, 6.48mmol, 94%).
Step 2: 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2-phenoxypyridine
Figure imgf000153_0002
[0477] 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2-fluoropyridine (550mg, 2.15mmol) was dissolved in NMP (2.8mL). Phenol (1.01g, 10.75mmol) and potassium carbonate (1.48g, 10.75mmol) were added and the mixture was heated in the MW at 120°C for 20min. The crude mixture was purified using flash chromatography to obtain 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2-phenoxypyridine (260mg, 0.79mmol, 37%).
Step 3: 2-(benzyloxy)-5-((4-bromo-1H-pyrazol-1-yl)methyl)pyridine
Figure imgf000153_0003
[0478] Phenylmethanol (845mg, 7.81mmol) was added to a suspension of sodium hydride (60% w/mineral oil, 312mg, 7.81mmol) in DMF (4mL). After no more gases evolved, a solution of 5-((4- bromo-1H-pyrazol-1-yl)methyl)-2-fluoropyridine (500mg, 1.95mmol) in DMF (2mL) was added and the mixture was stirred at 21-25°C for 1h. The reaction mixture was poured into a stirring mixture of ice- water (50mL) and ethyl acetate (150mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine (30mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give 2-(benzyloxy)-5-((4-bromo-1H-pyrazol-1- yl)methyl)pyridine (440mg, 1.28mmol, 66%).
Step 4: 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2-(phenylthio)pyridine
Figure imgf000153_0004
[0479] 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2-fluoropyridine (500mg, 1.95mmol) was dissolved in NMP (2.8mL) and sodium benzenethiolate (516mg, 3.91mmol) was added. The mixture was heated in the MW at 100°C for 15min. The crude mixture was purified using flash chromatography to obtain 5-((4- bromo-1H-pyrazol-1-yl)methyl)-2-(phenylthio)pyridine (270mg, 0.78mmol, 40%). Step 5: 3-(1-((6-phenoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine
Figure imgf000154_0001
[0480] 5-((4-bromo-1H-pyrazol-1-yl)methyl)-2-phenoxypyridine (130mg, 0.39mmol) and 3-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-amine (139mg, 0.63mmol) were mixed in a sealable tube with dioxane (3.5mL). A 2M solution of sodium carbonate in water (492mL, 0.98mmol) was added followed by Pd(dppf)2Cl2 (CH2Cl2 adduct, 32mg, 0.04mmol) and the tube was flushed with argon and sealed. The mixture was heated in the MW at 100 °C for 20min. The cooled reaction mixture was poured into a stirring mixture of water (30mL) and ethyl acetate (50mL). The layers were separated the aqueous phase was further extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine (10mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate).
[0481] Fractions containing the product also contained a small amount of inseparable impurities and were re-purified using RP flash chromatography (Biotage). Fractions containing the product were lyophilized to obtain 3-(1-((6-phenoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine (80mg, 0.23mmol, 59%).400 MHz 1H NMR (TFA-salt, DMSO-d6) d 8.34 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.03 – 7.81 (m, 6H), 7.46– 7.36 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.14– 7.06 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 6.8 Hz, 1H), 5.38 (s, 2H). MS: 344.4 [M+H]+.
[0482] Example 64: Synthesis of 2-phenoxy-5-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)pyridine
Figure imgf000154_0002
[0483] The title compound was prepared according to the procedure described for Example 63 using pyridin-3-ylboronic acid (121mg, 0.98mmol) to yield 2-phenoxy-5-((4-(pyridin-3-yl)-1H-pyrazol-1- yl)methyl)pyridine (78mg, 0.24mmol, 60%). 400 MHz 1H NMR (DMSO-d6) d 9.21 (d, J = 2.0 Hz, 1H), 8.81– 8.65 (m, 3H), 8.26 (d, J = 0.8 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 8.2, 5.7 Hz, 1H), 7.83 (dd, J = 8.5, 2.5 Hz, 1H), 7.47– 7.36 (m, 2H), 7.28– 7.16 (m, 1H), 7.15– 7.07 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H), 5.40 (s, 2H). MS: 329.3 [M+H]+.
[0484] Example 65: Synthesis of 2-(benzyloxy)-5-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)pyridine
Figure imgf000154_0003
[0485] The title compound was prepared according to the procedure described for Example 63 using 2- (benzyloxy)-5-((4-bromo-1H-pyrazol-1-yl)methyl)pyridine (130mg, 0.38mmol) and pyridin-3-ylboronic acid (84mg, 0.68mmol) to yield 2-(benzyloxy)-5-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)pyridine (75mg, 0.22mmol, 58%). MS: 343.3 [M+H]+.
[0486] Example 66: Synthesis of 2-(phenylthio)-5-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)pyridine
Figure imgf000155_0001
[0487] The title compound was prepared according to the procedure described for Example 63 using 5- ((4-bromo-1H-pyrazol-1-yl)methyl)-2-(phenylthio)pyridine (130mg, 0.38mmol) and pyridin-3-ylboronic acid (83mg, 0.68mmol) to yield 2-(phenylthio)-5-((4-(pyridin-3-yl)-1H-pyrazol-1-yl)methyl)pyridine (25mg, 0.07mmol, 19%). MS: 345.3 [M+H]+.
[0488] Example 67: Synthesis of 3-(1-((6-(phenylthio)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2- amine
Figure imgf000155_0002
[0489] The title compound was prepared according to the procedure described for Example 63 using 5- ((4-bromo-1H-pyrazol-1-yl)methyl)-2-(phenylthio)pyridine (130mg, 0.38mmol) and 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (149mg, 0.68mmol) to yield 3-(1-((6- (phenylthio)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine (40mg, 0.11mmol, 30%). MS: 360.4 [M+H]+.
[0490] Example 68: Synthesis of 5-(1-((6-(benzyloxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2- amine
Figure imgf000155_0003
[0491] The title compound was prepared according to the procedure described for Example 63 using 2- (benzyloxy)-5-((4-bromo-1H-pyrazol-1-yl)methyl)pyridine (170mg, 0.49mmol) and (6-aminopyridin-3- yl)boronic acid (123mg, 0.89mmol) to yield 5-(1-((6-(benzyloxy)pyridin-3-yl)methyl)-1H-pyrazol-4- yl)pyridin-2-amine (82mg, 0.23mmol, 47%). 400 MHz 1H NMR (DMSO-d6) d 8.16 (m, 2H), 8.10 (s, 1H), 7.75 (s, 1H), 7.66 (dd, J = 8.5, 2.5 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.46– 7.25 (m, 5H), 6.86 (d, J = 8.6, 1H), 6.46 (d, J = 7.5 Hz, 1H), 5.87 (s, 2H), 5.33 (s, 2H), 5.26 (s, 2H). MS: 358.4 [M+H]+.
[0492] Example 69: Synthesis of 3-(3-(4-((2-fluoropyridin-3-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000155_0004
[0493] The title compound was prepared according to the procedure described for Example 8 using (6- fluoropyridin-2-yl)boronic acid (94.0mg, 0.67mmol) to yield 3-(3-(4-((2-fluoropyridin-3- yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (62mg, 0.17mmol, 52%) as a white solid. MS: 361.4 [M+H]+. [0494] Example 70: Synthesis of 3-(3-(4-(((2-fluoropyridin-4-yl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000156_0001
[0495] The title compound was prepared according to the procedure described for Example 31 using 2,4-difluoropyridine (185mg, 1.61mmol) to yield 3-(3-(4-(((2-fluoropyridin-4- yl)amino)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (36mg, 0.10mmol, 36%) as a white solid. MS: 376.4 [M+H]+.
[0496] Example 71: Synthesis of 4-((5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)pyridin-2- yl)oxy)-2,5-dimethylfuran-3(2H)-one
Figure imgf000156_0002
[0497] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 4-hydroxy-2,5-dimethylfuran-3(2H)-one (190mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 4-((5-((5-(2-aminopyridin-3- yl)isoxazol-3-yl)methyl)pyridin-2-yl)oxy)-2,5-dimethylfuran-3(2H)-one (3.3mg, 0.0087mmol, 4.7%) as a white solid. MS: 379.3 [M+H]+.
[0498] Example 72: Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,3- difluorophenyl)pyridin-2-amine
Figure imgf000156_0003
[0499] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) and 2,3-difluoroaniline (191mg, 1.48mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the stirred mixture was heated to 90°C for 2 hours. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate).
Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 5-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)-N-(2,3-difluorophenyl)pyridin-2-amine (21mg, 0.055mmol, 30.%) as a white solid. MS: 380.3 [M+H]+. [0500] Example 73: Synthesis of 3-(3-((6-(furan-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000157_0001
[0501] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) furan-2-ylmethanol (181mg, 1.85mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(furan-2-ylmethoxy)pyridin-3-yl)methyl)isoxazol- 5-yl)pyridin-2-amine (32mg, 0.092mmol, 50.%) as a white solid. MS: 349.3 [M+H]+.
[0502] Example 74: Synthesis of 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2- fluorobenzyl)pyridin-2-amine
Figure imgf000157_0002
[0503] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) 2-fluorobenzylamine (139mg, 1.10mmol) was added
diisopropylethylamine (0.323mL, 1.85mmol), DMSO (1.0mL), THF (1.0mL) and the mixture was stirred for 16 hours. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 5-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)-N-(2-fluorobenzyl)pyridin-2-amine as a white solid. MS: 376.2 [M+H]+.
[0504] Example 75: Synthesis of 3-(3-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000157_0003
[0505] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol) 2,4-difluorophenol (144mg, 1.10mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred at 90 °C for 2 hours. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate).
Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(2,4-difluorophenoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (29mg, 0.075mmol, 41%) as a white solid. MS: 381.3 [M+H]+.
[0506] Example 76: Synthesis of 4-(((5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)pyridin-2- yl)oxy)methyl)benzonitrile
Figure imgf000158_0001
[0507] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50 mg, 0.19mmol), 4-(hydroxymethyl)benzonitrile (197mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 4-(((5-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)pyridin-2-yl)oxy)methyl)benzonitrile (4.3mg, 0.011mmol, 6.0%) as a white solid. MS: 384.2 [M+H]+.
[0508] Example 77: Synthesis of 3-(3-((6-(2-fluorophenethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000158_0002
[0509] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol) 2-(2-fluorophenyl)ethan-1-ol (156mg, 1.10mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(2-fluorophenethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (24mg, 0.062mmol, 33%) as a white solid. MS: 391.1 [M+H]+.
[0510] Example 78: Synthesis of 3-(3-((6-phenethoxypyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000158_0003
[0511] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol) 2-(2-fluorophenyl)ethan-1-ol (156mg, 1.10mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-phenethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (28mg, 0.074mmol, 40.%) as a white solid. MS: 373.0 [M+H]+.
[0512] Example 79: Synthesis of 3-(3-((6-(4-fluorophenethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000159_0001
[0513] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol) 2-(4-fluorophenyl)ethan-1-ol (207mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-phenethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (25mg, 0.046mmol, 25%) as a white solid. MS: 391.4 [M+H]+.
[0514] Example 80: Synthesis of 3-(3-((6-((3-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000159_0002
[0515] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol), (3-fluorophenyl)methanol (187mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((3-fluorobenzyl)oxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (45mg, 0.12mmol, 65%) as a white solid. MS: 377.3 [M+H]+.
[0516] Example 81: Synthesis of 3-(3-((6-(3,5-difluorophenoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000159_0003
[0517] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol) 3,5-difluorophenol (193mg, 1.48mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred at 90°C for 2 hours. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(3,5-difluorophenoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (7.4mg, 0.019mmol, 11%) as a white solid. 500 MHz 1H NMR (DMSO-d6) d 8.21 (dt, J = 2.4, 0.7 Hz, 1H), 8.09 (dd, J = 4.9, 1.9 Hz, 1H), 7.90– 7.83 (m, 2H), 7.13– 7.05 (m, 2H), 7.00– 6.91 (m, 2H), 6.86 (s, 1H), 6.70 (ddd, J = 7.7, 4.7, 0.5 Hz, 1H), 6.27 (s, 2H), 4.06 (s, 2H). MS: 381.1 [M+H]+.
[0518] Example 82: Synthesis of 3-(3-((6-((4-methylthiazol-2-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000160_0001
[0519] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol), 4-methylthiazol-2-yl)methanol (191mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((4-methylthiazol-2- yl)methoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (46mg, 0.12mmol, 66%) as a white solid. MS: 380.2 [M+H]+.
[0520] Example 83: Synthesis of 3-(3-((6-((2-chloropyridin-4-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000160_0002
[0521] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol), 2-chloropyridin-4-yl)methanol (32mg, 0.22mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((2-chloropyridin-4- yl)methoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (2.7mg, 0.0068mmol, 3.7%) as a white solid. MS: 394.2 [M+H]+.
[0522] Example 84: Synthesis of 3-(3-((6-((3,5-difluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000161_0001
[0523] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol), (3,5-difluorophenyl)methanol (213mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((3,5-difluorobenzyl)oxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (49mg, 0.12mmol, 67%) as a white solid. MS: 395.2 [M+H]+.
[0524] Example 85: Synthesis of 3-(3-((6-((3-chlorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000161_0002
[0525] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol), (3-chlorophenyl)methanol (211mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((3-chlorobenzyl)oxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (40mg, 0.10mmol, 55%) as a white solid. MS: 393.2 [M+H]+.
[0526] Example 86: Synthesis of 3-(3-((2-((3-fluorobenzyl)oxy)pyridin-4-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000161_0003
[0527] To a neat mixture of 3-(3-((2-fluoropyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine (40 mg, 0.15mmol), (3-fluorophenyl)methanol (187mg, 1.48mmol) was added potassium 2-methylpropane-2- olate (1M in THF, 1.48mL, 1.48mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((2-((3-fluorobenzyl)oxy)pyridin-4-yl)methyl)isoxazol-5-yl)pyridin- 2-amine (23mg, 0.061mmol, 41%) as a white solid.500 MHz 1H NMR (DMSO-d6) d 8.11 (dd, J = 5.2, 0.7 Hz, 1H), 8.09 (dd, J = 4.8, 1.8 Hz, 1H), 7.87 (dd, J = 7.7, 1.9 Hz, 1H), 7.43– 7.38 (m, 1H), 7.29– 7.24 (m, 2H), 7.16– 7.11 (m, 1H), 6.98 (dd, J = 5.2, 1.4 Hz, 1H), 6.88– 6.85 (m, 2H), 6.70 (dd, J = 7.7, 4.8 Hz, 1H), 6.26 (s, 2H), 5.35 (s, 2H), 4.05 (s, 2H). MS: 377.0 [M+H]+.
[0528] Example 87: Synthesis of 3-(3-((6-((3-chloro-5-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol- 5-yl)pyridin-2-amine
Figure imgf000162_0001
[0529] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol), (3-chloro-5-fluorophenyl)methanol (178mg, 1.11mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((3-chloro-5-fluorobenzyl)oxy)pyridin- 3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (52mg, 0.13mmol, 69%) as a white solid. MS: 411.3
[M+H]+.
[0530] Example 88: Synthesis of 3-(3-((2-((phenoxypyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000162_0002
[0531] To a neat mixture of 3-(3-((2-fluoropyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine (40 mg, 0.148mmol), phenol (139mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.48mL, 1.48mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((2-((phenoxypyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine (7.4mg, 0.021mmol, 15%) as a white solid. MS: 345.1 [M+H]+.
[0532] Example 89: Synthesis of 3-(3-((6-((3-fluorobenzyl)oxy)pyridin-2-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000162_0003
[0533] To a neat mixture of 3-(3-((6-fluoropyridin-2-yl)methyl)isoxazol-5-yl)pyridin-2-amine (40mg, 0.15mmol), (3-fluorophenyl)methanol (187mg, 1.48mmol) was added potassium 2-methylpropane-2- olate (1M in THF, 1.48mL, 1.48mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((3-fluorobenzyl)oxy)pyridin-2-yl)methyl)isoxazol-5-yl)pyridin- 2-amine (10mg, 0.027mmol, 18%) as a white solid. MS: 377.3 [M+H]+.
[0534] Example 90: Synthesis of 3-(3-((6-((2-fluorobenzyl)oxy)pyridin-2-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000163_0001
[0535] To a neat mixture of 3-(3-((6-fluoropyridin-2-yl)methyl)isoxazol-5-yl)pyridin-2-amine (40mg, 0.15mmol), (2-fluorophenyl)methanol (187mg, 1.48mmol) was added potassium 2-methylpropane-2- olate (1M in THF, 1.48mL, 1.48mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((2-fluorobenzyl)oxy)pyridin-2-yl)methyl)isoxazol-5-yl)pyridin- 2-amine (25mg, 0.065mmol, 44%) as a white solid. MS: 377.2 [M+H]+.
[0536] Example 91: Synthesis of 3-(3-((6-(3-fluorophenethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000163_0002
[0537] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol), 2-(3-fluorophenyl)ethan-1-ol (207mg, 1.48mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(3-fluorophenethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (10mg, 0.026mmol, 14%) as a white solid. MS: 391.4 [M+H]+.
[0538] Example 92: Synthesis of 3-(3-((6-((4-chloropyridin-2-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000163_0003
[0539] To a neat mixture of 3-(3-((6-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
(Intermediate E, 50mg, 0.19mmol), (4-chloropyridin-2-yl)methanol (159mg, 1.11mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(3-fluorophenethoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (10mg, 0.025mmol, 14%) as a white solid. MS: 394.2 [M+H]+.
[0540] Example 93: Synthesis of 3-(3-(4-((((1H-pyrazol-5-yl)methyl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000164_0001
[0541] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 0.10 g, 0.33 mmol) and (1H-pyrazol-5-yl)methanamine (0.16 g, 1.7 mmol) were suspended in tetrahydrofuran (2 mL).
Diisopropylethylamine (0.14 mL, 0.80 mmol) was added and the mixture was stirred at 60◦C for 18h. The mixture was diluted with water and ethyl acetate, and the layers were partitioned. The aqueous phase was extracted twice more with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified using Biotage reverse- phase flash chromatography (12g C18 SNAP, 5-95% acetonitrile/water with 0.1% formic acid). The desired fractions were combined and lyophilized to give the title compound as a formate salt (0.0040 g, 0.010 mmol, 3%). MS: 361.2 [M+H]+.
[0542] Example 94: Synthesis of 2-((4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)benzyl)amino)acetonitrile
Figure imgf000164_0002
[0543] Prepared according to the procedure described in Example 93 using 2-aminoacetonitrile hydrochloride (0.15 g, 1.7 mmol). The title compound was obtained as a formate salt (0.0087 g, 0.024 mmol, 7%). MS: 320.2 [M+H]+.
[0544] Example 95: Synthesis of 3-(3-(4-((((tetrahydro-2H-pyran-4- yl)methyl)amino)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000164_0003
[0545] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 0.10 g, 0.33 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.19 g, 1.7 mmol) were suspended in tetrahydrofuran (2 mL). Diisopropylethylamine (0.14 mL, 0.80 mmol) was added the heterogeneous mixture was stirred at room temperature for 3 hours. LCMS indicated a small peak with m/z corresponding to the desired product. The milky yellow mixture was heated at 60◦C for 72h. Significant progress was noted, but the mixture was still mostly starting material. The mixture was diluted with water and ethyl acetate, and the layers were partitioned. The aqueous phase was extracted twice more with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified using Biotage reverse phase flash chromatography (12g C18 SNAP, 5-95% acetonitrile/water with 0.1% formic acid). The desired fractions were combined and lyophilized to give the titled compound as a formate salt (0.0055 g, 0.013 mmol, 4%). MS: 379.3 [M+H]+.
[0546] Example 96: Synthesis of 3-((4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)benzyl)amino)azepan-2-one
Figure imgf000165_0001
[0547] Prepared according to the procedure described in Example 93 using 3-aminoazepan-2-one (0.21 g, 1.7 mmol) and a 2-day reaction time. The title compound was obtained as a formate salt (0.056 g, 0.13 mmol, 39%). MS: 392.3 [M+H]+.
[0548] Example 97: Synthesis of 3-(3-(4-Vinylbenzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000165_0002
Step 1: synthesis of Di-tert-butyl [3-(3-(4-vinylbenzyl)isoxazol-5-yl)pyridin-2-yl]imidodicarbonate
[0549] Di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (Intermediate A, 1.7 g, 4.5 mmol), (4-vinylphenyl)boronic acid (0.82 g, 5.5 mmol), bis[(2-diphenylphosphino)phenyl] ether (0.11 g, 0.21 mmol), palladium(II) acetate (0.048 g, 0.21 mmol), potassium carbonate (0.76 g, 5.5 mmol), dimethylformamide (17 mL) and water (1.2 mL) were combined in a 50 mL sealed tube and heated at 60◦C for 18 hours. The mixture was cooled to ambient temperature, and then diluted with water and toluene. The layers were partitioned, and the aqueous phase was extracted twice more with toluene. The combined organic phase was washed with water, and then brine. The organic phase was dried over sodium sulfate and then the solvents were evaporated. The residue was purified in two portions, each using Biotage normal-phase flash chromatography (50 g SNAP Ultra, 5-65% ethyl acetate / hexane). The desired fractions from each purification were combined to give the title compound as a pale-yellow oil (1.3 g, 2.7 mmol, 65%). This material was taken forward without further purification.
Step 2: synthesis of 3-(3-(4-Vinylbenzyl)isoxazol-5-yl)pyridin-2-amine
[0550] Di-tert-butyl [3-(3-(4-vinylbenzyl)isoxazol-5-yl)pyridin-2-yl]imidodicarbonate (0.017 g, 0.036 mmol) was dissolved in formic acid (3 mL). The mixture was stirred at room temperature for 4 days. The solution was treated with pH7 buffer (3 mL), and then basified with 5N aqueous sodium hydroxide to pH 9-10. Ethyl acetate was added, and the layers were partitioned. The aqueous phase was extracted twice more with ethyl acetate. The combined organic phase was washed with water, and then brine. The organic phase was dried over sodium sulfate, and then the solvents were evaporated. The residue was purified using Biotage reverse-phase flash chromatography (12 g C18 SNAP, 5-95% acetonitrile/water with 0.1% formic acid). The desired fractions were combined and lyophilized to give the title compound as a white solid (0.0020g, 0.0072 mmol, 20%). MS: 378.3 [M+H]+.
[0551] Example 98: Synthesis of 2-((4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenethyl)thio)ethyl formate
Figure imgf000166_0001
[0552] Di-tert-butyl [3-(3-(4-vinylbenzyl)isoxazol-5-yl)pyridin-2-yl]imidodicarbonate (0.20 g, 0.42 mmol), 2,2-dimethoxy-2-phenylacetophenone (0.0054 g, 0.021 mmol), 2-mercaptoethanol (0.030 mL, 0.42 mmol), dichloromethane (0.7 mL) were combined in a 2 mL sealed tube and stirred under UV light (365 nm, 4W) at ambient temperature for 4h. The mixture was concentrated somewhat and then purified using Biotage normal-phase flash chromatography (25 g SNAP Ultra, 5-65% acetone/hexane). The desired fractions were combined and evaporated to give the di-BOC protected product. This material was dissolved in formic acid (6 mL) and stirred at room temperature for 13 hours. The mixture was treated with pH7 buffer (20 mL), and then basified to pH 10 with 45% aqueous potassium hydroxide. The mixture was stirred for 15 minutes, then ethyl acetate was added and the mixture stirred for another 5 hours. The layers were partitioned. The aqueous phase was extracted twice more with ethyl acetate. The combined organic phase was washed with water, and then brine. The organic phase was dried over sodium sulfate, and then the solvents were evaporated. The residue was partially dissolved in methanol. The insoluble material was further (but not completely) dissolved in dimethyl sulfoxide. Both crude solutions were purified separately using Biotage reverse phase flash chromatography (12 g C18 SNAP, 5-95% acetonitrile/water with 0.1% formic acid). The like fractions from each purification were combined to give the title compound as a white solid (40 mg, 0.10 mmol, 25%). MS: 384.1 [M+H]+.
[0553] Example 99: Synthesis of (E)-3-(3-(4-(2-cyclohexylvinyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000166_0002
[0554] Di-tert-butyl [3-(3-(4-vinylbenzyl)isoxazol-5-yl)pyridin-2-yl]imidodicarbonate (0.50 g, 1.1 mmol), vinylcyclohexane (0.29 mL, 4.2 mmol), Grubbs catalyst 2nd generation (0.053 g, 0.0.064 mmol), and dichloromethane (7 mL) were combined in a sealed tube. The mixture was sparged with argon for 2 minutes, and then heated to 40◦C. After 16 hours, another 2 equivalents of vinylcyclohexane (0.29 mL, 4.2 mmol) and another 0.03 equivalents of catalyst (0.026 g, 0.032) were added. The vial was sealed and sparged with argon for 2 min. The mixture was again heated to 40◦C and stirred for another 24 hours. After cooling to room temperature the reaction was quenched by addition of Isolute Si-Thiol resin (10 equivalents relative to Ru, 0.74 g, 0.96 mmol). The mixture was stirred for 3 hours before filtering through a plug of Celite. The filtrate was evaporated and the residue was purified using Biotage normal- phase flash chromatography (100 g SNAP Ultra, 5-60% ethyl acetate / hexane. The desired fractions were combined and evaporated to give di-tert-butyl [(E)-3-(3-(4-(2-cyclohexylvinyl)benzyl)isoxazol-5- yl)pyridin-2-yl]imidodicarbonate (0.17 g, 0.30 mmol, 28%). A portion of this material (0.10 g, 0.18 mmol) was dissolved in formic acid (5 mL) and stirred at room temperature for 4 hours. The solution was cooled to 0◦C and then basified to pH 10 with 50% aqueous sodium hydroxide solution. The mixture was further diluted with water and extracted three times with ethyl acetate. The combined organic phase was washed with water, and then brine. The organic phase was dried over sodium sulfate, and then the solvents were evaporated to give a solid residue. The solid was dissolved in 1,2-dimethoxyethane (5 mL), transferred through a 0.45µ syringe filter into a 50 mL conical tube, and then treated with 4M hydrogen chloride in dioxane (1.5 mL). No precipitate formed. The solvent was evaporated to give an off-white solid. The material was washed into a 50 mL conical tube using 1,2-dimethoxyethane (5 mL). The tube was centrifuged at 3200 rpm for 7 minutes. The supernatant was decanted, more 1,2-dimethoxyethane was added to the pellet. The suspension was vortexed, and then centrifuged at 3200 rpm for 7 min. The supernatant was decanted and the white pellet was dissolved with acetonitrile, transferred to a round bottom flask, and extensively dried under vacuum to give the title compound as a white solid
hydrochloride salt (0.066 g, 0.17 mmol, 93%). MS: 360.2 [M+H]+.
[0555] Example 100: Synthesis of 3-(3-(4-(2-cyclohexylethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000167_0001
[0556] Palladium on carbon (10 wt%, 3 mg) was placed into a round bottom flask and covered with ethanol (0.5 mL). Di-tert-butyl [(E)-3-(3-(4-(2-cyclohexylvinyl)benzyl)isoxazol-5-yl)pyridin-2- yl]imidodicarbonate (0.070 g, 0.13 mmol) was transferred into the flask with more ethanol (0.5 mL). The head-space was purged with argon, and then with hydrogen. A balloon filled with hydrogen was affixed to the flask with a needle through a rubber septum. The mixture was stirred briskly for 3 hours, before carefully filtering through a pad of Celite with methanol. The solvent was evaporated to give an oil which was purified using Biotage normal-phase flash chromatography (10 g SNAP Ultra, 5-60% ethyl acetate/hexane). The desired fractions were combined and evaporated to give di-tert-butyl [3-(3-(4-(2- cyclohexylethyl)benzyl)isoxazol-5-yl)pyridin-2-yl]imidodicarbonate (0.050 g, 0.089 mmol, 69%). This material was dissolved in formic acid (1 mL) and stirred at room temperature for 18 hours. The solution was cooled to 0◦C and then basified to pH 10 with 50% aqueous sodium hydroxide solution. The mixture was further diluted with water and extracted three times with ethyl acetate. The combined organic phase was washed with water, and then brine. The organic phase was dried over sodium sulfate, and then the solvents were evaporated. The residue was dissolved in 1,2-dimethoxyethane (5 mL), transferred through a 0.45µ syringe filter into a 50 mL conical tube, and then treated with 4M hydrogen chloride in dioxane (1.5 mL). A white precipitate formed. The tube was centrifuged at 3200 rpm for 7 minutes. The supernatant was decanted, more 1,2-dimethoxyethane was added to the pellet. The suspension was vortexed, and then centrifuged at 3200 rpm for 7 min. The centrifuge procedure was repeated for a third time. The supernatant was decanted and the white pellet was dissolved with acetonitrile, transferred to a round bottom flask, and extensively dried under vacuum to give the title compound as a white solid hydrochloride salt (0.030 g, 0.076 mmol, 85%). MS: 362.1 [M+H]+.
[0557] Example 101: Synthesis of 3-(1-((6-(benzyloxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2- amine
Figure imgf000168_0001
[0558] The title compound was prepared according to the procedure described for Example 63 using 2- (benzyloxy)-5-((4-bromo-1H-pyrazol-1-yl)methyl)pyridine (130mg, 0.38mmol) and 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (150mg, 0.68mmol) to yield 3-(1-((6- (benzyloxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine (50mg, 0.14mmol, 37%). MS: 358.3 [M+H]+.
[0559] Example 102: Synthesis of (1-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-1H- pyrazol-4-yl)methanol
Figure imgf000168_0002
[0560] The title compound was prepared according to the procedure described for Example 4 using (1H- pyrazol-4-yl)methanol (105mg, 1.07mmol) to yield (1-(4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)benzyl)-1H-pyrazol-4-yl)methanol (59mg, 0.16mmol, 61%) as a white solid. MS: 362.4
[M+H]+.
[0561] Example 103: Synthesis of 3-(3-(4-((3-propylphenoxy)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000168_0003
[0562] A solution of 3-propylphenol (182mg, 1.33mmol) in NMP (0.5mL) was added to a suspension of sodium hydride (60% w/mineral oil, 40mg, 1.00mmol) in NMP (1.5mL). After stirring for 20min at 21- 25°C, a solution of 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 100mg, 0.33mmol) in NMP (1ml) was added and the mixture was stirred for 4min at 60°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by HPLC to yield 3-(3-(4-((3-propylphenoxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (35mg, 0.09mmol, 26%). MS: 400.4 [M+H]+.
[0563] Example 104: Synthesis of 3-(3-(4-((3,4-dimethoxyphenoxy)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000169_0001
[0564] The title compound was prepared according to the procedure described for Example 103 using 3,4-dimethoxyphenol (206mg, 1.33mmol) to yield 3-(3-(4-((3,4- dimethoxyphenoxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (64mg, 0.15mmol, 46%) as a white solid. MS: 418.4 [M+H]+.
[0565] Example 105: Synthesis of 3-(3-(4-((pyridin-3-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000169_0002
[0566] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 120mg,
0.40mmol), pyridine-3-ol (305mg, 3.20mmol) and potassium carbonate (443mg, 3.20mmol) were mixed in DMF (2mL). The mixture was stirred for 1h at 80°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by HPLC to yield 3-(3-(4-((pyridin-3- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (12mg, 0.03mmol, 8%).400 MHz 1H NMR (CDCl3) d 8.38 (dd, J = 2.8, 0.9 Hz, 1H), 8.23 (dd, J = 4.4, 1.6 Hz, 1H), 8.14 (dd, J = 4.9, 1.8 Hz, 1H), 7.70 (dd, J = 7.7, 1.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.28– 7.19 (m, 2H), 6.71 (dd, J = 7.7, 4.9 Hz, 1H), 6.26 (s, 1H), 5.41 (s, 2H), 5.10 (s, 2H), 4.08 (s, 2H). MS: 359.4 [M+H]+.
[0567] Example 106: Synthesis of 3-(3-(4-(((2-fluorophenyl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000169_0003
[0568] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 80mg, 0.27mmol) was dissolved in DMF (1.5mL) and 2-fluoroaniline (297mg, 2.67mmol) was added. The mixture was stirred for 40min at 90°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-(4-(((2-fluorophenyl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine (54mg, 0.14mmol, 54%). MS: 375.3 [M+H]+.
[0569] Example 107: Synthesis of 3-(3-(4-(((3-fluorophenyl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000169_0004
[0570] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 80mg, 0.27mmol) was dissolved in DMF (1.5mL) and 3-fluoroaniline (297mg, 2.67mmol) was added. The mixture was stirred for 40min at 90°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-(4-(((3-fluorophenyl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine (67mg, 0.18mmol, 67%). MS: 375.3 [M+H]+.
[0571] Example 108: Synthesis of 3-(3-(4-(((2,3-difluorophenyl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000170_0001
[0572] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridin-2-amine (Intermediate B, 80mg, 0.27mmol) was dissolved in DMF (1.5mL) and 2,3-difluoroaniline (345mg, 2.67mmol) was added. The mixture was stirred for 2h at 110°C. The cooled reaction mixture was directly purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-(4-(((2,3-difluorophenyl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine (46mg, 0.12mmol, 44%). MS: 393.4 [M+H]+.
[0573] Example 109: Synthesis of 3-(3-(4-((4-methoxybenzyl)oxy)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000170_0002
[0574] The title compound was prepared according to the procedure described for Example 26 using 1- (chloromethyl)-4-methoxybenzene (56mg, 0.36mmol) to yield 3-(3-(4-((4- methoxybenzyl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine (64mg, 0.16mmol, 55%) as a white solid. MS: 388.3 [M+H]+.
[0575] Example 110: Synthesis of 3-(3-(4-(pyridin-2-yloxy)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000170_0003
[0576] 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (100mg, 0.37mmol) was dissolved in DMF (1mL) and potassium 2-methylpropane-2-olate (1M in THF, 0.33mL, 0.33mmol) was added dropwise. The mixture was stirred for 5min and a solution of 2,6-difluoropyridine (51mg, 0.52mmol) in DMF (0.5mL) was added. The resulting mixture was stirred for 6h at 90°C and directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by reversed phase flash chromatography (C18,
acetonitrile/water) to yield 3-(3-(4-(pyridin-2-yloxy)benzyl)isoxazol-5-yl)pyridin-2-amine (35mg, 0.10mmol, 27%) as a white solid. MS: 345.3 [M+H]+. [0577] Example 111: Synthesis of 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000171_0001
[0578] 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (80mg, 0.30mmol) was dissolved in DMF (1mL) and potassium 2-methylpropane-2-olate (1M in THF, 0.33mL, 0.33mmol) was added dropwise. The mixture was stirred for 5min and a solution of 2,6-difluoropyridine (48.2mg, 0.42mmol) in DMF (0.5mL) was added. The resulting mixture was stirred for 3min at 90°C and directly purified by column chromatography (SiO2, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by reversed phase flash chromatography (C18,
acetonitrile/water) to yield 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine (65mg, 0.18mmol, 60%) as a white solid.400 MHz 1H NMR (CDCl3) d 8.14 (s, 1H), 7.80– 7.69 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.77– 6.68 (m, 2H), 6.60 (dd, J = 7.8, 2.6 Hz, 1H), 6.30 (s, 1H), 5.43 (s, 2H), 4.07 (s, 2H). MS: 363.3 [M+H]+.
[0579] Example 112: Synthesis of 3-(3-(4-(thiazol-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000171_0002
The title compound was prepared according to the procedure described for Example 26 using 2- (chloromethyl)thiazole (48mg, 0.36mmol) to yield 3-(3-(4-(thiazol-2-ylmethoxy)benzyl)isoxazol-5- yl)pyridin-2-amine (62mg, 0.17mmol, 57%) as a white solid. MS: 365.3 [M+H]+.
[0580] Example 113: Synthesis of 4-((4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenoxy)methyl)benzonitrile
Figure imgf000171_0003
[0581] The title compound was prepared according to the procedure described for Example 26 using 4- (chloromethyl)benzonitrile (54mg, 0.36mmol) to yield 4-((4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenoxy)methyl)benzonitrile (69mg, 0.18mmol, 60%) as a white solid. MS: 383.3 [M+H]+.
[0582] Example 114: Synthesis of 3-(3-(4-((5-methylpyridin-3-yl)methoxy)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000171_0004
[0583] The title compound was prepared according to the procedure described for Example 26 using 3- (chloromethyl)-5-methylpyridine hydrochloride (75mg, 0.42mmol) and potassium 2-methylpropane-2- olate (1M in THF, 0.75mL, 0.75mmol) to yield 3-(3-(4-((5-methylpyridin-3-yl)methoxy)benzyl)isoxazol- 5-yl)pyridin-2-amine (87mg, 0.23mmol, 78%) as a white solid. MS: 373.3 [M+H]+.
[0584] Example 115: Synthesis of 3-(3-(4-((5-fluoropyridin-3-yl)methoxy)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000172_0001
[0585] The title compound was prepared according to the procedure described for Example 26 using 3- (chloromethyl)-5-fluoropyridine hydrochloride (76mg, 0.42mmol) and potassium 2-methylpropane-2- olate (1M in THF, 0.75mL, 0.75mmol) to yield 3-(3-(4-((5-fluoropyridin-3-yl)methoxy)benzyl)isoxazol- 5-yl)pyridin-2-amine (50mg, 0.13mmol, 44%) as a white solid. MS: 377.3 [M+H]+.
[0586] Example 116: Synthesis of 3-(3-(4-((6-fluoropyridin-3-yl)methoxy)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000172_0002
[0587] The title compound was prepared according to the procedure described for Example 26 using 5- (chloromethyl)-2-fluoropyridine (59mg, 0.40mmol) to yield 3-(3-(4-((6-fluoropyridin-3- yl)methoxy)benzyl)isoxazol-5-yl)pyridin-2-amine (56mg, 0.15mmol, 44%) as a white solid. MS: 377.4 [M+H]+.
[0588] Example 117: Synthesis of 3-(3-(4-((2-chloropyridin-4-yl)methoxy)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000172_0003
[0589] The title compound was prepared according to the procedure described for Example 26 using 2- chloro-4-(chloromethyl)pyridine (66mg, 0.40mmol) to yield 3-(3-(4-((2-chloropyridin-4- yl)methoxy)benzyl)isoxazol-5-yl)pyridin-2-amine (54mg, 0.14mmol, 41%) as a white solid. MS: 393.5 [M+H]+.
[0590] Example 118: Synthesis of 6-((4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenoxy)methyl)picolinonitrile
Figure imgf000172_0004
[0591] The title compound was prepared according to the procedure described for Example 26 using 6- (chloromethyl)picolinonitrile (62mg, 0.40mmol) to yield 6-((4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenoxy)methyl)picolinonitrile (65mg, 0.17mmol, 50%) as a white solid. MS: 384.4 [M+H]+. [0592] Example 119: Synthesis of 3-(4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenoxy)pyrazine 1-oxide
Figure imgf000173_0001
[0593] The title compound was prepared according to the procedure described for Example 111 using 3- chloropyrazine 1-oxide (55mg, 0.42mmol) to yield 3-(4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenoxy)pyrazine 1-oxide (64mg, 0.18mmol, 60%) as a white solid. MS: 362.4 [M+H]+.
[0594] Example 120: Synthesis of 3-(3-(4-(furan-3-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000173_0002
[0595] The title compound was prepared according to the procedure described for Example 8 using furan-3-ylboronic acid (56mg, 0.50mmol) to yield 3-(3-(4-(furan-3-ylmethyl)benzyl)isoxazol-5- yl)pyridin-2-amine (69mg, 0.21mmol, 62%) as a white solid. MS: 332.2 [M+H]+.
[0596] Example 121: Synthesis of 3-(3-(4-(furan-2-ylmethyl)benzyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000173_0003
[0597] The title compound was prepared according to the procedure described for Example 8 using furan-2-ylboronic acid (56mg, 0.50mmol) to yield 3-(3-(4-(furan-2-ylmethyl)benzyl)isoxazol-5- yl)pyridin-2-amine (62mg, 0.19mmol, 56%) as a white solid. MS: 332.3 [M+H]+.
[0598] Example 122: Synthesis of 3-(3-(4-((5-methylfuran-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000173_0004
[0599] The title compound was prepared according to the procedure described for Example 8 using 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (104mg, 0.50mmol) to yield 3-(3-(4-((5- methylfuran-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (73mg, 0.21mmol, 63%) as a white solid. MS: 346.3 [M+H]+.
[0600] Example 123: Synthesis of 3-(3-(4-((2,5-dihydrofuran-3-yl)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000173_0005
[0601] The title compound was prepared according to the procedure described for Example 8 using 2- (2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (98mg, 0.50mmol) to yield 3-(3-(4- ((2,5-dihydrofuran-3-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (68mg, 0.20mmol, 61%) as a white solid. MS: 334.3 [M+H]+.
[0602] Example 124: Synthesis of 3-(3-(4-((5-fluorofuran-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000174_0001
[0603] The title compound was prepared according to the procedure described for Example 8 using 2-(5- fluorofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (106mg, 0.50mmol) to yield 3-(3-(4-((5- fluorofuran-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (84mg, 0.24mmol, 72%) as a white solid. MS: 350.3 [M+H]+.
[0604] Example 125: Synthesis of 3-(3-((2-(benzylthio)pyrimidin-5-yl)methyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000174_0002
[0605] Di-tert-butyl [3-(3-(chloromethyl)-1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (1.67g, 4.06mmol) and (2-(benzylthio)pyrimidin-5-yl)boronic acid (1.00g, 4.06mmol) were mixed in DME (20mL) in a sealable tube. A 2M solution of sodium carbonate in water (4.67mL, 9.34mmol) and palladium tetrakis triphenylphosphine (470mg, 0.41mmol) were added and the sealable tube was flushed with argon and sealed. The mixture was stirred for 5h at 95°C. The cooled reaction mixture was poured into ethyl acetate (400mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give the di-Boc protected coupling product as a yellow oil to which was added formic acid (8mL). This mixture was stirred for 13h at 21-25°C to complete the di-Boc de-protection. To this mixture was added ice-water (80mL) and ethyl acetate (160mL). A 5M solution of NaOH in water was added until the pH of the aqueous layer was adjusted to 8-9. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-((2-(benzylthio)pyrimidin-5-yl)methyl)isoxazol-5-yl)pyridin-2-amine (620mg, 1.65mmol, 41%) as a white solid. MS: 376.4 [M+H]+.
[0606] Example 126: Synthesis of 1-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)pyridin- 2(1H)-one
Figure imgf000175_0001
[0607] 3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (200mg, 0.56mmol) was dissolved in acetonitrile (2.5mL) and lithium iodide (224mg, 1.68mmol) was added. The mixture was heated in the MW at 180 °C for 10min. The cooled reaction mixture was poured into ethyl acetate (50mL) and water (30mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 1-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)pyridin- 2(1H)-one (46mg, 0.13mmol, 23%) as a white solid. MS: 359.4 [M+H]+.
[0608] Example 127: Synthesis of 3-(3-((6-((2-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000175_0002
[0609] To a neat mixture of 3-(3-((6-fluoropyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine (60.mg, 0.22mmol), (2-fluorophenyl)methanol (168mg, 1.33mmol) was added potassium 2-methylpropane-2- olate (1M in THF, 2.22mL, 2.22mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((2-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin- 2-amine (27mg, 0.073mmol, 33%) as a white solid. MS: 377.0 [M+H]+.
[0610] Example 128: Synthesis of 3-(3-((6-((2-(trifluoromethyl)benzyl)oxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000175_0003
[0611] To a neat mixture of 3-(3-((6-fluoropyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine (50.mg, 0.19mmol), (2-trifluoromethylphenyl)methanol (196mg, 1.33mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 2.22mL, 2.22mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((2-(trifluoromethyl)benzyl)oxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (38mg, 0.089mmol, 48%) as a light pink solid. MS: 427.0 [M+H]+.
[0612] Example 129: Synthesis of 3-(3-((6-((5,6,7,8-tetrahydroquinolin-8-yl)oxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
Figure imgf000176_0001
[0613] To a neat mixture of 3-(3-((6-fluoropyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine (50.mg, 0.19mmol), 5,6,7,8-tetrahydroquinolin-8-ol (221mg, 1.48mmol) was added potassium 2-methylpropane- 2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 30min. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-((5,6,7,8-tetrahydroquinolin-8-yl)oxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine (30mg, 0.076mmol, 41%) as an orange glassy solid. MS: 400.3 [M+H]+.
[0614] Example 130: Synthesis of 3-(3-((6-(3-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000176_0002
[0615] To a neat mixture of 3-(3-((6-fluoropyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine (50.mg, 0.19mmol), 3-fluorophenol (124mg, 1.11mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 45min at 140°C in a sealed high pressure reaction vessel. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(3-fluorophenoxy)pyridin- 3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (32mg, 0.088mmol, 48%) as a white solid. MS: 363.1
[M+H]+.
[0616] Example 131: Synthesis of 3-(3-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000176_0003
[0617] To a neat mixture of 3-(3-((6-fluoropyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine (50.mg, 0.19mmol), 2-fluorophenol (207mg, 1.85mmol) was added potassium 2-methylpropane-2-olate (1M in THF, 1.85mL, 1.85mmol) and the mixture was stirred for 45min at 140°C in a sealed high pressure reaction vessel. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-((6-(2-fluorophenoxy)pyridin- 3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (19mg, 0.052mmol, 28%) as a white solid. MS: 363.2
[M+H]+.
[0618] Example 132: Synthesis of 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine
Figure imgf000177_0001
Step 1: Synthesis of 3-((trimethylsilyl)ethynyl)pyridine-2,6-diamine
Figure imgf000177_0002
[0619] 3-iodopyridine-2,6-diamine (2.640 g, 11.23 mmol), ethynyltrimethylsilane (2.207 g, 22.47 mmol), DIEA (4.90 ml, 28.1 mmol), and copper (I) iodide (0.214 g, 1.123 mmol) were combined in N- Methyl-2-pyrrolidinone (10 ml) under argon and was stirred for 2.5 hours at 45 °C. The reaction mixture was poured into water and extracted with ethyl acetate three times. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. Combined fractions were concentrated under reduced pressure to give 3- ((trimethylsilyl)ethynyl)pyridine-2,6-diamine (1.20 g, 5.84 mmol, 52.0 % yield). MS: 206.3 [M+H]+. Step 2: Synthesis of 3-ethynylpyridine-2,6-diamine
Figure imgf000177_0003
[0620] To a solution of 3-((trimethylsilyl)ethynyl)pyridine-2,6-diamine (1.200 g, 5.84 mmol) in THF (10 ml) was added TBAF (1.169 ml, 1.169 mmol) at 0 °C. Reaction mixture was slowly brought up to room temperature and stirred at room temperature for 10 minutes. Water was added to the reaction mixture and then extracted with ethyl acetate three times. Combined organic phase was dried over sodium sulfate and the solvent was removed at reduced pressure. The residue was purified by silica gel chromatography to give 3-ethynylpyridine-2,6-diamine (0.724 g, 5.44 mmol, 93 % yield). MS: 134.1 [M+H]+.
Step 3: Synthesis of 1-(benzyloxy)-4-(2-nitroethyl)benzene
Figure imgf000177_0004
[0621] To a mixture of (E)-1-(benzyloxy)-4-(2-nitrovinyl)benzene (5.000 g, 19.59 mmol), acetic acid (5.000 ml, 87 mmol), and DMSO (60 ml) was added sodium borohydride (1.250 g, 33.0 mmol) at room temperature and stirred for 40 minutes. Water was added to the reaction mixture and organics were extracted with ethyl acetate. Solvents removed at reduced pressure. Residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3). Combined fractions were concentrated under reduced pressure to give 1-(benzyloxy)-4-(2-nitroethyl)benzene (1.500 g, 5.83 mmol, 29.8 % yield). MS: 258.3 [M+H]+.
Step 4: Synthesis of (Z)-2-(4-(benzyloxy)phenyl)-N-hydroxyacetimidoyl chloride
Figure imgf000178_0001
[0622] To a mixture of 1-(benzyloxy)-4-(2-nitroethyl)benzene (1.500 g, 5.83 mmol) in Methanol (15 ml) was added lithium methanolate (11.66 ml, 11.66 mmol) and was stirred for 15 minutes at room temperature. The reaction mixture was concentrated at reduced pressure. Dichloromethane (12 ml) and tetrahydrofuran (6 ml) were added to the residue. Reaction mixture was cooled to -78 °C and titanium tetrachloride (18.66 ml, 18.66 mmol) was added and stirred at 0 °C for 1 hour. The reaction mixture was cooled to -78 °C and water was added. Reaction mixture was gradually warmed to room temperature. Organics were dissolved in DCM and washed with brine. Residue was purified by normal phase chromatography to give (Z)-2-(4-(benzyloxy)phenyl)-N-hydroxyacetimidoyl chloride (1.500 g, 5.44 mmol, 93 % yield) MS: 276.7 [M+H]+.
Step 5: Synthesis of 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine
Figure imgf000178_0002
[0623] To a mixture of (Z)-2-(4-(benzyloxy)phenyl)-N-hydroxyacetimidoyl chloride (1.500 g, 5.44 mmol) and 3-ethynylpyridine-2,6-diamine (0.724 g, 5.44 mmol) in THF was added triethylamine (1.517 ml, 10.88 mmol) and let stir overnight at room temperature. Reaction mixture was concentrated under reduced pressure. Residue was purified by silica gel chromatography. Combined fractions were concentrated under reduced pressure to give 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridine-2,6- diamine (0.425 g, 1.141 mmol, 20.98 % yield). MS: 373.3 [M+H]+.
[0624] Example 133: Synthesis of 3-(3-(4-(thiazol-2-ylmethoxy)benzyl)isoxazol-5-yl)pyridine-2,6- diamine
Figure imgf000178_0003
[0625] To a neat mixture of 4-((5-(2,6-diaminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (Intermediate F, 55mg, 0.20mmol), 2-(chloromethyl)thiazole (31mg, 0.23mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 0.21mL, 0.21mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-(4-(thiazol-2-ylmethoxy)benzyl)isoxazol- 5-yl)pyridine-2,6-diamine (22mg, 0.057mmol, 30%) as a white solid. MS: 380.4 [M+H]+.
[0626] Example 134: Synthesis of 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridine- 2,6-diamine
Figure imgf000179_0001
[0627] To a neat mixture of 4-((5-(2,6-diaminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (Intermediate F, 55mg, 0.20mmol), 2,6-difluoropyridine (31mg, 0.27mmol) was added potassium 2-methylpropane-2- olate (1M in THF, 0.21mL, 0.21mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5- yl)pyridine-2,6-diamine (2.7mg, 0.0072mmol, 3.7%) as a white solid. MS: 378.4 [M+H]+.
[0628] Example 135: Synthesis of 3-(3-(4-((3-methylbut-2-en-1-yl)oxy)benzyl)isoxazol-5-yl)pyridine- 2,6-diamine
Figure imgf000179_0002
[0629] To a neat mixture of 4-((5-(2,6-diaminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (Intermediate F, 45mg, 0.16mmol), 1-bromo-3-methylbut-2-ene (29mg, 0.19mmol) was added potassium 2- methylpropane-2-olate (1M in THF, 0.35mL, 0.35mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-(4-((3-methylbut-2-en-1- yl)oxy)benzyl)isoxazol-5-yl)pyridine-2,6-diamine (17mg, 0.049mmol, 30%) as a white solid. MS: 351.4 [M+H]+.
[0630] Example 136: Synthesis of 3-(3-(4-((phenylamino)methyl)benzyl)isoxazol-5-yl)pyridine-2,6- diamine
Figure imgf000179_0003
[0631] 3-(3-(4-(chloromethyl)benzyl)isoxazol-5-yl)pyridine-2,6-diamine (Intermediate G, 75mg, 0.24mmol) and aniline (31mg, 0.27mmol) were dissolved in THF and the mixture was stirred for 18 hours at room temperature. The mixture was transferred to a silica gel samplet which was subsequently loaded on to a Biotage Snap column. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate). Combined fractions were concentrated under reduced pressure. Residue was dissolved in acetonitrile (5mL) and water (10mL), frozen and lyophilized to yield 3-(3-(4- ((phenylamino)methyl)benzyl)isoxazol-5-yl)pyridine-2,6-diamine (36mg, 0.098mmol, 41%) as a white solid. MS: 372.5 [M+H]+.
[0632] Example 137: Synthesis of 3-(3-(4-(((6-fluoropyridin-2-yl)oxy)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
Figure imgf000180_0001
Step 1: Synthesis of (4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)methanol
Figure imgf000180_0002
[0633] 3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (1.5g, 4.19mmol) was dissolved in dioxane (20mL) and water (20mL) was added. Concentrated sulfuric acid (0.82g, 8.37mmol) was added and the mixture was heated to reflux for 6h. The cooled mixture was poured into ice-cold pH7 phosphate buffer (150mL) containing 330mg of NaOH (to neutralize excess of H2SO4) and was extracted with EtOAc (3x50mL). The combined organic layers were washed with brine (50mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography to give (4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)methanol (1.09g, 3.87mmol, 93%) as a white solid. MS: 282.4 [M+H]+. Step 2: Synthesis of (4-((5-(2-(di-tert-butoxycarbonyl)-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenyl)methanol tert-butyl carbonate
Figure imgf000180_0003
[0634] (4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)methanol (1g, 3.55mmol) was dissolved in THF (8mL) and N,N-dimethylpyridin-4-amine (DMAP, 0.043g, 0.355mmol) and di-tert- butyl dicarbonate ((Boc)2O, 2.72g, 12.44mmol) were added. The mixture was stirred for 15min at 21- 25°C and then for another 15min at 50°C. The mixture was loaded directly onto celite and purified by flash chromatography to give (4-((5-(2-(di-tert-butoxycarbonyl)-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenyl)methanol tert-butyl carbonate (1.21g, 2.08mmol, 58%). MS: 604.4 [M+Na]+. Step 3: Synthesis of (4-((5-(2-(di-tert-butoxycarbonyl)-aminopyridin-3-yl)isoxazol-3- yl)methyl)phenyl)methanol
Figure imgf000181_0003
[0635] (4-((5-(2-(di-tert-butoxycarbonyl)-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)methanol tert- butyl carbonate (1g, 1.72mmol) was dissolved in MeOH (20mL) and sodium methanolate (25%Wt in MeOH, 1.86g, 8.60mmol) was added. The mixture was stirred at 21-25°C for 2h. The reaction mixture was poured into a stirring mixture of water (100mL) and ethyl acetate (100mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×40mL). The combined organic layers were washed with brine (40mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to give (4-((5-(2-(di-tert-butoxycarbonyl)-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)methanol (320mg, 0.66mmol, 38%). MS: 482.5 [M+H]+.
Step 4: Synthesis of di-tert-butyl [3-(3-(4-(((6-fluoropyridin-2-yl)oxy)methyl)benzyl)-1,2-oxazol-5- yl)pyridin-2-yl]imidodicarbonate
Figure imgf000181_0001
[0636] Sodium hydride (60% w/mineral oil, 13mg, 0.32mmol) was added at 0°C to a solution of (4-((5- (2-(di-tert-butoxycarbonyl)-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)methanol (130mg,
0.27mmol) and 2,6-difluoropyridine (155mg, 1.35mmol) in DMF (5mL) and the mixture was stirred at 50°C for 30min. The cooled reaction mixture was poured into a stirring mixture of water (50mL) and ethyl acetate (50mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine (10mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to obtain di-tert-butyl [3-(3-(4-(((6-fluoropyridin-2-yl)oxy)methyl)benzyl)- 1,2-oxazol-5-yl)pyridin-2-yl]imidodicarbonate (116mg, 0.20mmol, 75%). MS: 577.5 [M+H]+. Step 5: Synthesis of 3-(3-(4-(((6-fluoropyridin-2-yl)oxy)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
Figure imgf000181_0002
[0637] Di-tert-butyl [3-(3-(4-(((6-fluoropyridin-2-yl)oxy)methyl)benzyl)-1,2-oxazol-5-yl)pyridin-2- yl]imidodicarbonate (116mg, 0.20mmol) was dissolved in DCM (3mL) and dioxane (3mL). TFA (77µL, 1.01mmol) and HCl (4M in dioxane, 0.3mL, 1.20mmol) were added and the mixture was stirred for 3days at 21-25°C. The mixture was poured into an ice-cold mixture of pH7 phosphate buffer solution (0.5M, 50mL) containing an additional amount of NaOH (89mg, 2.22mmol), to neutralize the excess of acids, and ethyl acetate (50mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate) to yield 3-(3-(4-(((6-fluoropyridin-2- yl)oxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (48mg, 0.13mmol, 63%). MS: 377.2 [M+H]+.
[0638] Examples 138-171 can be synthesized as described in any of the examples above.
[0639] Example 172: Synthesis of (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate
Figure imgf000182_0001
[0640] Sodium iodide (2.379g, 15.87mmol) and N-ethyl-N-isopropylpropan-2-amine (0.205g,
1.587mmol) were added to THF (7mL). Di-tert-butyl (chloromethyl) phosphate (2.463g, 9.52mmol) was added and the mixture was stirred at 45°C for 1.5h.3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5- yl)pyridin-2-amine (2.3g, 6.35mmol) and toluene (7mL) were added followed by the addition of sodium hydroxide (5N, 7mL, 35mmol). The mixture was stirred at 45°C for 30min and then for 1h at 23°C. Another batch of freshly prepared iodomethyl phosphate (following the same procedure as described above, but using 1.2g sodium iodide, 0.1g N-ethyl-N-isopropylpropan-2-amine and 1.25g di-tert-butyl (chloromethyl) phosphate in 4mL of THF) was added and the mixture was stirred at 23°C for 12h. The organic layer was separated and the aq. phase extracted 3x with 5mL of mixture of THF/toluene (1:1). The combined organic layers were cooled to 0°C and 5N HCl (7mL) was added. The mixture was stirred at 23°C for 2h. Water, ice and EtOAc were added and the pH of the aqueous phase was adjusted to 8-10. The aq. layer was extracted 3x with EtOAc and then its pH was adjusted to about 7 to 7.5. The mixture became slightly cloudy during this process, but no significant precipitation occurred. The mixture was now filtered through a plug of reversed phase C18 silica gel (or alternatively a 0.45micrometer PTFE filter). The pH of the clear filtrate was adjusted slowly to 4-5, while precipitation of the product occurred. The mixture was stirred for about 1.5h and the product collected by filtration. The filter cake was thoroughly washed with water and 1x with a small amount of MeOH and finally dried under vacuum to give (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (1.45g, 3.07mmol, 48 % yield). MS: 473.4 [M+H]+.31P NMR (200MHz, DMSO- d6/D2O) ^ 3.61.1H NMR (400MHz, DMSO-d6/D2O) d 7.83 (q, J = 8.1 Hz, 1H), 7.73 (d, J = 7.0 Hz, 2H), 7.30 (m, 2H), 7.00 (m, 2H), 6.76 (s, 1H), 6.72 (m, 2H), 6.33 (t, J = 7.0 Hz, 1H), 5.39 (d, J = 7.4 Hz, 2H), 3.99 (s, 2H), signals for -NH2, and -OH not observed.
[0641] Example 173: Synthesis of (2-amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1- yl)methyl hydrogen phosphate
[0642] The title compound was prepared according to the procedure of Example 146 using sodium iodide (944mg, 6.3mmol), N-ethyl-N-isopropylpropan-2-amine (81mg, 0.63mmol), di-tert-butyl (chloromethyl) phosphate (977mg, 3.78mmol), 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine (900mg, 2.52mmol) and sodium hydroxide (5N, 2.77mL, 13.85mmol) to give (2-amino-3-(3-(4- (benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (390mg, 0.83mmol, 33 % yield).31P NMR (200MHz, DMSO-d6/D2O) d 3.21.1H NMR (500MHz, DMSO-d6/D2O) d 7.64– 7.55 (m, 2H), 7.37– 7.21 (m, 5H), 7.20– 7.13 (m, 2H), 6.92– 6.85 (m, 2H), 6.75– 6.71 (m, 1H), 6.07 (t, J = 7.0 Hz, 1H), 5.28 (d, J = 6.9 Hz, 2H), 5.00 (s, 2H), 3.88 (s, 2H), signals for -NH2, and -OH not observed. MS: 468.4 [M+H]+.
[0643] Example 174: Synthesis (2-amino-3-(3-((6-(benzyloxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate
[0644] The title compound was prepared similarly to the procedure Example 146 using sodium iodide (1.5g, 9.8mmol), N-ethyl-N-isopropylpropan-2-amine (0.17 mL, 0.98mmol), di-tert-butyl (chloromethyl) phosphate (1.4mL, 5.9mmol), 3-(3-((6-(benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (1.4g, 3.9mmol) and sodium hydroxide (5N, 4.4mL, 22mmol) to give (2-amino-3-(3-((6- (benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (0.58g, 1.2mmol, 32 % yield). MS: 469.4 [M+H]+.
[0645] Example 175: Synthesis of (2-amino-3-(3-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate
[0646] The title compound was prepared according to the procedure of Example 146 using sodium iodide (2.64g, 17.59mmol), N-ethyl-N-isopropylpropan-2-amine (0.227g, 1.76mmol), di-tert-butyl (chloromethyl) phosphate (2.73g, 10.56mmol), 3-(3-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)isoxazol- 5-yl)pyridin-2-amine (2.55g, 7.04mmol) and sodium hydroxide (5N, 7.74mL, 38.7mmol) to give (2- amino-3-(3-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate (340mg, 0.72mmol, 10 % yield). MS: 473.4 [M+H]+.
[0647] Example 176: (2-amino-3-(3-((6-(3,5-difluorophenoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate
[0648] The compound was synthesized from Example 81 according to methods described above. MS: 491.1 [M+H]+.
[0649] Examples 177-184 can be synthesized as described in any of the above examples. [0650] Example 185: 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0651] The compound was synthesized from Intermediate A and (4-(benzyloxy)phenyl)boronic acid according to methods described above.400 MHz 1H NMR (CDCl3) d 8.12 (dd, J = 4.9, 1.8 Hz, 1H), 7.70 (dd, J = 7.7, 1.8 Hz, 1H), 7.47– 7.27 (m, 5H), 7.26– 7.16 (m, 2H), 7.02– 6.90 (m, 2H), 6.70 (dd, J = 7.7, 4.9 Hz, 1H), 6.24 (s, 1H), 5.50 (s, 2H), 5.05 (s, 2H), 4.00 (s, 2H). MS: 358.3 [M+H]+.
[0652] Example 186: 3-(3-((6-(phenylthio)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0653] The compound was synthesized from Intermediate E and benzenethiol according to methods described above. MS: 361.3 [M+H]+.
[0654] Example 187: 3-(3-((6-((4-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0655] The compound was synthesized from Intermediate E and (4-fluorophenyl)methanol according to methods described above. MS: 377.2 [M+H]+.
[0656] Example 188: 3-(3-((6-(2-phenylazetidin-1-yl)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2- amine
[0657] The compound was synthesized from Intermediate E and 2-phenylazetidine according to methods described above. MS: 384.2 [M+H]+.
[0658] Example 189: 3-(3-(4-((2,5-difluorophenoxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0659] The compound was synthesized from Intermediate B and 2,5-difluorophenol according to methods described above. MS: 393.8 [M+H]+.
[0660] Example 190: 3-(3-(4-((2,3,5-trifluorophenoxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0661] The compound was synthesized from Intermediate B and 2,3,5-trifluorophenol according to methods described above. MS: 411.9 [M+H]+.
[0662] Example 191: (4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenyl)(phenyl)methanone
[0663] The compound was synthesized from Intermediate A and (4-benzoylphenyl)boronic acid according to methods described above.500 MHz 1H NMR (DMSO-d6) d 8.10 (dd, J = 4.8, 1.8 Hz, 1H), 7.88 (dd, J = 7.7, 1.8 Hz, 1H), 7.76– 7.62 (m, 5H), 7.59– 7.50 (m, 4H), 6.87 (s, 1H), 6.70 (dd, J = 7.7, 4.7 Hz, 1H), 6.28 (s, 2H), 4.17 (s, 2H). MS: 356.1 [M+H]+.
[0664] Example 192: 3-(3-(4-((5-fluoro-2-methoxyphenoxy)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
[0665] The compound was synthesized from Intermediate B and 5-fluoro-2-methoxyphenol according to methods described above. MS: 406.0 [M+H]+.
[0666] Example 193: 3-(3-(4-(((2,3,4-trifluorophenyl)amino)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
[0667] The compound was synthesized from Intermediate B and 2,3,4-trifluoroaniline according to methods described above. MS: 411.1 [M+H]+.
[0668] Example 194: (E)-3-(3-(4-(3-phenylprop-1-en-1-yl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0669] The compound was synthesized from Example 97 according to methods described for Example 99, but using allylbenzene.500 MHz 1H NMR (DMSO-d6) d 8.08 (dd, J = 4.8, 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 1.8 Hz, 1H), 7.40– 7.16 (m, 9H), 6.79 (s, 1H), 6.69 (dd, J = 7.7, 4.7 Hz, 1H), 6.50– 6.36 (m, 2H), 6.25 (s, 2H), 4.00 (s, 2H), 3.51 (d, J = 6.4 Hz, 2H). MS: 368.2 [M+H]+.
[0670] Example 195: 3-(3-((6-((2-bromopyridin-4-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0671] The compound was synthesized from Intermediate E and (2-bromopyridin-4-yl)methanol according to methods described above. MS: 440.2 [M+H]+.
[0672] Example 196: 3-(3-(4-(((2,5-difluorophenyl)amino)methyl)benzyl)isoxazol-5-yl)pyridin-2- amine
[0673] The compound was synthesized from Intermediate B and 2,5-difluoroaniline according to methods described above. MS: 293.2 [M+H]+.
[0674] Example 197: (2-amino-3-(3-((6-(3-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-1- ium-1-yl)methyl hydrogen phosphate
[0675] The compound was synthesized from Example 130 according to methods described above. 31P NMR (200MHz, DMSO-d6/D2O) d 5.16.1H NMR (500MHz, DMSO-d6/D2O) d 8.15 (dd, J = 7.5, 1.5 Hz, 1H), 8.10– 8.04 (m, 2H), 7.79 (dd, J = 8.5, 2.5 Hz, 1H), 7.38 (td, J = 8.5, 6.9 Hz, 1H), 7.01– 6.83 (m, 6H), 5.59 (d, J = 8.0 Hz, 2H), 4.04 (s, 2H), signals for -NH2 and -OH not observed. MS: 473.3 [M+H]+.
[0676] Example 198: 3-(3-(4-(((3,5-difluoro-2-methoxyphenyl)amino)methyl)benzyl)isoxazol-5- yl)pyridin-2-amine
[0677] The compound was synthesized from Intermediate B and 3,5-difluoro-2-methoxyaniline according to methods described above. MS: 423.1 [M+H]+.
[0678] Example 199: 3-(3-(4-((1H-1,2,4-triazol-1-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0679] The compound was synthesized from Intermediate B and 1H-1,2,4-triazole according to methods described above.500 MHz 1H NMR (DMSO-d6) d 8.64 (s, 1H), 8.08 (dd, J = 4.8, 1.8 Hz, 1H), 7.96 (s, 1H), 7.85 (dd, J = 7.7, 1.9 Hz, 1H), 7.34– 7.28 (m, 2H), 7.28– 7.22 (m, 2H), 6.79 (s, 1H), 6.69 (dd, J = 7.7, 4.8 Hz, 1H), 6.24 (s, 2H), 5.39 (s, 2H), 4.01 (s, 2H). MS: 333.1 [M+H]+.
[0680] Example 200: 3-(3-(4-((4H-1,2,4-triazol-4-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0681] The compound was synthesized from Intermediate B and 1H-1,2,4-triazole according to methods described above.500 MHz 1H NMR (DMSO-d6) d 8.59 (s, 2H), 8.08 (dd, J = 4.8, 1.9 Hz, 1H), 7.85 (dd, J = 7.7, 1.8 Hz, 1H), 7.37– 7.24 (m, 4H), 6.79 (s, 1H), 6.69 (dd, J = 7.7, 4.7 Hz, 1H), 6.24 (s, 2H), 5.25 (s, 2H), 4.02 (s, 2H). MS: 333.2 [M+H]+.
[0682] Example 201: 3-(3-(4-(((3-fluoro-5-methoxyphenyl)amino)methyl)benzyl)isoxazol-5-yl)pyridin- 2-amine
[0683] The compound was synthesized from Intermediate B and 3-fluoro-5-methoxyaniline according to methods described above. MS: 405.2 [M+H]+.
[0684] Example 202: 3-(3-((6-(2-(1H-1,2,4-triazol-1-yl)ethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0685] The compound was synthesized from Intermediate E and 2-(1H-1,2,4-triazol-1-yl)ethan-1-ol according to methods described above. MS: 364.2 [M+H]+. [0686] Example 203: 3-(3-(4-(pyridin-2-yl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0687] The compound was synthesized from Intermediate A and 4-(2-Pyridinyl)phenylboronic acid pinacol ester according to methods described above.500 MHz 1H NMR (DMSO-d6) d 8.79 (ddd, J = 5.5, 1.8, 0.8 Hz, 1H), 8.44– 8.33 (m, 2H), 8.31– 8.19 (m, 4H), 8.15– 8.09 (m, 2H), 7.81– 7.74 (m, 1H), 7.60– 7.54 (m, 2H), 7.12 (s, 1H), 7.05 (dd, J = 7.6, 6.2 Hz, 1H), 4.21 (s, 2H). MS: 329.1 [M+H]+.
[0688] Example 204: 3-(3-(4-(pyridin-4-yl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0689] The compound was synthesized from Intermediate A and 4-(Pyridin-4-yl)phenylboronic acid pinacol ester according to methods described above. MS: 329.2 [M+H]+.
[0690] Example 205: 3-(3-((6-(4-fluorophenyl)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0691] The compound was synthesized from Intermediate A and 6-(4-Fluorophenyl)pyridine-3-boronic acid according to methods described above.500 MHz 1H NMR (DMSO-d6) d 8.75 (dd, J = 2.3, 1.0 Hz, 1H), 8.39 (dd, J = 7.7, 1.6 Hz, 1H), 8.28– 8.02 (m, 7H), 7.42– 7.33 (m, 2H), 7.12 (s, 1H), 7.05 (dd, J = 7.6, 6.1 Hz, 1H), 4.26 (s, 2H). MS: 347.1 [M+H]+.
[0692] Example 206:3-(3-((6-(imidazo[1,2-a]pyridine-7-ylmethoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0693] The compound was synthesized from Intermediate E and imidazo[1,2-a]pyridin-7-ylmethanol according to methods described above. MS: 399.2 [M+H]+.
[0694] Example 207: 3-(3-((6-((5-fluoro-2-methoxypyridin-4-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0695] The compound was synthesized from Intermediate E and (5-fluoro-2-methoxypyridin-4- yl)methanol according to methods described above. MS: 408.0 [M+H]+.
[0696] Example 208: 3-(3-(4-(3-fluorobenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0697] The compound was synthesized from Intermediate B and (3-fluorophenyl)boronic acid according to methods described above.500 MHz 1H NMR (DMSO-d6) d 8.08 (dd, J = 4.8, 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 1.9 Hz, 1H), 7.34– 7.28 (m, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.09– 7.03 (m, 2H), 7.02– 6.96 (m, 1H), 6.79 (s, 1H), 6.69 (dd, J = 7.7, 4.8 Hz, 1H), 6.24 (s, 2H), 3.98 (s, 2H), 3.93 (s, 2H). MS: 360.0 [M+H]+.
[0698] Example 209: 2-(3-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)phenyl)propan-2-ol
[0699] The compound was synthesized from Intermediate B and (3-(2-hydroxypropan-2- yl)phenyl)boronic acid according to methods described above. MS: 400.3 [M+H]+.
[0700] Example 210: 3-(3-((6-((2-chloro-3-fluoropyridin-4-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine.
[0701] The compound was synthesized from Intermediate E and (2-chloro-3-fluoropyridin-4- yl)methanol according to methods described above. MS: 412.2 [M+H]+.
[0702] Example 211: N-(3-(4-((5-(2-aminopyridin-3-yl)isoxazol-3- yl)methyl)benzyl)phenyl)methanesulfonamide
[0703] The compound was synthesized from Intermediate B and (3-(methylsulfonamido)phenyl)boronic acid according to methods described above. MS: 435.3 [M+H]+. [0704] Example 212: 3-(3-(4-(3,5-difluorobenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0705] The compound was synthesized from Intermediate B and (3,5-difluorophenyl)boronic acid according to methods described above. 500 MHz 1H NMR (DMSO-d6) d 8.08 (dd, J = 4.8, 1.9 Hz, 1H), 7.86 (dd, J = 7.7, 1.9 Hz, 1H), 7.25 (q, J = 8.3 Hz, 4H), 7.06– 6.93 (m, 3H), 6.80 (s, 1H), 6.69 (dd, J = 7.7, 4.7 Hz, 1H), 6.24 (s, 2H), 3.99 (s, 2H), 3.93 (s, 2H). MS: 377.9 [M+H]+.
[0706] Example 213: 3-(3-((6-(3-phenylpropoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0707] The compound was synthesized from Intermediate E and 3-phenylpropan-1-ol according to methods described above. MS: 387.2 [M+H]+.
[0708] Example 214: 3-(3-((6-(3-(4-(benzyloxy)phenyl)propoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0709] The compound was synthesized from Intermediate E and 3-(4-(benzyloxy)phenyl)propan-1-ol according to methods described above. MS: 493.1 [M+H]+.
[0710] Example 215: 3-(3-((6-(2,2-diphenylethoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0711] The compound was synthesized from Intermediate E and 2,2-diphenylethan-1-ol according to methods described above. MS: 449.3 [M+H]+.
[0712] Example 216: 3-(3-(4-(3-fluoro-5-methoxybenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0713] The compound was synthesized from Intermediate B and (3-fluoro-5-methoxyphenyl)boronic acid according to methods described above. MS: 390.0 [M+H]+.
[0714] Example 217: 3-(3-((6-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0715] The compound was synthesized from Intermediate E and (3-methyl-4-(2,2,2- trifluoroethoxy)pyridin-2-yl)methanol according to methods described above. MS: 472.3 [M+H]+.
[0716] Example 218: 3-(3-((6-((3-chloropyridin-4-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0717] The compound was synthesized from Intermediate E and (3-chloropyridin-4-yl)methanol according to methods described above. MS: 394.1 [M+H]+.
[0718] Example 219: 3-(3-((6-((2,6-dichloropyridin-4-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0719] The compound was synthesized from Intermediate E and (2,6-dichloropyridin-4-yl)methanol according to methods described above. MS: 428.1 [M+H]+.
[0720] Example 220: 3-(3-((6-((2-chlorothiazol-4-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0721] The compound was synthesized from Intermediate E and (2-chlorothiazol-4-yl)methanol according to methods described above. MS: 399.9 [M+H]+.
[0722] Example 221: 3-(3-((6-((5-chlorothiophen-2-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0723] The compound was synthesized from Intermediate E and (5-chlorothiophen-2-yl)methanol according to methods described above. MS: 398.9 [M+H]+. [0724] Example 222: 3-(3-((6-((6-chloropyridin-2-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0725] The compound was synthesized from Intermediate E and (6-chloropyridin-2-yl)methanol according to methods described above. MS: 393.8 [M+H]+.
[0726] Example 223: 3-(3-((6-((6-bromopyridin-2-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0727] The compound was synthesized from Intermediate E and (6-bromopyridin-2-yl)methanol according to methods described above. MS: 440.2 [M+H]+.
[0728] Example 224:3-((5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)pyridin-2- yl)oxy)propanenitrile
[0729] The compound was synthesized from Intermediate E and 3-hydroxypropanenitrile according to methods described above. MS: 322.2 [M+H]+.
[0730] Example 225: 3-(3-((6-(but-3-yn-1-yloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0731] The compound was synthesized from Intermediate E and but-3-yn-1-ol according to methods described above. MS: 321.2 [M+H]+.
[0732] Example 226: 3-(3-((6-((6-fluoropyridin-2-yl)methoxy)pyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0733] The compound was synthesized from Intermediate E and (6-fluoropyridin-2-yl)methanol according to methods described above. MS: 377.8 [M+H]+.
[0734] Example 227: 3-(3-((6-morpholinopyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0735] The compound was synthesized from Intermediate A and 6-Morpholinopyridin-3-ylboronic acid pinacol ester according to methods described above. MS: 338.5 [M+H]+.
[0736] Example 228: 3-(3-(4-(morpholinosulfonyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0737] The compound was synthesized from Intermediate A and 4-(4-(4,4,5,5-Tetramethyl-1,3,2- dioxaborolan-2-yl)phenylsulfonyl)morpholine according to methods described above. MS: 401.4
[M+H]+.
[0738] Example 229: 3-(3-((6-(2-phenylpyrrolidin-1-yl)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2- amine
[0739] The compound was synthesized from Intermediate E and 2-phenylpyrrolidine according to methods described above. MS: 398.2 [M+H]+.
[0740] Example 230: 3-(3-((6-(piperidin-1-yl)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0741] The compound was synthesized from Intermediate A and 2-(Piperidin-1-yl)pyridine-5-boronic acid pinacol ester according to methods described above.500 MHz 1H NMR (HCl-salt, DMSO-d6) d 8.36 (dd, J = 7.4, 1.5 Hz, 1H), 8.21 (dd, J = 6.1, 1.6 Hz, 1H), 8.12 (bs, 2H), 8.01 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 9.4, 2.2 Hz, 1H), 7.42 (d, J = 9.5 Hz, 1H), 7.08 (s, 1H), 7.05 (dd, J = 7.6, 6.1 Hz, 1H), 4.10 (s, 2H), 3.73 (t, J = 5.4 Hz, 4H), 1.70– 1.57 (m, 6H). MS: 336.4 [M+H]+.
[0742] Example 231: 3-(3-(4-(((3-azidophenyl)amino)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine [0743] The compound was synthesized from Intermediate B and 3-azidoaniline according to methods described above.500 MHz 1H NMR (CDCl3) d 8.14 (dd, J = 4.9, 1.8 Hz, 1H), 7.70 (dd, J = 7.7, 1.8 Hz, 1H), 7.35– 7.29 (m, 2H), 7.30– 7.23 (m, 2H), 7.12 (t, J = 8.0 Hz, 1H), 6.70 (dd, J = 7.7, 4.9 Hz, 1H), 6.43– 6.37 (m, 2H), 6.28– 6.21 (m, 2H), 5.39 (s, 2H), 4.30 (s, 2H), 4.16 (s, 1H), 4.05 (s, 2H). MS: 398.2 [M+H]+.
[0744] Example 232: 4-((4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)amino)-5- fluoropyrimidin-2(1H)-one
[0745] The compound was synthesized from Intermediate B and Flucytosine according to methods described above. MS: 393.3 [M+H]+.
[0746] Example 233: (E)-3-(3-(4-(3-fluorostyryl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0747] The compound was synthesized from Example 97 according to methods described for Example 99, but using 1-fluoro-3-vinylbenzene. MS: 371.9 [M+H]+.
[0748] Example 234: 3-(3-(4-((6-chloropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0749] The compound was synthesized from Intermediate C and 2,6-dichloropyridine according to methods described above. MS: 378.9 [M+H]+.
[0750] Example 235: 3-(3-(4-((3-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0751] The compound was synthesized from Intermediate C and 2,3-difluoropyridine according to methods described above. MS: 363.1 [M+H]+.
[0752] Example 236: 3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0753] The compound was synthesized from Intermediate C and 5-chloro-2,3-difluoropyridine according to methods described above. MS: 397.1 [M+H]+.
[0754] Example 237: 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,6-difluorophenyl)pyridin- 2-amine
[0755] The compound was synthesized from Intermediate E and 2,6-difluoroaniline according to methods described above. MS: 380.2 [M+H]+.
[0756] Example 238: 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(3,5-difluorophenyl)pyridin- 2-amine
[0757] The compound was synthesized from Intermediate E and 3,5-difluoroaniline according to methods described above. MS: 380.0 [M+H]+.
[0758] Example 239: 3-(3-(4-((4,6-difluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0759] The compound was synthesized from Intermediate C and 2,4,6-trifluoropyridine according to methods described above. MS: 380.9 [M+H]+.
[0760] Example 240: 3-(3-(4-((4-chlorothiazol-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0761] The compound was synthesized from Intermediate C and 2,4-dichlorothiazole according to methods described above. MS: 385.1 [M+H]+.
[0762] Example 241: 3-(3-(4-((3,5,6-trifluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0763] The compound was synthesized from Intermediate C and 2,3,5,6-tetrafluoropyridine according to methods described above. MS: 398.9 [M+H]+. [0764] Example 242: 3-(3-(4-((3,5-difluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0765] The compound was synthesized from Intermediate C and 2,3,5-trifluoropyridine according to methods described above. MS: 380.9 [M+H]+.
[0766] Example 243: 3-(3-(4-(pyrimidin-2-yloxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0767] The compound was synthesized from Intermediate C and 2-chloropyrimidine according to methods described above. MS: 346.0 [M+H]+.
[0768] Example 244: 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,5-difluorophenyl)pyridin- 2-amine
[0769] The compound was synthesized from Intermediate E and 2,5-difluoroaniline according to methods described above. MS: 380.1 [M+H]+.
[0770] Example 245: 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,3,4- trifluorophenyl)pyridin-2-amine
[0771] The compound was synthesized from Intermediate E and 2,3,4-trifluoroaniline according to methods described above. MS: 398.0 [M+H]+.
[0772] Example 246: 3-(3-(4-((5-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0773] The compound was synthesized from Intermediate C and 2,5-difluoropyridine according to methods described above. MS: 363.1 [M+H]+.
[0774] Example 247: 3-(3-((6-(cyclopropylmethoxy)-5-fluoropyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0775] The compound was synthesized from Intermediate J and cyclopropylmethanol according to methods described above. MS: 340.7 [M+H]+.
[0776] Example 248: 3-(3-((2-(3,5-difluorophenoxy)pyrimidin-5-yl)methyl)isoxazol-5-yl)pyridin-2- amine
[0777] 3,5-difluorophenol (109mg, 0.834mmol) was dissolved in DMF (0.5mL) and KOtBu (1M in THF, 730µL, 0.730mmol) was added dropwise. The mixture was stirred for 5min and a solution of 3-(3- ((2-chloropyrimidin-5-yl)methyl)isoxazol-5-yl)pyridin-2-amine (Intermediate L, 30mg, 0.104mmol) in DMF (0.5mL) was added. The resulting mixture was stirred for 1h at 60°C and directly purified by flash chromatography to give 3-(3-((2-(3,5-difluorophenoxy)pyrimidin-5-yl)methyl)isoxazol-5-yl)pyridin-2- amine (17mg, 0.045mmol, 42.8 % yield).500 MHz 1H NMR (DMSO-d6) d 8.70 (s, 2H), 8.10 (dd, J = 4.8, 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 1.9 Hz, 1H), 7.21– 7.06 (m, 3H), 6.89 (s, 1H), 6.71 (dd, J = 7.7, 4.8 Hz, 1H), 6.28 (s, 2H), 4.10 (s, 2H). MS: 382.0 [M+H]+.
[0778] Example 249: 3-(3-((2-((3-fluorobenzyl)oxy)pyrimidin-5-yl)methyl)isoxazol-5-yl)pyridin-2- amine
[0779] The compound was synthesized from Intermediate L and according to methods described above. MS: 378.1 [M+H]+.
[0780] Example 250: 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-3-fluoro-N-(2- fluorophenyl)pyridin-2-amine [0781] The compound was synthesized from Intermediate J and 2-fluoroaniline according to methods described above. MS: 380.0 [M+H]+.
[0782] Example 251: 3-(3-((5-fluoro-6-((3-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin- 2-amine
[0783] The compound was synthesized from Intermediate J and (3-fluorophenyl)methanol according to methods described above. MS: 394.7 [M+H]+.
[0784] Example 252: 3-(3-((6-(3,5-difluorophenoxy)-5-fluoropyridin-3-yl)methyl)isoxazol-5- yl)pyridin-2-amine
[0785] The compound was synthesized from Intermediate J and 3,5-difluorophenol according to methods described above. MS: 398.5 [M+H]+.
[0786] Example 253: 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,6-difluorophenyl)-3- fluoropyridin-2-amine
[0787] The compound was synthesized from Intermediate J and 2,6-difluoroaniline according to methods described above. MS: 398.0 [M+H]+.
[0788] Example 254: 3-(3-((5-fluoro-6-(2-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2- amine
[0789] The compound was synthesized from Intermediate J and 2-fluorophenol according to methods described above. MS: 380.9 [M+H]+.
[0790] Example 255: 3-(3-((5-fluoro-6-phenoxypyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0791] The compound was synthesized from Intermediate J and phenol according to methods described above. MS: 362.7 [M+H]+.
[0792] Example 256: 3-(3-((5-fluoro-6-(3-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2- amine
[0793] The compound was synthesized from Intermediate J and 3-fluorophenol according to methods described above. MS: 380.8 [M+H]+.
[0794] Example 257: 3-(3-((6-(benzyloxy)-5-fluoropyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine
[0795] The compound was synthesized from Intermediate J and benzyl alcohol according to methods described above. MS: 376.6 [M+H]+.
[0796] Example 258: 3-(3-(3-fluoro-4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0797] 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-2-fluorophenol (Intermediate K, 100mg, 0.351mmol) was dissolved in DMF (1mL) and potassium 2-methylpropan-2-olate (1M in THF, 421µL, 0.421mmol) was added dropwise. The mixture was stirred for 5min and a solution of 2,6- difluoropyridine (81mg, 0.701mmol) in DMF (0.5mL) was added. The resulting mixture was stirred for 16h at 60 °C and directly purified by flash chromatography to give 3-(3-(3-fluoro-4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine.500 MHz 1H NMR (DMSO-d6) d 8.10 (dd, J = 4.8, 1.8 Hz, 1H), 8.05 (q, 1H), 7.89 (dd, J = 7.6, 1.8 Hz, 1H), 7.40 (dd, J = 11.6, 2.0 Hz, 1H), 7.33 (t, 1H), 7.23 (ddd, J = 8.3, 1.9, 0.8 Hz, 1H), 7.04 (dd, J = 7.9, 1.5 Hz, 1H), 6.94– 6.85 (m, 2H), 6.71 (dd, J = 7.7, 4.8 Hz, 1H), 6.29 (s, 2H), 4.11 (s, 2H). MS: 380.9 [M+H]+. [0798] Example 259: 3-(3-(3-fluoro-4-(pyrimidin-2-yloxy)benzyl)isoxazol-5-yl)pyridin-2-amine
[0799] The compound was synthesized from Intermediate K and 2-chloropyrimidine according to methods described above. MS: 363.9 [M+H]+.
[0800] Example 260: 3-(3-((5-fluoro-6-((2-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin- 2-amine
[0801] The compound was synthesized from Intermediate J and (2-fluorophenyl)methanol according to methods described above. MS: 394.7 [M+H]+.
[0802] Example 261: 3-(3-(4-((2,6-difluoropyridin-4-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine
[0803] The compound was synthesized from Intermediate B and (2,6-difluoropyridin-4-yl)boronic acid according to methods described above. MS: 379.3 [M+H]+.
[0804] Examples 262-495 can be synthesized as described in any of the examples above.
[0805] Example 496: Evaluation of compound activity against C. neoformans and C. gattii isolates
[0806] In this study, compound activity against C. neoformans and C. gattii isolates were evaluated. N- phosphonooxymethyl prodrugs of these molecules were synthesized and two of these prodrugs were evaluated in a disseminated C. neoformans infection model where 100 mg/kg ABT had been
administered orally 2 h prior to therapy.
[0807] Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here, the in vitro and in vivo activity of several compounds including Compound 2 and its prodrug Compound 1 were evaluated. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidyl inositol (GPI)-anchored cell wall mannoproteins in fungi.
[0808] The Gwt1 inhibitors had low MIC values, ranging from 0.004 µg/mL to 0.5 µg/mL against both C. neoformans and C. gattii. Compound 2 and 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine demonstrated in vitro synergy with fluconazole (FICI 0.37). In a CM model, Compound 1 and fluconazole each, alone, reduced log10 colony forming units (CFU)/g brain (0.78 and 1.04, respectively), whereas the combination resulted in a reduction of 3.52 log10 CFU/g brain.
[0809] Efficacy as measured by a reduction in brain and lung fungal burden was also observed for another Gwt1 inhibitor prodrug, (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, where dose dependent reductions in fungal burden ranged between 5.91 and 1.79 log10 CFU/g lung and between 7.00 and 0.92 log10 CFU/g brain, representing near or complete sterilization of lung and brain tissue at the higher doses. These data support further clinical evaluation of this new class of antifungal agents for CM.
In vitro activity of Gwt1 inhibitors vs Cryptococcus
[0810] Antifungal susceptibility profile. Several compounds were highly active against all 4 fungal strains evaluated (Table 3), with MIC or MEC values ranging from 0.004 to 0.25 µg/mL against C. neoformans, C. gattii, Candida albicans and Aspergillus fumigatus. When compared to the MIC values of Compound 2 vs Cryptococcus, 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine and 3-(3- ((6-(benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine demonstrated 4 to 8-fold lower MIC values, whereas 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine demonstrated 32-fold lower MIC values. (Table 3).
Table 3. In vitro susceptibility profiles of Gwt1 Inhibitors
Figure imgf000193_0001
[0811] Gwt1 inhibitors are synergistic with FLC. The synergy of Compound 2 and 3-(3-(4- (benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine in combination with FLC using standard microtiter dilution techniques was evaluated. Synergy (FICI values <0.5) was observed for both compounds vs C. neoformans H99: FLC/ Compound 2 (0.37), FLC/3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2- amine (0.37). Importantly, no antagonism was observed.
[0812] The activity of Gwt1 inhibitors against susceptible and FLC non-susceptible/resistant strains. The activities of Compound 2, 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine, 3-(3- (4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine, 3-(3-((6-(benzyloxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine, AMB and FLC were examined against a collection of susceptible and FLC nonsusceptible/resistant (MIC ³16 µg/mL) strains of C. neoformans and C. gattii.3- (3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine was the most active compound tested with MIC values ranging between 0.004 to 0.031 µg/mL against all 18 strains tested, followed by 3-(3-((6-(benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine (range 0.016 to 0.125 µg/mL), 3- (3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine (range 0.031 to 0.25 µg/mL), and Compound 2 (range 0.125 to 0.5 µg/mL) (Table 2). Consistent with different mechanisms of action, the activities of the exemplary compounds as well as AMB were unchanged for FLC-resistant strains DUMC118 and RSA-MW-3615, relative to susceptible strains (Table 2). FLC-resistant C. neoformans DUMC158.03 demonstrated somewhat higher MIC values for the four exemplary compounds as well as AMB, suggesting that additional non-target-based mutations may be present in this strain.
In vivo activity of Gwt1 inhibitors vs C. neoformans [0813] Efficacy of Compound 1 alone and in combination with FLC in a murine model of cryptococcal meningitis. The efficacy of Compound 1 and FLC were evaluated in a well-established mouse CM model. Since Cryptococcus infections can be hematogenously disseminated to other organs, both lung and brain CFU were evaluated. Male CD-1 mice were infected with 5.9 x 104 CFU C.
neoformans strain H99 via lateral tail vein injection. Mice were assigned to four groups (n=10) consisting of: a) treatment with Compound 1; b) treatment with Compound 1 plus FLC, c) treatment with FLC, or d) no treatment control. Treatment was initiated within 1 h after infection. Compound 1 was
administered by oral gavage at a dose of 390 mg/kg thrice daily, roughly eight hours apart. ABT was not used in this model, thus TID dosing of Compound 1 was necessitated by the short half-life of
Compound 2 in mice (1.40 to 2.75 h) (34). FLC (2 mg/mL, Sagent Pharmaceuticals, Schaumburg, IL) was administered at a dose of 80 mg/kg/day intraperitoneally (IP).
[0814] The mean log10 CFU/g brain and lung counts in untreated control mice were 7.81 ± 0.19 and 5.97 ± 0.47, respectively. Significant differences (P = <0.05) in lung fungal burden were observed in all treatment groups (Compound 1, FLC, and Compound 1 plus FLC) as compared to the untreated control. In lung, the log10 CFU/g reductions in fungal burden were similar for all three treatments groups as compared to the untreated control: Compound 1 (1.50), FLC (1.30) and combined therapy (1.84), with no statistically significant differences between the treatment groups.
[0815] In brain, mice treated with Compound 1 demonstrated a reduction of 0.78 log10 CFU/g fungal burden versus the control group, which was not significantly different. However, significant reductions in log10 CFU/g fungal burden versus the control group were observed for FLC alone (1.04) and the combination of Compound 1 and FLC (3.51) (P <0.01 and P <0.001, respectively).
[0816] Effect of ABT on the pharmacokinetics of exemplary compounds.
[0817] The PK of Compound 2, 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2- amine, 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine and 3-(3-((6-(benzyloxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine were compared in male CD-1 mice after the administration of 26 mg/kg of the corresponding prodrug (Compound 1, (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, (2-amino-3-(3-(4- (benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, (2-amino-3-(3-((6- (benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate) either orally or by IP injection (Table 4). In half of the cohorts, 100 mg/kg ABT was administered 2 h prior to compound administration. Although the AUC values of the analytes differed up to 4-fold after oral administration of the four prodrugs, the addition of ABT resulted in similar exposures for Compound 2, 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine and 3-(3-((6-(benzyloxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine. The resulting exposure for 3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine was approximately 2-fold higher than the three other compounds evaluated. The addition of ABT resulted in 8.6 to 15-fold increased exposure after oral administration of the prodrugs. Table 4. Exposures of Gwt1 Inhibitors Following Oral or IP Dosing of Prodrugs in the Presence or Absence of 100 mg/kg ABT Pre-Treatment
Figure imgf000195_0001
[0818] When the prodrugs were administered IP, similar exposures were obtained for the analytes
Compound 2, 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine and 3-(3-((6- (benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine, while 3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine demonstrated an approximately 2-fold higher AUC than the other compounds evaluated (Table 4). The addition of ABT prior to IP drug administration increased exposures from 5.6 to 15.5-fold. IP dosing was chosen as the route of administration for Compound 1, (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate and (2-amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate in the CM model.
[0819] Efficacy of exemplary compounds in a murine model of cryptococcal meningitis when dosed in the presence of the pan-CYP inhibitor ABT. In a preliminary experiment, the efficacies of Compound 1, (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate and (2-amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate were evaluated in the disseminated model of CM (n=5 mice/cohort).100 mg/kg ABT was administered orally to male CD-1 mice 2 h prior to compound administration. Mice were injected with 6.9 x 104 CFU C. neoformans strain H99 per mouse via lateral tail vein at T= 0 h. Treatment with each prodrug was initiated about 1 h post-infection by IP administration and continued daily for 7 days with 100 mg/kg ABT administered orally 2 h prior to each dose of compound. The mean log10 CFU/g brain and lung counts in untreated control mice were 7.83 ± 0.09 and 4.67 ± 0.88, respectively (FIG.1).
[0820] In lung, neither the 34 mg/kg or the 85 mg/kg dose of Compound 1 achieved a statistically significant reduction in log10 CFU/g tissue vs the untreated control. Of note is that 390 mg/kg
Compound 1 dosed orally TID results in higher AUC values than 85 mg/kg Compound 1 dosed IP QD with ABT (FIG.2), thus better efficacy in lung was observed with Compound 1 monotherapy. In lung, administration of 60 mg/kg or 34 mg/kg (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate reduced tissue burdens below the limit of detection (approximately 4.67 log10 CFU/g lung tissue). For (2-amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5- yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, the reduction of CFU in lung was 3.28 log10 CFU/g (85 mg/kg QD) and 1.07 log10 CFU/g (34 mg/kg QD).
[0821] In brain, administration of 60 mg/kg or 34 mg/kg (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate resulted in a reduction of 7.13 and 7.05 log10 CFU/g brain tissue, respectively. For (2-amino-3-(3-(4-(benzyloxy)benzyl)isoxazol- 5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, the reduction of CFU in brain was 2.72 log10 CFU/g (85 mg/kg QD) and 1.66 log10 CFU/g (34 mg/kg QD). Administration of 85 mg/kg Compound 1 demonstrated a modest reduction in log10 CFU/g (0.85), which did not, however, achieve statistical significance.
[0822] A dose response study was performed with (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate and (2-amino-3-(3-(4- (benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate to confirm the observed activity. In this study, QD doses of 7.5, 20 and 60 mg/kg were evaluated in conjunction with the administration of ABT. A 60 mg/kg dose QD without ABT was also evaluated as a control.
[0823] The mean log10 CFU/g tissue counts in untreated control mice were 7.83 ± 0.07 (brain) and 5.91 ± 0.24 (lung) (FIG.2). Control animals which received daily doses of 100 mg/kg ABT without compound had log10 CFU/g tissue values of 8.07 ± 0.28 (brain) and 7.04 ± 0.34 (lung).
[0824] Both (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1- yl)methyl hydrogen phosphate and (2-amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1- yl)methyl hydrogen phosphate demonstrated a dose response in the reduction of log10 CFU/g brain and lung tissue when ABT was utilized. Cohorts which received 60 mg/kg/day of exemplary compounds without ABT showed either a numerical but non-significant reduction in lung burden of 0.74 log10 CFU/g ((2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate) or no reductions in log10 CFU/g mouse tissue, consistent with a shorter half-life and lower exposure.
[0825] For (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate with ABT, dose dependent reductions in log10 CFU/g ranged between 5.91 to 1.79 for lung and between 7.00 to 0.92 for brain. All ABT plus (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate treatment cohorts demonstrated reductions in fungal lung burden that were statistically significant from the ABT- administered control group (P £0.05). The two highest ABT plus (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate dosing levels also showed reductions in brain fungal burden, ranging from 6.99 to 2.95 log10 CFU/g (P £0.05)
[0826] For (2-amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, dose dependent changes in log10 CFU/g ranged between a reduction of 1.55 log10 CFU/g to an increase of 1.20 for lung and between a reduction of 1.45 to an increase of 0.24 for brain. However, none of these reductions reached statistical significance vs the ABT-administered control group. Statistical significance was also not achieved when these cohorts were evaluated versus the no ABT vehicle control. [0827] The results of the dose response experiment were consistent with the preliminary finding that (2- amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate demonstrated near or complete sterilization of lung and brain tissue at doses of 34 and 60 mg/kg (plus ABT).
[0828] Analysis of AUC values vs change in log10 CFU/g tissue. The three compounds evaluated in the efficacy model had MIC values for the infecting strain (C. neoformans H99) that differed by 8 to 32- fold: Compound 2 (0.25 µg/mL), 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine (0.031 µg/mL), and 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine (0.008 µg/mL) (Table 1). The data in Table 4 show that AUC values after IP dosing (plus ABT) ranged from 24.3 to 97.3 µg·h/mL, representing a 4-fold difference. To understand the influence of AUC vs MIC differences, the magnitude of log10 CFU/g tissue changes across the three experiments were assessed.
[0829] AUC values across the three experiments for Compound 1 (with or without ABT) ranged from 7.0 µg·h/mL (7.5 mg/kg Compound 1 QD plus ABT) to 196.3 µg·h/mL (390 mg/kg TID). At an AUC of 196.3 µg·h/mL, a modest but significant reduction in lung burden was observed (1.5 log10 CFU/g).
Lower AUC values were not efficacious. AUC values ranged from 10.0 to 116.4 µg·h/mL for (2-amino- 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, and from 27 to 224.3 µg·h/mL for (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1- yl)methyl hydrogen phosphate. The efficacy of the three compounds at a dose that gave rise to similar AUC values were compared.
[0830] AUC values of approximately 80 µg·h/mL. In the presence of ABT, doses of 20 mg/kg (2-amino- 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, 60 mg/kg (2-amino-3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, and 80 mg/kg Compound 1 resulted in very similar AUC values of 74.8, 82.1, and 79.4 µg·h/mL respectively. However, log10 CFU/g brain reductions were 2.95, 1.45 and 0.85, respectively and log10 CFU/g lung reductions were 3.69, 1.55 and 0.9. Thus, despite the same AUC values for the 3 compounds, better efficacy was associated with lower MIC values (0.008 µg/mL, 0.031 µg/mL and 0.25 µg/mL, respectively) suggesting that improved microbiological activity largely accounts for improved efficacy
[0831] Efficacy of (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium- 1-yl)methyl hydrogen phosphate and AMB in a delayed model of cryptococcal meningitis. A delayed treatment model was used to compare the efficacy of once daily treatment using 60 mg/kg (IP) (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, 3 mg/kg (IP) AMB vs vehicle control (IP 5% dextrose). As in the previous mouse model, 100 mg/kg ABT (PO) was administered 2 h prior to each (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate dose (n=5 mice/cohort). Infection was initiated on Day 1 and treatment was initiated 24 h later (Day 2) rather than 1 h. Treatments were administered for 7 days (final dose on Day 8) and mice were sacrificed on Day 9 for CFU enumeration. [0832] The mean log10 CFU/g tissue counts in untreated control mice were 8.15 ± 0.24 (brain) and 6.22 ± 0.93 (lung) (FIG.3). Both (2-amino-3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin- 1-ium-1-yl)methyl hydrogen phosphate and AMB demonstrated a statistically significant reduction of log10 CFU/g lung (4.59 and 4.02, respectively) vs the untreated control group (P £0.05). (2-amino-3-(3- (4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate also showed a reduction of 6.84 log10 CFU/g brain vs the untreated control, which was significant (P £0.01). These data are very similar to the reductions observed in the 60 mg/kg (2-amino-3-(3-(4-((6- fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate plus ABT cohort shown FIG.2, demonstrating the reproducibility of these findings. Although AMB demonstrated a 4.40 log10 CFU/g brain reduction, this did not meet statistical significance.
[0833] Two additional compounds, 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine and 3-(3- (4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine, demonstrated 8 to 32-fold improved anti-C. neoformans H99 activity with MIC values of 0.031 and 0.008 µg/mL, respectively compared to Compound 2. This difference in activity was also seen against a larger panel of 18 isolates where MIC90 values were 0.5 µg/mL (Compound 2), 0.25 µg/mL (3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2- amine) and 0.031 µg/mL (3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine) (Table 4). These values compare favorably to other drugs in clinical use for CM. In a global study that evaluated antifungal activity versus 46 strains of C. neoformans, MIC90 values for the azoles range from 0.06 µg/mL (isavuconazole) to 4 µg/mL (FLC), whereas the echinocandins were largely inactive with MIC90 values ³ 16 µg/mL (35). Similarly, in a study of US isolates, MIC90 values versus C. neoformans were: AMB (2 µg/mL), and 5-flucytosine (8 µg/mL), with only itraconazole (0.125 µg/mL) and ketoconazole (0.06 µg/mL) demonstrating low MIC90 values.
Table 4. Activity of Gwt1 Inhibitors vs Susceptible and FLC Non-Susceptible/Resistant Strains of Cryptococcus
Figure imgf000198_0001
Figure imgf000199_0001
[0834] In this study, a collection of clinically isolated FLC-susceptible and FLC-nonsusceptible/resistant strains of C. neoformans and C. gattii were examined. Consistent with a different mechanism of action, the potency of the four Gwt1 compounds relative to FLC was maintained, although one strain (DUMC 158.03) had higher MIC values for the exemplary compounds as well as AMB, suggesting that additional non-target-based mutations may be present in this strain. Despite the elevated MIC values for this strain, it is anticipated that appropriate clinical exposures may still be achieved for coverage of these types of strains.
[0835] Standard microtiter checkerboard dilution experiments demonstrated that both Compound 2 and 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine are synergistic with FLC vs C. neoformans H99. These data are consistent with previous reports of Compound 2 synergy with FLC against 9 of 10 Candida tropicalis strains and 2 of 20 strains of C. albicans. Importantly, no antagonism was observed. Improved activity in combination with FLC was also observed in the CM mouse model. Monotherapy of Compound 1 or FLC resulted in a reduction of 0.78 and 1.04 log10 CFU/g brain tissue vs the untreated control, whereas the combination of Compound 1 and FLC resulted in a reduction of 3.52 log10 CFU/g brain tissue as compared to control. This combination therapy was significantly more active in the reduction of fungal burden in the brain than monotherapy with Compound 1.
[0836] ABT has been used to increase exposure of drugs in other therapeutic animal models; however, the use of ABT for improving efficacy in infectious disease models has not been widespread. Two studies utilized ABT in short-term models, where log10 CFU/g tissue were examined after 24 to 48 h. The antibacterial efficacy of experimental adenosine analogs targeting DNA ligase were evaluated at 24 h post-infection in a thigh model in which mice received a single dose of 100 mg/kg ABT 2 h prior to infection to reduce the high hepatic clearance. The efficacy of Compound 1 was examined after ABT administration in disseminated Candida infection models where C. albicans kidney burdens were reduced 6.0 ± 0.1 log10 CFU/g kidney after 48 h. Since efficacy models can require treatments lasting 7 days or longer, the ability to maintain good drug exposures by administration of ABT over the treatment period is important. One study examined the pharmacokinetic parameters of antipyrine in mice administered as a 14-day continuous infusion of 20 or 60 mg ABT per ALZET osmotic pump. In that study AUC values increased 3 to 4-fold when antipyrine was dosed intravenously (IV) and 8 to 10-fold after oral administration, demonstrating the feasibility of long-term ABT administration. Here, it was shown that 7 days of daily administration of 100 mg/kg ABT 2 h prior to treatment with exemplary compounds dramatically increased the efficacy of three Gwt1 inhibitors. Pharmacokinetic studies demonstrated that ABT increased exposures 5.6 to 15.5-fold when exemplary molecules were dosed orally, and 8.6 to 15-fold, when exemplary molecules were dosed IP. These data support the use of ABT in infectious disease animal models for analysis of both clinical candidates and early discovery molecules, where proof-of-concept data are required.
[0837] Clinical studies have clearly shown that rapid killing of cryptococcal cells in the CNS is associated with an improved host outcome. The animal model data of the present disclosure provide evidence of effective brain penetration, one of the key factors in the choice of a drug for the treatment of CM. These data are consistent with 14C- Compound 1 distribution studies which demonstrated significant radioactivity in tissues associated with invasive fungal infections, including brain tissue; whereas poor CNS penetration has been observed for the echinocandins. Notably, (2-amino-3-(3-(4-((6- fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate significantly reduced lung and brain tissue fungal burden in a murine CM model, where in past experience, only AMB has shown a similar reduction in CFU in this model. In the current study, (2-amino-3-(3-(4-((6- fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate was at least comparable to or better than AMB in a delayed treatment model. Thus, an oral agent, with the potential to kill yeasts rapidly in the CNS of a host, such as (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, is of significant interest. Further pharmacodynamics studies will be performed after the optimal Gwt1 inhibitor is identified.
[0838] Example 497: Materials and Methods
[0839] Isolates tested. C. neoformans strains H99, DUMC 118.00, DUMC 158.03 and C. gattii strains R272, and RSA-MW-3515 were obtained from Duke University. C. albicans 90028, A. fumigatus MYA3626, C. neoformans 14116, C. neoformans 76484 and the pathogenic Cryptococcus reference strains panel (ATCC MP-11) were obtained from American Type Culture Collection (ATCC, Manassas, VA, USA). The MP-11 panel consists of strains representing eight molecular types and three subtypes of C. neoformans and C. gattii.
[0840] Antifungal agents. All drug stock solutions were prepared at 10 mg/mL in 100% dimethyl sulfoxide (DMSO) and aliquots stored at -20 ^C: AMB (VWR, Radnor, PA, USA), FLC, (Alfa Aesar, Tewksbury, MA, USA or Sagent Pharmaceuticals, Schaumburg, IL), caspofungin (Sigma, St. Louis, MO, USA), Compound 2, 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine 3-(3-(4-((6- fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine, 3-(3-((6-(benzyloxy)pyridin-3- yl)methyl)isoxazol-5-yl)pyridin-2-amine.
[0841] For pharmacokinetic and efficacy studies, the prodrugs Compound 1, (2-amino-3-(3-(4-((6- fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, (2-amino- 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, (2-amino-3-(3- ((6-(benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate were used. Compound 1, the N-phosphonooxymethyl prodrug, is soluble in water. On adding Compound 1 to water, the pH is less than 7.0. Sodium hydroxide was added to bring pH back to a neutral range, maintain solubility, and allow dosing of the formulated material. Prodrugs (2-amino-3-(3-(4-((6-fluoropyridin-2- yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, (2-amino-3-(3-(4- (benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate and (2-amino-3-(3-((6- (benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate were formulated similarly to enable oral and IP dosing of compounds for pharmacokinetic and efficacy studies. Final prodrug solutions were in 5% dextrose and dosed orally (PO) or IP on a per gram mouse body daily weight basis. A 10 mg/mL solution of ABT (Fisher Scientific, Hampton, NH) in water was administered orally 2 h prior to infection as 10 µL per gram mouse body weight resulting in a dose of 100 mg/kg.
[0842] Antifungal susceptibility testing. To establish antimicrobial activity, broth microdilution susceptibility testing was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines M27-A3 for yeasts and M38-A2 for molds. Compound 2 and analogs were first diluted in DMSO to obtain intermediate dilutions. These were further diluted in microtiter plates to obtain a final concentration of 2 to 0.002 µg/mL.1 ^l of DMSO was added to“No drug” control wells. The solutions were mixed on a plate shaker for 10 mins and plates incubated at 35 ^C for 40 to 48 h (C. albicans, A. fumigatus) and 72 h (C. neoformans). The minimum concentration that led to 50% reduction in fungal growth as compared to the control (with the aid of a reading mirror) was determined as the minimum inhibitory concentration (MIC) for C. albicans and C. neoformans. The minimum concentration that led to shortening of hyphae as compared to hyphal growth in DMSO control wells was determined as the minimum effective concentration (MEC) for A. fumigatus (as read for echinocandins). The use of the MIC and MEC endpoints for Compound 2 against yeasts and molds, respectively has been described previously. For the cryptococcal synergy studies, Compound 2 and 3-(3-(4-(benzyloxy)benzyl)isoxazol- 5-yl)pyridin-2-amine MIC values were read at 50% inhibition.
[0843] Pharmacokinetic analysis. Single dose PK experiments were performed in healthy male CD-1 mice following IP or oral dosing of 26 mg/kg of the prodrugs Compound 1, (2-amino-3-(3-(4-((6- fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate, (2-amino- 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate and (2-amino- 3-(3-((6-(benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate. In half of the cohorts, mice received a single oral dose of 100 mg/kg ABT at 2 h prior to prodrug dosing. Plasma was collected at 0.083, 0.5, 2, 4, 8, and 24 h post-dose (n=3 per time point). AUC is the area under the curve, calculated from T=0 to the last measurable concentration. The active metabolite concentrations in plasma (Compound 2, 3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5- yl)pyridin-2-amine, 3-(3-(4-(benzyloxy)benzyl)isoxazol-5-yl)pyridin-2-amine and 3-(3-((6- (benzyloxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine) were determined by LC-MS/MS. PK parameters were determined using Phoenix WinNonlin (v7.0) and a non-compartmental model. Samples that were below the limit of quantification (0.5 or 1 ng/mL) were not used in the calculation of averages.
[0844] Cryptococcal meningitis model. C. neoformans strain H99 was grown in YPD broth at 30 °C on a shaker (220 rpm) for 24 h, centrifuged (1980 rcf) and washed twice in PBS, resuspended in PBS, and quantified by hemacytometric count. CD-1 male mice were infected with ~5 x 104 CFU per mouse via lateral tail vein injection of 100µL. Mice were weighed, and treatment was within 1 h after infection. Treatments were administered daily for seven days. Mice were weighed daily and observed for acute and chronic adverse symptoms. Mice were sacrificed on day 8, and brain and left lung were homogenized and cultured for quantitative determination of tissue burden (CFU per gram of tissue). Tissues were homogenized for 25 seconds in 1 mL phosphate buffered saline using two 6.5 mm steel beads and a Mini-Beadbeater 16 (Biospec Products, Inc., Bartlesville, OK), and serially diluted in 10-fold steps. Aliquots (100 µL) of homogenate were plated and incubated for 3 to7 days at 37oC. Fungal burden data were log10 transformed and evaluated using Kruskal-Wallis tests with Dunn's Multiple Comparison Test for Post-hoc analysis (Prism 5; GraphPad Software, Inc., San Diego, CA). A P value of £0.05 is considered statistically significant.
[0845] Delayed treatment model. The delayed treatment model was similar to the cryptococcal meningitis model with the following exceptions: a) CD-1 male mice were infected with 5.4 x 104 CFU per mouse via lateral tail vein injection of 100 µL; b) treatment was initiated 24 h after infection and continued daily for seven days with 100 mg/kg ABT (PO) administered 2 h prior to each (2-amino-3-(3- (4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate dose; c) mice were sacrificed 24 h after the last dose, and brain and left lung were homogenized and cultured for quantitative determination of tissue burden (CFU per gram of tissue). Fungal burden data were log10 transformed and evaluated using Kruskal-Wallis tests with Dunn's Multiple Comparison Test for Post- hoc analysis (Prism 5; GraphPad Software, Inc., San Diego, CA). A P value of £0.05 is considered statistically significant
Example II: Parenteral Pharmaceutical Composition
[0846] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer is optionally added as well as optional acid or base to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection
Example III: Oral Solution
[0847] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s),optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution.
Example IV: Oral Tablet
[0848] A tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.
Example V: Oral Capsule
[0849] To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
[0850] In another embodiment, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.
Example VI: Topical Gel Composition
[0851] To prepare a pharmaceutical topical gel composition, a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with hydroxypropyl celluose, propylene glycol, isopropyl myristate and purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
Example VII: Inhalation Composition
[0852] To prepare a pharmaceutical composition for inhalation delivery, a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with anhydrous citric acid and 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
Example VIII: Ophthalmic Solution Composition
[0853] To prepare a pharmaceutical opthalmic solution composition, a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
BIOLOGICAL EXAMPLES
Example IX: In vitro Antifungal Assay
[0854] Measurement of antifungal activity: Antifungal activity of the compounds was evaluated in a microdilution broth assay as per Clinical and Laboratory Standard Institute methodology for yeast (for Candida and Cryptococcus) (1) and molds (for Aspergillus and Rhizomucor) (2). Candida albicans 90028, Aspergillus fumigatus MYA3626, Rhizomucor pusillus 46342 and Cryptococcus neoformans H99 strains were obtained from American Type Culture Collection (ATCC).
[0855] Preparation of Fungal Suspension: C. albicans 90028 and C. neoformans H99 strains were streaked from frozen stocks at -80 ^C onto Sabouraud Dextrose Agar (SDA) plates. These were allowed to grow for 24 h (C. albicans) and 48 h (C. neoformans) at 35 ^C before using them in the assay.5-6 individual colonies were picked and diluted into sterile water to obtain a fungal suspension. The cell density of the suspension was determined and the culture diluted with RPMI1640 medium to obtain a fungal suspension of 2.5 x 103 cells/mL. The suspension was used in the MIC measurement as described below.
[0856] A. fumigatus and R. pusillus were spread onto Potato Dextrose Agar (PDA) plates spores from - 80 ^C frozen stocks and incubated for 3-6 days at 30 ^C (A. fumigatus) and 35 ^C (R. pusillus). Water containing 1% Tween was directly added to the agar plate and gently agitated to wet and remove the Aspergillus conidia. For R. pusillus, water was added to the surface and gently massaged to wet and remove the spores. For both species, the conidia or spores and mycelial fragments were collected, followed by removal of mycelium, conidiophores and large clumps of conidia/spores.. The resulting spore suspension was counted and diluted into RPMI1640 medium to adjust to a final suspension of 1-2 x104 spores/mL. The suspension was used in the MEC measurement as described below.
[0857] Preparation of Compound Stocks and Intermediate Dilutions: The compounds were weighed and DMSO was added to prepare a 10 mg/mL stock. The solutions were mixed by vortexing and sonication at 37 ^C for 5-10 mins. The resulting solutions were sterile filtered using a PTFE filter, and aliquoted (12 µL or as needed) and stored at -20 ^C. Intermediate compound dilutions were prepared in sterile polypropylene tubes in 100% DMSO. The compound stock solution was first diluted in DMSO to obtain a concentration of 1600 µ g/mL. This was serially 2-fold diluted to obtain a dilution series from 1600 to 0.19 µ g/mL.
[0858] MIC/MEC Measurement: 99 µL of the fungal suspension in RPMI1640 prepared as above was added to each well of a 96-well round bottom assay plate.1 µ L of the intermediate compound dilutions (200-0.19 µ g/mL) were added to wells of the plate. This led to a 100-fold dilution of the intermediate dilutions resulting in a final compound concentration of 2-0.0019 µg/mL in the plate.1 µL of DMSO was added to“No drug” control wells. The solutions were mixed by shaking on a plate shaker for 10 mins and plates incubated at 35 ^C for 40-48 h (C. albicans, A. fumigatus, R. pusillus) and 72h (Cryptococcus). The minimum concentration that clearly inhibited fungal growth (³50% inhibition) as compared to the control by visual inspection was determined as the minimum inhibitory concentration (MIC) for C.
albicans and C. neoformans (as read for echinocandins). This was validated by thorough mixing and reading at 600 nm on a microplate reader. The minimum concentration that led to shortening of hyphae as compared to hyphal growth in DMSO control wells was determined as the minimum effective concentration (MEC) for A. fumigatus and R. pusillus (as read for echinocandins). The use of the MIC and MEC endpoints against yeasts and molds, respectively has been described by Pfaller MA, Duncanson F, Messer SA, Moet GJ, Jones RN, Castanheira M. Antimicrob Agents Chemother.2011.55(11):5155-8. In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Aspergillus spp. determined by CLSI and EUCAST broth microdilution methods. Results are shown in Table 2, and the letters indicate the following ranges in µg/mL:
A: MEC or MIC < 0.010; B: 0.010 < MEC or MIC < 0.10; C: 0.10 < MEC or MIC < 1.0;
D: MEC or MIC > 1.0; NT: Not tested Table 2.
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Example X: Systemic Candidal Infection Model in Mice
Preparation of Fungal Inoculant
[0859] C. albicans is subcultured in brain heart infusion broth and grown at 37 °C overnight. Cells are collected by centrifugation and washed three times with sterilized physiological saline and counted with a hemocytometer. The suspension is adjusted to 2×107 cells/mL with sterilized physiological saline to serve as the fungal inoculum.
Infection
[0860] 8-week-old BALB/c mice weighing ~20g are rendered neutropenic by receiving 150 mg/kg and 100 mg/kg of cyclophosphamide via IP injection on day -4 and day -1 prior to infection, respectively. The fungal inoculum is used in the amounts of 0.2 mL (4×106 cells/mouse).
Treatment
[0861] From 0.5 to 1 hour after fungal inoculation, 0.2 mL of agent solution containing a compound described herein (dissolved or suspended in sterilized physiological saline containing 6.5% dimethyl sulfoxide and 3.5% Tween 80 or another appropriate vehicle) is administered into orally using a peroral probe, 3 times every 4 hours. The agent concentration ranges from 1 mg/kg to 500 mg/kg, and the number of animals in one group ranges from 5 to 10 animals.
Determination of Effects
[0862] Animals are sacrificed after 48 hrs and organs such as kidney and brain are harvested. Colony forming units/gram of tissue are determined in order to assess the protective efffect of a compound vs a no drug (vehicle) control
Example XI: Murine Model of Cryptococcal Meningitis
Preparation of Fungal Inoculant
[0863] Cryptococcus neoformans strain H99 was grown in YPD broth at 30 °C on a shaker (220 rpm) for 24 hours, centrifuged (1980 rcf) and washed twice in PBS, resuspended in PBS, and quantified by hemacytometric, count.
Infection and treatment [0864] CD-1 male mice are infected with ~6 x 104 colony forming units (CFU) per mouse via lateral tail vein injection of 100µL. Compounds are administed by oral, intraperitoneal or intravenous routes from 1 to 3 times daily. Treatments were given for seven days.
Determination of Effects
[0865] Mice are sacrificed on day 8, and brain and left lung are homogenized and cultured for quantitative determination of tissue burden (CFU per gram of tissue). Colony forming units/gram of tissue are determined in order to assess the protective efffect of a compound vs a no drug (vehicle) control.
Example XII: Clinical Trial of a Compound Described Herein in Patients with a Fungal Infection The purpose of this study is to investigate whether a compound described herein can treat patients with fungal infections. Another purpose of this study is to assess the safety, tolerability, pharmacokinetics, bioavailability and food effect of single doses of a compound described herein administered
intravenously and orally, followed by an evaluation of the safety, tolerability, pharmacokinetics and drug-drug interaction potential of multiple doses of a compound described herein administered orally. Study Type:
Interventional
[0866] Study Design:
Allocation: Randomized
Interventional Model: Crossover Assignment
Masking: Double (Participant Investigator)
Primary Purpose: Treatment
Primary Outcome Measures:
Safety and tolerability of single and multiple oral doses of whether a compound described herein as measured by adverse events (AEs), physical examinations (PE), vital signs (VS), laboratory safety tests, urinalysis and 12-lead electrocardiograms (ECG). Time Frame: 21 days
Secondary Outcome Measures:
• Pharmacokinetics of single and multiple doses of a compound described herein as measured by maximum observed concentration (Cmax). Time Frame: 21 days
• Pharmacokinetics of single and multiple dose of a compound described herein as measured by area under the curve (AUC). Time Frame: 21 days
• Pharmacokinetics of single and multiple doses of a compound described herein as measured by terminal half life (t1/2). Time Frame: 21 days
• Pharmacokinetics of single and multiple doses of a compound described herein as measured by volume of distribution (Vd). Time Frame: 21 days
• Pharmacokinetics of single and multiple doses of a compound described herein as measured by elimination rate constant (Kel). Time Frame: 21 days
• Pharmacokinetics of single and multiple doses of a compound described herein as measured by accumulation ratio. Time Frame: 21 days • Eligibility:
Ages Eligible for Study: 18 Years to 55 Years (Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: Yes
Inclusion Criteria:
• Women of childbearing potential must agree to avoid pregnancy during the study and to use contraception at least 2 weeks before the start of the study until 3 months after the last dose of study drug.
• Males with partner(s) of childbearing potential must agree to use appropriate barrier
contraception from the screening period until 3 months after the last dose of study drug.
• Screening hematology, clinical chemistry, coagulation and urinalysis consistent with overall good health.
• No significantly abnormal findings on physical examination, ECG and vital signs.
• Willing and able to provide written informed consent.
Exclusion Criteria:
• Any uncontrolled or active major systemic disease including, but not limited to: cardiovascular, pulmonary, gastrointestinal, metabolic, urogenital, neurological, immunological, psychiatric, or neoplastic disorder with metastatic potential.
• History or presence of malignancy within the past year. Subjects who have been successfully treated with no recurrence of basal cell carcinoma of the skin or carcinoma in-situ of the cervix may be enrolled.
• Use of prescription medication within 14 days prior to the first dose of study drug and throughout the study.
• Use of non-prescription or over-the-counter medications within 7 days prior to the first dose of study drug and throughout the study.
[0867] Although the invention has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A pharmaceutically acceptable salt of a compound of Formula (III-C), or a solvate, hydrate, or a deuterated variant thereof:
Figure imgf000213_0001
.
X15 is–O–,–NH–,–S–,–SO2–, or a bond;
L is a bond or substituted or unsubstituted C1-6 alkylene;
Ring Q is monocyclic 6-membered heteroaryl, monocyclic 5-membered heteroaryl, bicyclic heteroaryl, phenyl, naphthyl, monocyclic cycloalkyl, bicyclic cycloalkyl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl;
X13 is C(R1B) or N;
X14 is C(R1B) or N;
each R1B and R10A is independently hydrogen, halogen, -CF3, -CN, -CH2-OH, -ORa, -SRa, - S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, - CO2Ra, -OCO2Ra, -C(=O)NRcRd, -OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, - NRaC(=O)ORa, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ra is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6
alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Rb is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl,
substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rc and Rd is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
z3 is 1, 2, or 3,
wherein the compound of Formula (III-C) is not (2-amino-3-(3-(4-((pyridin-2- yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate.
2. The pharmaceutically acceptable salt of claim 1, or a solvate, hydrate, or a deuterated variant thereof, wherein:
each R1B is independently hydrogen, halogen, -CF3, -CN, -CH2-OH, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, - C(=O)NRcRd, -NRaC(=O)Rb, or substituted or unsubstituted C1-C6 alkyl.
3. The pharmaceutically acceptable salt of claim 1 or claim 2, or a solvate, hydrate, or a deuterated variant thereof, wherein:
X13 is CH, CF or N; and
X14 is CH, CF or N.
4. The pharmaceutically acceptable salt of claim 1 or claim 2, or a solvate, hydrate, or a deuterated variant thereof, having the structure:
Figure imgf000214_0001
5. The pharmaceutically acceptable salt of claim 4, or a solvate, hydrate, or a deuterated variant thereof, wherein:
R1B is hydrogen of F; and
X14 is CH, CF, or N.
6. The pharmaceutically acceptable salt of any one of claims 1-5, or a solvate, hydrate, or a
deuterated variant thereof, wherein:
Figure imgf000214_0002
X15 is–O–,–NH–,–S–,–SO2–, or a bond; and
L is a bond, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, - CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.
7. The pharmaceutically acceptable salt of any one of claims 1-5, or a solvate, hydrate, or a deuterated variant thereof, wherein:
Figure imgf000215_0001
X15 is–O–,–NH–,–S–,–SO2–, or a bond; and
L is a bond, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, - CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.
8. The pharmaceutically acceptable salt of any one of claims 1-7, or a solvate, hydrate, or a deuterated variant thereof, wherein:
X15 is–O–,–NH–, or a bond; and
L is a bond, -CH2-, or -CH2CH2-.
9. The pharmaceutically acceptable salt of any one of claims 1-8, or a solvate, hydrate, or a deuterated variant thereof, wherein:
X15 is–O–,–NH–, or a bond; and
L is a bond or -CH2-.
10. The pharmaceutically acceptable salt of any one of claims 1-9, or a solvate, hydrate, or a deuterated variant thereof, wherein:
X15 is–O–.
11. The pharmaceutically acceptable salt of any one of claims 1-9, or a solvate, hydrate, or a deuterated variant thereof, wherein:
X15 is–NH-.
12. The pharmaceutically acceptable salt of any one of claims 1-9, or a solvate, hydrate, or a deuterated variant thereof, wherein:
X15 is a bond.
13. The pharmaceutically acceptable salt of any one of claims 1-12, or a solvate, hydrate, or a deuterated variant thereof, wherein:
Ring Q is monocyclic 6-membered heteroaryl, monocyclic 5-membered heteroaryl, bicyclic heteroaryl, phenyl, naphthyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl.
14. The pharmaceutically acceptable salt of any one of claims 1-12, or a solvate, hydrate, or a deuterated variant thereof, wherein:
Ring Q is monocyclic 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; or Ring Q is monocyclic 5-membered heteroaryl selected from the group consisting of imidazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, and thiadiazolyl; or
Ring Q is phenyl or naphthyl; or
Ring Q is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or
Ring Q is aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, methyl-2-oxo-1,3- dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl; or
Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl,
benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
15. The pharmaceutically acceptable salt of any one of claims 1-12, or a solvate, hydrate, or a
deuterated variant thereof, wherein:
Ring Q is pyridinyl.
16. The pharmaceutically acceptable salt of any one of claims 1-12, or a solvate, hydrate, or a
deuterated variant thereof, wherein:
Ring Q is phenyl.
17. The pharmaceutically acceptable salt of any one of claims 1-12, or a solvate, hydrate, or a
deuterated variant thereof, wherein:
Ring Q is monocyclic 5-membered heteroaryl selected from the group consisting of imidazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, and thiadiazolyl.
18. The pharmaceutically acceptable salt of any one of claims 1-12, or a solvate, hydrate, or a
deuterated variant thereof, wherein:
Ring Q is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
19. The pharmaceutically acceptable salt of any one of claims 1-12, or a solvate, hydrate, or a
deuterated variant thereof, wherein:
Ring Q is azetidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydropyranyl, and thiomorpholinyl.
20. The pharmaceutically acceptable salt of any one of claims 1-12, or a solvate, hydrate, or a
deuterated variant thereof, wherein:
Ring Q is bicyclic heteroaryl selected from the group consisting of indolizinyl, indolyl,
benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
21. The pharmaceutically acceptable salt of any one of claims 1-20, or a solvate, hydrate, or a deuterated variant thereof, wherein:
R10A is selected from the group consisting of hydrogen, F, Cl, Br, -CF3, -CN, -CH2-OH, -OH, - OCH3, -OCH2CH3 -OCH(CH3)2, -OC(CH3)3, -OCF3, methyl, ethyl, isopropyl, isobutyl, and butyl;
z3 is 1 or 2.
22. A pharmaceutically acceptable salt of a compound selected from:
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
,
Figure imgf000224_0001
, ,
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
or a solvate, hydrate, or a deuterated variant thereof.
23. A pharmaceutically acceptable salt of a compound selected from:
3-(3-(4-((6-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((6-chloropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((3-fluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((3,5-difluoropyridin-2-yl)oxy)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(3-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((5-fluorofuran-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-phenoxypyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-((3-fluorobenzyl)oxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2-fluorophenyl)pyridin-2-amine; 5-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)-N-(2,6-difluorophenyl)pyridin-2-amine; 3-(3-(4-benzylbenzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-((6-fluoropyridin-2-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(2-fluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(3,5-difluorophenoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((6-(cyclopropylmethoxy)pyridin-3-yl)methyl)isoxazol-5-yl)pyridin-2-amine; 3-(3-(4-(3,5-difluorobenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-((2-((3-fluorobenzyl)oxy)pyridin-4-yl)methyl)isoxazol-5-yl)pyridin-2-amine;
3-(3-(4-(3-fluorobenzyl)benzyl)isoxazol-5-yl)pyridin-2-amine; and
3-(3-(4-(((3-fluorophenyl)amino)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine,
or a solvate, hydrate, tautomer, or a deuterated variant thereof.
24. A pharmaceutical composition, comprising a pharmaceutically acceptable salt of any one of claims 1-23, or a solvate, hydrate, or a deuterated variant thereof, and at least one
pharmaceutically acceptable excipient.
25. Use of a pharmaceutically acceptable salt of any one of claims 1-23, or a solvate, hydrate, or a deuterated variant thereof, or the pharmaceutical composition of claim 24, in the treatment of a fungal disease in a subject.
26. The use of claim 25, wherein the fungal disease is selected from the group consisting of
aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (Valley Fever), cryptococcosis, fungal eye infection, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), ringworm, sporotrichosis, and talaromycosis.
27. The use of claim 25 or 26, wherein the fungal disease is caused by a fungal species selected the group consisting of Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatitidis, Ajellomyces dermatitidis, Candida albicans, Candida glabrata, Candida rugosa, Candida auris, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus,
Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species, Basidiobolus species, Sporothrix schenckii, Pneumocystis jirovecii, Talaromyces marneffei, Asclepias albicans, Fusarium solani, Scedosporium apiospermum, and Rhizomucor pusillus.
28. The use of any one of claims 25-27, wherein the subject is immunocompromised.
29. The use of claim of any one of claims 25-28, wherein the subject has received chemotherapy treatment.
30. The use of claim of any one of claims 25-29, wherein the subject is infected with HIV/AIDS.
31. The use of claim of any one of claims 25-30, wherein the fungal disease is caused by
Cryptococcus neoformans or Cryptococcus gattii.
PCT/US2020/036400 2019-06-07 2020-06-05 Heterocycle substituted pyridine derivative antifungal agents WO2020247804A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962858897P 2019-06-07 2019-06-07
US62/858,897 2019-06-07

Publications (1)

Publication Number Publication Date
WO2020247804A1 true WO2020247804A1 (en) 2020-12-10

Family

ID=73652296

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/036400 WO2020247804A1 (en) 2019-06-07 2020-06-05 Heterocycle substituted pyridine derivative antifungal agents

Country Status (1)

Country Link
WO (1) WO2020247804A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022127782A1 (en) * 2020-12-15 2022-06-23 南京明德新药研发有限公司 Aminopyridine compound and application thereof
US11512079B2 (en) 2017-12-07 2022-11-29 Amplyx Pharmaceuticals, Inc. Heterocycle substituted pyridine derivative antifungal agents
US11771688B2 (en) 2018-06-25 2023-10-03 Amplyx Pharmaceuticals, Inc. Pyridine derivatives substituted by heterocyclic ring and amino group

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090233883A1 (en) * 2007-12-27 2009-09-17 Eisai R&D Management Co. Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
US20100331282A1 (en) * 2009-06-24 2010-12-30 Masayuki Matsukura Pyridine derivative containing ((phosphonooxy)methyl)pyridinium ring, and antifungal agent containing these derivative
US20110201649A1 (en) * 2008-09-19 2011-08-18 Sumitomo Chemical Company, Limited agricultural composition
US20120029023A1 (en) * 2005-10-31 2012-02-02 Keigo Tanaka Heterocycles substituted pyridine derivatives and antifungal agent containing thereof
WO2019113542A1 (en) * 2017-12-07 2019-06-13 Amplyx Pharmaceuticals, Inc. Heterocycle substituted pyridine derivative antifungal agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120029023A1 (en) * 2005-10-31 2012-02-02 Keigo Tanaka Heterocycles substituted pyridine derivatives and antifungal agent containing thereof
US20090233883A1 (en) * 2007-12-27 2009-09-17 Eisai R&D Management Co. Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
US20110201649A1 (en) * 2008-09-19 2011-08-18 Sumitomo Chemical Company, Limited agricultural composition
US20100331282A1 (en) * 2009-06-24 2010-12-30 Masayuki Matsukura Pyridine derivative containing ((phosphonooxy)methyl)pyridinium ring, and antifungal agent containing these derivative
WO2019113542A1 (en) * 2017-12-07 2019-06-13 Amplyx Pharmaceuticals, Inc. Heterocycle substituted pyridine derivative antifungal agents

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11512079B2 (en) 2017-12-07 2022-11-29 Amplyx Pharmaceuticals, Inc. Heterocycle substituted pyridine derivative antifungal agents
US11771688B2 (en) 2018-06-25 2023-10-03 Amplyx Pharmaceuticals, Inc. Pyridine derivatives substituted by heterocyclic ring and amino group
WO2022127782A1 (en) * 2020-12-15 2022-06-23 南京明德新药研发有限公司 Aminopyridine compound and application thereof

Similar Documents

Publication Publication Date Title
US10577367B2 (en) IRAK4 inhibiting agents
EP3720438B1 (en) Heterocycle substituted pyridine derivative antifungal agents
US11014881B2 (en) Hepatitis B capsid assembly modulators
JP7033079B2 (en) Aromatic sulfonamide derivative
WO2020247804A1 (en) Heterocycle substituted pyridine derivative antifungal agents
CN105339351B (en) Arginine methyltransferase inhibitor and application thereof
US8859768B2 (en) Heteroaryls and uses thereof
US20130065918A1 (en) Soluble guanylate cyclase activators
CN110036005A (en) Amide derivatives and its application in drug
CN108440515A (en) Substituted benzofuranyl and benzoxazole based compound and application thereof
TWI749024B (en) Compounds and their use for reducing uric acid levels
CN109251166A (en) The aminated compounds for inhibiting SSAO/VAP-1 and its application in medicine
TW201302730A (en) Pyrazole compounds
US20210009564A1 (en) Calpain modulators and therapeutic uses thereof
US20110294858A1 (en) Substituted 6-methylnicotinamides as mglur5 positive allosteric modulators
US11939329B2 (en) PARP1 inhibitors and uses thereof
OA19832A (en) Heterocycle substituted pyridine derivative antifungal agents.
CN117466873A (en) Pyrimidine compound and application thereof in medicines

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20818300

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20818300

Country of ref document: EP

Kind code of ref document: A1