WO2023009618A1 - Inhibiteurs de pgdh bicycliques et leurs procédés de fabrication et d'utilisation - Google Patents

Inhibiteurs de pgdh bicycliques et leurs procédés de fabrication et d'utilisation Download PDF

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Publication number
WO2023009618A1
WO2023009618A1 PCT/US2022/038515 US2022038515W WO2023009618A1 WO 2023009618 A1 WO2023009618 A1 WO 2023009618A1 US 2022038515 W US2022038515 W US 2022038515W WO 2023009618 A1 WO2023009618 A1 WO 2023009618A1
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substituted
unsubstituted
compound
solvate
pharmaceutically acceptable
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PCT/US2022/038515
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English (en)
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Sundeep Dugar
Bruce Fahr
Roopa Rai
Michael J. Green
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Epirium Bio, Inc.
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Priority to EP22850242.3A priority Critical patent/EP4377314A1/fr
Publication of WO2023009618A1 publication Critical patent/WO2023009618A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • Prostaglandins are a group of physiologically active lipid compounds with diverse biological effects including vasodilation, inhibition of platelet aggregation, bronchodilation, bronchoconstriction, immune responses, contraction and relaxation of gastrointestinal smooth muscles, gastric acid secretion, gastric mucus secretion, uterus contraction, lipolysis inhibition, neurotransmission, clotting, hyperalgesia, and pyrexia.
  • Treatment of diseases or disorders may require activation of prostaglandins, or inhibition of inactivation of prostaglandins.
  • Hydroxyprostaglandin dehydrogenases such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) are involved in the inactivation of prostaglandins. As such, diseases/disorders associated with prostaglandins can be prevented, treated and/or managed using inhibitors of hydroxyprostaglandin dehydrogenase such as inhibitors of 15-PGDH.
  • a PGDH inhibitor having the structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: Formula (V) wherein, ring Q is C 6 aryl or 5 to 10-membered heteroaryl; A 1 is CR 1 or N and A 2 is CR 2 or N, provided that at least one of A 1 or A 2 is N; A 3 is N or CR 7 ; W is -CR 6 R 6 - , -O-, -S-, -NR 5 -, -S(O)-, -S(O) 2 -, or -C(O)-; R 1 and R 2 are each independently H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl
  • ring Q is a bicyclic or monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N. In some embodiments, wherein ring Q is a phenyl, pyrimidinyl, or pyridinyl.
  • the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof: Formula (VI) wherein, X 2 is N, NR 3A , or CR 3A ; X 3 is N or CR 3B ; X 4 is N, NR 3C , or CR 3C ; and R 3A , R 3B , and R 3C are each independently H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , – C(O)NR 8 R 9 , –SOR 11 , –SO 2 R 11 , –SO 2 NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , –NR 12 C(O)NR 8 R 9 , –NR 12 SO 2 R 10 , –NR 12 SO 2 NR 8 R 9 , –NR 12 SO 2 R 10 ,
  • the compound has the structure of Formula (VIa), (VIb), or (VIc), or a pharmaceutically acceptable salt or solvate thereof: [0008]
  • the compound has the structure of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof: Formula (VII) wherein, X 2 is N or CH; and R 3C is H or halogen and R 3B is selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , – C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl
  • the compound has the structure of Formula (VIIa), (VIIb), or (VIIc), or a pharmaceutically acceptable salt or solvate thereof: o u a c .
  • Q is a 5-membered heteroaryl selected from triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl.
  • ring Q is wherein Y 1 is O, S, or NR 3D ; Y 2 is N or CR 3A ; Y 3 and Y 4 are each independently N or CR 3B ; R 3A and R 3B are each independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , - NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • a PGDH inhibitor having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: Formula (I), wherein, ring Q is C6 aryl or 5- to 10-membered heteroaryl; L is -CR 13A R 13B -, -C(O)-, -S-, -S(O)-, -S(O)2-, or -S(O2)NH-; A 1 is N or CR 1 and A 2 is N or CR 2 , provided that at least one of A 1 or A 2 is N; A 3 is N or CR 7 ; R 1 and R 2 are each independently H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , –C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl
  • the compound has the structure of Formula (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof: ormu a c .
  • the compound is selected from Table 1a or Table 1b, or a pharmaceutically acceptable salt or solvate thereof.
  • is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable excipient.
  • a method of promoting and/or stimulation skin pigmentation comprising administering one or more of the compositions described herein to a subject in need thereof.
  • provided herein is a method of inhibiting hair loss, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • method of preventing and/or treating skin inflammation and/or damage comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of preventing and/or treating vascular insufficiency comprising administering one or more of the compositions described herein to a subject in need thereof.
  • provided herein is a method of preventing, treating, minimizing and/or reversing congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of reducing cardiac ejection fraction comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of preventing and/or treating a gastrointestinal disease comprising administering one or more of the compositions described herein to a subject in need thereof.
  • provided herein is a method of preventing and/or treating renal dysfunction, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of stimulation bone resorption and bone formation comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of stimulating tissue regeneration by stimulating comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of modulating cervical ripening comprising administering one or more of the compositions described herein to a subject in need thereof.
  • provided herein is a method of promoting neuroprotection and/or stimulating neuronal regeneration, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of treating and/or preventing a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder comprising administering one or more of the compositions described herein to a subject in need thereof.
  • provided herein is a method of treating and/or preventing fibrotic or adhesion disease, disorder or condition, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of reducing and/or preventing scar formation comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of treating and/or preventing muscle disorder, muscle injury and/or muscle atrophy comprising administering one or more of the compositions described herein to a subject in need thereof.
  • provided herein is a method of treating and/or preventing fibrosis, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of treating and/or preventing idiopathic pulmonary fibrosis comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of treating and/or preventing kidney fibrosis comprising administering one or more of the compositions described herein to a subject in need thereof.
  • provided herein is a method of stimulating muscle regeneration, comprising administering one or more of said compositions described herein to a subject in need thereof.
  • a method of promoting organ fitness comprising administering one or more of said compositions described herein to a subject in need thereof.
  • a method of promoting wound healing comprising administering one or more of said compositions described herein to a subject in need thereof.
  • a method of treating acute kidney injury comprising administering one or more of said compositions described herein to a subject in need thereof.
  • provided herein is a method of treating sarcopenia, comprising administering one or more of said compositions described herein to a subject in need thereof.
  • a method of treating a neuromuscular disease comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-penty
  • a numerical range such as “C 1 -C 6 alkyl” or “C1-6alkyl”, means that the alkyl group may consist 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 C1-10alkyl.
  • the alkyl is a C1-6alkyl.
  • the alkyl is a C1-5alkyl.
  • the alkyl is a C1-4alkyl.
  • the alkyl is a C1-3alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, - OMe, -NH2, or -NO2.
  • Alkenyl refers to a straight-chain, or 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.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C2-6alkenyl”, 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.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, - OMe, -NH 2 , or -NO 2 .
  • Alkynyl refers to a straight-chain or 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” or “C 2 - 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.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, - CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain.
  • an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.
  • Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined.
  • an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • 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 (phenyl).
  • 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.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • Carbocycle refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon.
  • Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • An aromatic ring e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • carbocyclic Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl), from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl), from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-
  • the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7- dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • Cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • 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 or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • haloalkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3- halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.).
  • halogen substituted alkanes e.g., Cl, Br, F, I, etc.
  • each halogen may be independently selected e.g., 1-chloro,2-fluoroethane.
  • fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls.
  • the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. [0064] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines.
  • Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. - NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, for example, - CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , - CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N(CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 .
  • Heterocycloalkyl refers to a 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, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, 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, tetrahydropyrany
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • 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).
  • the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • Heteroaryl or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the heteroatom(s) in the heteroaryl radical may be optionally oxidized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzthiazole, and imdazopyridine.
  • An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring.
  • a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-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,
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, - OMe, -NH2, or -NO2.
  • an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, - CFHCHF2, etc.).
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • the term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents.
  • substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants. [0073] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.
  • Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • isotopic variations of the compounds of the present disclosure are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium).
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art. [0076] “Isomers” are different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • Diastereoisomers or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form).
  • certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • the single enantiomers or diastereomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers.
  • Racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high- pressure liquid chromatography (HPLC) column.
  • HPLC high- pressure liquid chromatography
  • a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
  • certain small molecules include Z- and E- forms (or cis- and trans- forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • the term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that may induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit can include, for example, 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 subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • a “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the term “co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time.
  • Co- administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
  • antagonists are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein or enzyme. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.
  • a biological function e.g., activity, expression, binding, protein-protein interaction
  • a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein, ring Q is C6 aryl or 5- to 10-membered heteroaryl; L is -CR 13A R 13B -, -C(O)-, -S-, -S(O)-, -S(O)2-, or -S(O2)NH-; A 1 is N or CR 1 and A 2 is N or CR 2 , provided that at least one of A 1 or A 2 is N; A 3 is N or CR 7 ; R 1 and R 2 are each independently H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycl
  • a 1 is CR 1 ; and A 2 is N; In some embodiments, A 1 is N; and A 2 is CR 2 . In some embodiments, A 1 is CH; and A 2 is N; In some embodiments, A 1 is N; and A 2 is CH; [0091] In some embodiments, the compound of Formula (I) is a compound having the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: [0092] Formula (IIa). [0093] In some embodiments, the compound of Formula (I) is a compound having the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof: Formula (IIb).
  • the compound of Formula (I) is a compound having the structure of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof: Formula (IIc).
  • a 3 is CR 7 . In some embodiments, A 3 is CH. In some embodiments, A 3 is N.
  • R 1 is H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , – C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • R 1 is H, halogen, -CN, –OR 10 , or –NR 8 R 9 .
  • R 1 is –C(O)R 10 , – C(O)OR 10 , or –C(O)NR 8 R 9 .
  • R 1 is substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, R 1 is H. [0097] In some embodiments, R 2 is H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , – C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • R 2 is H, halogen, -CN, –OR 10 , or –NR 8 R 9 .
  • R 2 is –C(O)R 10 , – C(O)OR 10 , or –C(O)NR 8 R 9 .
  • R 2 is substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl.
  • R 2 is H.
  • a compound having the structure of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof wherein, ring Q is C6 aryl or 5- to 10-membered heteroaryl; L is -CR 13A R 13B -, -C(O)-, -S-, -S(O)-, -S(O)2-, or -S(O2)NH-; R 1 and R 2 are each independently H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , - NR 10 C(O)R 11 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C3- C8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalky
  • ring Q is C6 aryl or 5- to 10-membered heteroaryl
  • L is -CR 13A R 13B -, -C(O)-, -S-, -S(O)-, -S(O)2-, or -S(O2)NH-
  • R 1 and R 2 are each independently H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl
  • each R 3 is independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(
  • ring Q is an aryl or heteroaryl. In some embodiments, ring Q is aryl. In some embodiments, ring Q is a bicyclic or monocyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl. In some embodiments, ring Q is a monocyclic heteroaryl. In some embodiments, ring Q is a 5- to 6-membered heteroaryl. [0101] In some embodiments, ring Q is C6 aryl. In some embodiments, ring Q is a 6-membered monocyclic heteroaryl. In some embodiments, ring Q is phenyl or a 6-membered monocyclic heteroaryl.
  • ring Q is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring Q is phenyl or pyridinyl. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is pyridinyl. In some embodiments, ring Q is pyrazinyl. In some embodiments, ring Q is pyrimidinyl. In some embodiments, ring Q is pyridazinyl.
  • ring Q is: wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are each independently N or CR 3 ; and wherein at least two of X 1 -X 5 is CR 3 .
  • X 2 is N; and X 1 , X 3 , X 4 , and X 5 are each CR 3 .
  • X 3 is N; and X 1 , X 2 , X 4 , and X 5 are each CR 3 .
  • X 1 is N; and X 2 , X 3 , X 4 , and X 5 are each CR 3 .
  • X 2 and X 4 are each N; and X 1 , X 3 and X 5 are each CR 3 . In some embodiments, X 2 and X 3 are each N; and X 1 , X 4 and X 5 are each CR 3 . In some embodiments, X 1 and X 4 are each N; and X 2 , X 3 and X 5 are each CR 3 . In some embodiments, X 1 , X 2 , and X 4 are N; and X 3 and X 5 are each CR 3 .
  • ring Q is: wherein, X 1 and X 5 are each independently N or CH; X 2 is N or CR 3A ; X 3 is N or CR 3B ; X 4 is N, NR 3C , or CR 3C ; and R 3A , R 3B , and R 3C are each independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –SOR 11 , –SO2R 11 , –SO2NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , – NR 12 C(O)NR 8 R 9 , –NR 12 SO2R 10 , –NR 12 SO2NR 8 R 9 , -OC(O)NR 8 R 9 , substituted or un
  • the compound of Formula (I) has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof: Formula (III), wherein, X 2 is N or CR 3A ; and R 3A , R 3B , and R 3C are each independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –SOR 11 , –SO2R 11 , –SO2NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , – NR 12 C(O)NR 8 R 9 , –NR 12 SO2R 10 , –NR 12 SO2NR 8 R 9 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or
  • the compound of Formula (Ie) has the structure of Formula (IIIe), or a pharmaceutically acceptable salt or solvate thereof: wherein, X 2 is N or CR 3A ; and R 3A , R 3B , and R 3C are each independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –SOR 11 , –SO 2 R 11 , –SO 2 NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , – NR 12 C(O)NR 8 R 9 , –NR 12 SO 2 R 10 , –NR 12 SO 2 NR 8 R 9 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or
  • X 2 is N. In some embodiments, X 2 is CR 3A . In some embodiments, X 2 is CH. [0108] In some embodiments, R 3B is H or halogen; and R 3C is selected from substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B is H or halogen; and R 3C is substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B is H, Br, Cl, or F; and R 3C is substituted or unsubstituted 5-membered heteroaryl.
  • R 3C is H or halogen; and R 3B is selected from substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3C is H or halogen; and R 3B is substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3C is H, Br, Cl, or F; and R 3B is substituted or unsubstituted 5-membered heteroaryl.
  • R 3B is selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3B is selected from H, –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3B is selected from– C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -OC(O)NR 8 R 9 .
  • R 3B is selected from substituted or unsubstituted C 3 -C 8 heterocycloalkyl. In some embodiments, R 3B is selected from substituted or unsubstituted 5-membered heteroaryl.
  • the heteroaryl is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.
  • R 3B is H.
  • R 3C is selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3C is selected from H, –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.
  • R 3C is selected from– C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -OC(O)NR 8 R 9 .
  • R 3C is selected from substituted or unsubstituted C 3 -C 8 heterocycloalkyl. In some embodiments, R 3C is selected from substituted or unsubstituted 5-membered heteroaryl.
  • the heteroaryl is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.
  • R 3C is H.
  • ring Q is a 5-membered heteroaryl.
  • ring Q is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.
  • ring Q is: wherein, Y 1 is O, S, or NR 3D ; Y 2 is N or CR 3A ; Y 3 and Y 4 are each independently N or CR 3B ; R 3A and R 3B are each independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl; and R 3
  • Y 1 is O or S; Y 2 is CR 3A ; and Y 3 and Y 4 are each independently N or CR 3B .
  • Y 1 is O; Y 2 is CR 3A ; and Y 3 and Y 4 are each independently N or CR 3B .
  • Y 1 is S; Y 2 is CR 3A ; and Y 3 and Y 4 are each independently N or CR 3B .
  • Y 1 is O or S; Y 2 is N; and Y 3 and Y 4 are each independently N or CR 3B .
  • Y 1 is O; Y 2 is N; and Y 3 and Y 4 are each independently N or CR 3B . In some embodiments, Y 1 is S; Y 2 is N; and Y 3 and Y 4 are each independently N or CR 3B .
  • R 3A , R 3B , and R 3C are each independently selected from H, halogen, – NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.
  • R 3A , R 3B , and R 3C are each independently selected from –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 .
  • R 3A , R 3B , and R 3C are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl.
  • R 3A , R 3B , and R 3C are each independently selected from substituted or unsubstituted 5- membered heteroaryl. In some embodiments, R 3A , R 3B , and R 3C are each independently selected from H or halogen. [0117] In some embodiments, R 3D is H. In some embodiments, R 3D is C 1 -C 6 alkyl. [0118] In some embodiments, the compound has the structure of Formula (IVa) or (IVb), or a pharmaceutically acceptable salt or solvate thereof: Formula (IVb). [0119] In some embodiments, the compound has the structure of Formula (IVc) or (IVd), or a pharmaceutically acceptable salt or solvate thereof: Formula (IVd).
  • each R 3 is independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –SOR 11 , –SO 2 R 11 , –SO 2 NR 8 R 9 , –NR 12 C(O)R 10 , – NR 12 C(O)NR 8 R 9 , –NR 12 C(O)OR 10 , –NR 12 SO 2 R 10 , –NR 12 SO 2 NR 8 R 9 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycl
  • each R 3 is independently selected from H, halogen, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, substituted or unsubstituted C 6 aryl, or substituted or unsubstituted 5-membered heteroaryl.
  • each R 3 is independently selected from H, Cl, F, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. [0122] In some embodiments, each R 3 is independently selected from substituted or unsubstituted C 3 -C 8 heterocycloalkyl or substituted or unsubstituted 5-membered heteroaryl., substituted or unsubstituted with one or two -NH2, CF3, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl. In some embodiments, each R 3 is independently a substituted or unsubstituted 5-membered heteroaryl.
  • each R 3 is independently selected from triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.
  • each R 3 is independently triazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl, each of which is substituted or unsubstituted with one or two halogen, -NH 2 , CF 3 , C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl. [0123] In some embodiments, each R 3 is independently selected from the group consisting of [0124] In some embodiments, each R 3 is independently selected from the group consisting of
  • each R 3 is independently –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , or – NR 12 C(O)OR 10 . In some embodiments, each R 3 is independently –C(O)R 10 , –C(O)NR 8 R 9 , or – NR 12 C(O)OR 10 . In some embodiments, each R 3 is independently –C(O)R 10 . In some embodiments, each R 3 is independently –C(O)OR 10 . In some embodiments, each R 3 is independently–C(O)NR 8 R 9 . In some embodiments, each R 3 is independently –NR 12 C(O)OR 10 .
  • each R 3 is independently selected from , , [0127] In some embodiments, the definitions of R 3 are each independently the same as the definitions of R 3A , R 3B , and R 3C . In some embodiments, the definitions of R 3 are the same as the definitions of R 3A . In some embodiments, the definitions of R 3 are the same as the definitions of R 3B . In some embodiments, the definitions of R 3 are the same as the definitions of R 3C . [0128] In some embodiments, ring Q is a bicyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl comprising 1-3 heteroatoms selected from N, O, and S atoms.
  • ring Q is a bicyclic heteroaryl comprising 1, 2, or 3 N atoms. In some embodiments, ring Q is [1,2,4]triazolo[1,5- a]pyridine. [0129] In some embodiments, ring Q is wherein, ring A is a 5-membered heteroaryl optionally comprising 1 or 2 N atoms; X 6 is C or N; and R 15 is H, halogen, –NR 8 R 9 , –substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl.
  • ring A is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.
  • ring Q is pyrazolyl.
  • ring Q is imidazolyl.
  • ring Q is triazolyl.
  • X 6 is C. In some embodiments, X 6 is N.
  • R 15 is H, halogen, –NR 8 R 9 , –C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, R 15 is H. In some embodiments, R 15 is –NR 8 R 9 . In some embodiments, R 15 is -NH 2 , - NHCH3, or -N(CH3)2. In some embodiments, R 15 is –C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments, R 15 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, or CHF2.
  • R 15 is substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, R 15 is substituted or unsubstituted C 3 -C 8 heterocycloalkyl. In some embodiments, R 15 is [0134] In some embodiments, L is -S-, -S(O)-, or -S(O)2-. In some embodiments, L is -S-. In some embodiments, L is -S(O)-. In some embodiments, L is -S(O)2-. In some embodiments, L is -C(O)-. In some embodiments, L is -O-. In some embodiments, L is -CR 6 R 6 - .
  • L is -C(O)R 10 -.
  • L is -S-, -S(O)-, or -S(O)2-; and R 4 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl.
  • L is -S-, -S(O)-, or -S(O) 2 -; and R 4 is substituted or unsubstituted C 1 -C 6 alkyl.
  • R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 1 -C 8 heteroalkyl. In some embodiments, R 4 is substituted or unsubstituted C 1 -C 8 alkyl. In some embodiments, R 4 is substituted or unsubstituted C 2 -C 8 alkenyl. In some embodiments, R 4 is substituted or unsubstituted C 1 -C 8 heteroalkyl. [0138] In some embodiments, L is C(O); and R 4 is .
  • the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof: Formula (VI), wherein, X 2 is N, NR 3A , or CR 3A ; X 3 is N or CR 3B ; X 4 is N, NR 3C , or CR 3C ; and R 3A , R 3B , and R 3C are each independently H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , – C(O)NR 8 R 9 , –SOR 11 , –SO2R 11 , –SO2NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , –NR 12 C(O)NR 8 R 9 , –NR 12 SO2R 10 , –NR 12 SO2NR 8 R 9 , -OC
  • the compound has the structure of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIa).
  • the compound has the structure of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIb).
  • the compound has the structure of Formula (VIc), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIc).
  • X 4 is N and X 5 is CH.
  • X 4 is CR 3C and X 5 is N.
  • X 4 is CR 3C and X 5 is CH.
  • X 2 is N and X 4 is CR 3C .
  • R 3B is H, and R 3C is – C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.
  • R 3C is H
  • R 3B is –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.
  • X 2 is C 3A and X 4 is N.
  • R 3A is H
  • R 3B is – C(O)R 10 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.
  • R 3B is H, and R 3A is –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.
  • X 2 is CR 3A and X 4 is CR 3C .
  • R 3A and R 3B are each H; and R 3C is –C(O)R 10 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.
  • R 3A and R 3C are each H; and R 3B is –C(O)R 10 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.
  • R 3B and R 3C are each H; and R 3A is –C(O)R 10 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.
  • the compound has the structure of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof: Formula (VII), wherein, X 2 is N or CH; and R 3C is H or halogen and R 3B is selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , – C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl; or R 3B is selected from H, halogen, -CN, –NR 8 R 9
  • the compound has the structure of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIIa).
  • the compound has the structure of Formula (VIIb), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIIb).
  • the compound has the structure of Formula (VIIc), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIIc).
  • the compound has the structure of Formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), or a pharmaceutically acceptable salt or solvate thereof:
  • ring Q is C 6 aryl or 5 or 10-membered heteroaryl
  • W is -CR 6 R 6 - , -O-, -S-, -NR 5 -, -S(O) 2 -, or -C(O)-
  • R 1 is H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl
  • each R 3 is independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)
  • the compound has the structure of Formula (X), or a pharmaceutically acceptable salt or solvate thereof:
  • Formula (X) X 2 is N or CR 3A ; and R 3A , R 3B , and R 3C are each independently selected from H, halogen, -CN, –NR 8 R 9 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5- membered heteroaryl; provided that R 3A , R 3B , and R3 are not all H at the same time.
  • the compound has the structure of Formula (XIa) or (XIb), or a pharmaceutically acceptable salt or solvate thereof: Formula (XIb).
  • the compound has the structure of Formula (XII), or a pharmaceutically acceptable salt or solvate thereof: Formula (XII) wherein, ring A is a 5-membered heteroaryl optionally comprising 1 or 2 N atoms; and R 15 is H, halogen, –NR 8 R 9 , –substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl.
  • W is -CR 6 R 6 -, -O-, -S-, -NR 5 -, -S(O)-, or -S(O)2-. In some embodiments, W is -O-, -S- or -S(O)2-. In some embodiments, W is -O-. In some embodiments, W is -S-. In some embodiments, W is -NR 5 -. In some embodiments, W is -S(O)2-. In some embodiments, W is -S(O)-. [0158] In some embodiments, W is -CR 6 R 6 -. In some embodiments, W is -CH2-. In some embodiments, W is -CF2-.
  • W is -CHF-.
  • each R 6 is independently H, halogen, CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , -NR 8 C(O)R 11 -–SOR 11 , –SO 2 R 11 , -SR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl.
  • each R 6 is independently H, halogen, CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , -NR 8 C(O)R 11 -– SOR 11 , –SO 2 R 11 , -SR 11 , substituted or unsubstituted C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.
  • each R 6 is independently H, halogen, CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , or substituted or unsubstituted C 1 -C 6 alkyl.
  • each R 6 is halogen.
  • each R 6 is independently F, -NH 2 , -CF 3 , -CHF 2 , -CF 2 CH 3 , -OH, -OCH 3 , or -CH 3 .
  • each R 6 is independently F, -NH 2 , -OH, -OCH 3 , or -CH 3 . In some embodiments, each R 6 is independently F. In some embodiments, each R 6 is independently -CH 3 . [0162] In some embodiments, two R 6 can join together with the atom(s) to which they are attached to form a C 3 -C 6 cycloalkyl ring. In some embodiments, two R 6 on the same carbon atom can join together to form a cycloalkyl ring. In some embodiments, two R 6 on different carbon atoms can join together to form a cycloalkyl ring. In some embodiments, the ring is a spirocycle.
  • R 6 join together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, two R 6 join together to form a cyclopropyl.
  • R 7 is H, halogen, –OR 10 , –C(O)R 10 , –C(O)OR 10 , or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 7 is H.
  • WSGR Docket No.55773-715.601 [0166] In some embodiments, or [0167] In some embodiments, , . so e e bod e ts, . some embodiments, . [0168] In some embodiments, . [0169] In some embodiments, . [0170] In some embodiments, .
  • each R 8 and R 9 are independently selected at each occurrence from H, C 1 - C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, and C 3 -C c 1 y 0 cloalkyl.
  • each R 8 and R 9 are independently selected at each occurrence from H or C 1 -C 6 alkyl.
  • each R 8 and R 9 are independently selected at each occurrence from H.
  • each R 8 and R 9 are independently selected at each occurrence from C 1 -C 6 alkyl.
  • each R 10 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 - C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl.
  • each R 10 is independently selected from H or C 1 -C 6 alkyl.
  • each R 10 is independently selected from C 1 -C 6 haloalkyl.
  • each R 10 is independently selected from C 3 -C 8 cycloalkyl.
  • each R 10 is independently selected from C 6 -C 10 aryl and 5- to 10-membered heteroaryl. In some embodiments, each R 10 is independently 5-membered heteroaryl. [0173] In some embodiments, each R 11 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 11 is independently selected from C 1 -C 6 alkyl. In some embodiments, each R 11 is selected from C 1 -C 6 haloalkyl.
  • each R 11 is selected from C 3 -C 8 cycloalkyl. In some embodiments, each R 11 is selected from C 6 -C 10 aryl, and 5- to 10-membered heteroaryl. [0174] In some embodiments, each R 12 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C1- C6 haloalkyl, and C 3 -C 8 cycloalkyl. In some embodiments, each R 12 is independently selected from H or C 1 -C 6 alkyl. In some embodiments, each R 12 is independently selected from C 1 -C 6 haloalkyl.
  • each R 12 is independently selected from C 3 -C 8 cycloalkyl.
  • each R 14 is independently selected from -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or C 3 -C 10 heterocycloalkyl.
  • each R 14 is independently selected from –NR 8 R 9 or –OR 10 . In some embodiments, each R 14 is independently selected from –C(O)R 10 , – C(O)OR 10 , or –C(O)NR 8 R 9 . In some embodiments, each R 14 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, or C 1 -C 6 haloalkyl. In some embodiments, each R 14 is independently selected fromC 3 -C 10 cycloalkyl or C 3 -C 1 h 0 eterocycloalkyl.
  • p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. I some embodiments, p is 3. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1. [0177] In some embodiments, q is q is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, q is 1 or 2. In some embodiments, q is 6. In some embodiments, q is 5. In some embodiments, q is 4. In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1. In some embodiments, q is 0.
  • n and m are independently 0, 1, or 2. In some embodiments, n and m are independently 0. In some embodiments, n and m are independently 1. In some embodiments, n and m are independently 2. In some embodiments, n is 0, 1, or 2; and m is 1 or 2. In some embodiments, n is 0; and m is 1 or 2. In some embodiments, n is 1; and m is 1 or 2. In some embodiments, n is 2; and m is 1 or 2. [0179] In some embodiments, the PDGH inhibitor is a compound presented in Table 1a, or pharmaceutically acceptable salt or solvate thereof. Table 1a. Representative sulfoxide PGDH inhibitors. [0180] In some embodiments, the PGDH inhibitor is a compound provided in Table 1b, or a pharmaceutically acceptable salt or solvate thereof. Table 1b. Representative sulfoxide PGDH inhibitors
  • the PGDH inhibitor is a compound provided in Table 1c, or a pharmaceutically acceptable salt or solvate thereof.
  • Table 1c Representative PGDH inhibitors.
  • Methods of Use [0182] In one aspect, provided herein are methods for treating various disorders in a subject in need thereof, comprising administering to said subject a compound described herein.
  • the inhibitors of hydroxyprostaglandin dehydrogenase provided herein may be used for the prevention or treatment of a disease or a disorder that is associated with hydroxyprostaglandin dehydrogenase (such as 15-PGDH) and/or decreased levels of prostaglandins.
  • the inhibitors of hydroxyprostaglandin dehydrogenase provided herein may be used for the prevention or treatment of a disease or a disorder in which it is desirable to increase prostaglandin levels in the subject having said disease or disorder.
  • the methods for treating the disorders comprises administering to said subject a 15-PGDH inhibitor.
  • a compound described herein is the 15-PGDH inhibitor (e.g. a compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof).
  • the methods comprise administering a therapeutically effective amount of a compound described herein.
  • the methods comprise administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof (e.g. a compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof).
  • the compound described herein is a 15-PGDH inhibitor (e.g. a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof).
  • the administration takes place in vitro. In other embodiments, the administration takes place in vivo.
  • a therapeutically effective amount of a 15-PGDH inhibitor refers to an amount sufficient to effect the intended application, including but not limited to, disease treatment, as defined herein.
  • a sub-therapeutic amount of a 15-PGDH inhibitor for treating an intended disease condition.
  • the amount of the 15-PGDH inhibitor administered may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • Measuring inhibition of biological effects of 15-PGDH can comprise performing an assay on a biological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to, blood samples (e.g.
  • a subject being treated with a 15-PGDH inhibitor may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject’s physiological response to treatment. For example, if inhibition of a biological effect of 15-PGDH is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively.
  • the methods can further comprise continuing the therapy if the therapy is determined to be efficacious.
  • the methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound in the therapy if the therapy is determined to be efficacious.
  • the methods can comprise increasing the administered amount of a compound in the therapy if it is determined not to be efficacious. Alternatively, the methods can comprise stopping therapy if it is determined not to be efficacious. In some embodiments, treatment with a 15-PGDH inhibitor is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction.
  • the biological effect may be a change in any of a variety of physiological indicators.
  • a 15-PGDH inhibitor is a compound that inhibits one or more biological effects of 15- PGDH. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • the subject methods are useful for treating a disease condition associated with 15-PGDH.
  • Any disease condition that results directly or indirectly from an abnormal activity or expression level of 15-PGDH can be an intended disease condition.
  • a method of promoting and/or stimulation skin pigmentation comprising administering one or more of the compositions described herein to a subject in need thereof.
  • Inhibitors of 15-PGDH are known to promote skin pigmentation (Markowitz et. al., WO 2015/065716).
  • the hydroxyprostaglandin dehydrogenase inhibitors described herein can be used for promoting and/or inducing and/or stimulating pigmentation of the skin and/or skin appendages, and/or as an agent for preventing and/or limiting depigmentation and/or whitening of the skin and/or skin appendages, in particular as an agent for preventing and/or limiting canities.
  • the 15-PGDH inhibitors provided herein can be applied to skin of a subject, e.g., in a topical application, to promote and/or stimulate pigmentation of the skin and/or hair growth, inhibit hair loss, and/or treat skin damage or inflammation, such as skin damage caused by physical or chemical irritants and/or UV-exposure.
  • a method of inhibiting hair loss comprising administering one or more of the compositions described herein to a subject in need thereof.
  • prostaglandins play an important role in hair growth.
  • Prostaglandins such as prostaglandin A1, F2a and E2 are stored in hair follicles or adjacent skin environments and have been shown to be essential in maintaining and increasing hair density (Colombe L et. al, 2007, Exp. Dermatol, 16(9), 762-9).
  • 15-PGDH which is involved in the degradation of prostaglandins is present in the hair follicle dermal papillae, inactivates prostaglandins, especially, PGF2a and PGE2, to cause scalp damage and alopecia
  • the hydroxyprostaglandin dehydrogenase inhibitors described herein that have a suppressive or inhibitory activity against 15-PGDH can improve scalp damage, prevent alopecia and promote hair growth and be used in a pharmaceutical composition for the prevention of alopecia and the promotion of hair growth.
  • provided herein is a method of preventing and/or treating skin inflammation and/or damage, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of preventing and/or treating vascular insufficiency comprising administering one or more of the compositions described herein to a subject in need thereof.
  • Prostaglandins including prostaglandin homologues produced in the body have been known to maintain the proper action of the blood vessel wall, especially to contribute to vasodilation for blood flow, preventing platelet aggregation and modulating the proliferation of smooth muscle that surrounds blood vessel walls (Yan. Cheng et. al., 2006, J.
  • the inhibition of prostaglandins production or the loss of their activity causes the degeneration of the endothelium in the blood vessel walls, platelet aggregation and the dysfunction of cellular mechanism in the smooth muscle.
  • the production of prostaglandins in blood vessels was shown to be decreased in hypertension patients, including pulmonary artery hypertension.
  • the 15-PGDH inhibitors described herein can be used in a pharmaceutical composition for the prevention or the treatment of cardiovascular disease and/or diseases of vascular insufficiency, such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary artery hypertension.
  • provided herein is a method of preventing, treating, minimizing and/or reversing congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • a method of reducing cardiac ejection fraction comprising administering one or more of the compositions described herein to a subject in need thereof. It has been shown that administration of a 15-PGDH inhibitor can be used to treat, prevent, minimize, and/or reverse congestive heart failure, cardiomyopathy, and/or reduction of cardiac ejection fraction (Markowitz et. al., WO2018/187810).
  • the hydroxyprostaglandin dehydrogenase inhibitors described herein can be administered to a subject in need to treat, prevent, minimize and/or reverse congestive heart failure, cardiomyopathy, and/or reduction of cardiac ejection fraction.
  • a method of preventing and/or treating a gastrointestinal disease comprising administering one or more of the compositions described herein to a subject in need thereof.
  • Prostaglandins are essential for maintaining the mechanism for protecting and defending gastric mucus membrane (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65, S. J.
  • hydroxyprostaglandin dehydrogenase inhibitors show a suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect gastric mucus membranes.
  • the hydroxyprostaglandin dehydrogenase inhibitors can be effective for the prevention or the treatment of gastrointestinal diseases, inter alia, gastritis and gastric ulcer.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein may be used to prevent and/or treat other forms of intestinal injury including toxicity from radiation and/or chemotherapy, and chemotherapy-induced mucositis.
  • 15-PGDH inhibitors alone or in combination with corticosteroids and/or TNF inhibitors can treat intestinal, gastrointestinal, or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn’s disease (Markowitz et. al., WO 2018/102552).
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat and/or prevent treat intestinal, gastrointestinal, or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn’s disease.
  • a method of preventing and/or treating renal dysfunction comprising administering one or more of the compositions described herein to a subject in need thereof.
  • prostaglandins modulate renal blood flow and may serve to regulate urine formation by both renovascular and tubular effects.
  • inhibitors of prostaglandin have been used to improve creatinine clearance in patients with chronic renal disease, to prevent graft rejection and cyclosporine toxicity in renal transplant patients, to reduce the urinary albumin excretion rate and N- acetyl-beta-D-glucosaminidase levels in patients with diabetic nephropathy (Porter, Am., 1989, J. Cardiol., 64: 22E-26E).
  • prostaglandins serve as vasodilators in the kidney, and, thus, the inhibition of prostaglandin production in the kidney results in renal dysfunction (Hao. C M, 2008, Annu Rev Physiol, 70, 357.about.77).
  • the hydroxyprostaglandin dehydrogenase inhibitors described herein have a suppressive or inhibitory activity against 15-PGDH that degrades prostaglandins and can be used for the prevention and/or treatment of renal diseases that are associated with renal dysfunction.
  • a method of stimulation bone resorption and bone formation comprising administering one or more of the compositions described herein to a subject in need thereof.
  • Prostaglandins have been shown to stimulate bone resorption and bone formation to increase the volume and the strength of the bone (H. Kawaguchi et. al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). Furthermore, inhibition of 15-PGDH increases callus size and mineralization after bone fracture (Collier et. al., ORS 2017 Annual Meeting Paper No.0190). Considering that 15-PGDH inhibits the activities of prostaglandins as mentioned in the above, the inhibition of 15-PGDH activity may lead to the promotion of bone resorption and bone formation that are inhibited by 15-PGDH.
  • the inhibitors of hydroxyprostaglandin dehydrogenase described herein can be effective for the promotion of bone resorption and bone formation by inhibiting 15-PGDH activity.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can also be used to increase bone density, treat osteoporosis, promote healing of fractures, promote healing after bone surgery or joint replacement, and/or to promote healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts.
  • a method of stimulating tissue regeneration by stimulating comprising administering one or more of the compositions described herein to a subject in need thereof.
  • Prostaglandin PGE2 supports expansion of several types of tissue stem cells.
  • 15- hydroxyprostaglandin dehydrogenase 15- hydroxyprostaglandin dehydrogenase
  • PGDH 15- hydroxyprostaglandin dehydrogenase
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for tissue regeneration by supporting the expansion of tissue stem cells.
  • Prostaglandin E2 is a known cervical ripening agent that mediates EP2-receptor- signaling pathways in human cervical stromal cells; targets its own synthesis by increasing COX-2 and PTGES expression; and decreases its metabolism by loss of its degradative enzyme 15-PGDH (Word et. Al., WO2019010482) Downregulation of 15-PGDH was also found to be crucial for PGE2-induced cervical ripening and preterm birth.
  • Modulation of 15-PDGH activity can be used to modulate cervical ripening; and induce or prevent preterm labor.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to induce cervical ripening and labor, alone or in combination with another labor inducing agent.
  • a method of promoting neuroprotection and/or stimulating neuronal regeneration comprising administering one or more of the compositions described herein to a subject in need thereof.
  • Prostaglandins via their specific G protein coupled receptors, have a variety of physiological functions in the central nervous system.
  • the major prostaglandin, prostaglandin E2 (PGE2) can activate receptor types EP1, 2, 3, and 4.
  • EP2 and EP4 receptors can regulate adenylate cyclase and the generation of 3, 5′-cyclic adenosine monophosphate (cAMP), whereas the activation of EP1 and EP3 receptors can regulate Ca2+ signaling.
  • cAMP 3, 5′-cyclic adenosine monophosphate
  • the EP1 and EP2 receptors are expressed in neurons and microglia as well as neurons of the cerebral cortex, striatum, and hippocampus.
  • PGE2 activation of the EP2 receptor by PGE2 is involved in long-term synaptic plasticity and cognitive function (Chemtob et al. Semin Perinatol.1994 Feb; 18(1):23-9; Yang et al., J Neurochem.2009 Jan; 108(1):295-304).
  • PGE2 receptors can contribute or protect against N-methyl-D-aspartate (NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp Transl Stroke Med.2010 Jul 8; 2(1):12).
  • NMDA N-methyl-D-aspartate
  • Other studies show that activation of the EP2 receptors protected neurons from amyloid ⁇ -peptide neurotoxicity in vitro (Echeverria et al., Eur J Neurosci.2005 Nov; 22(9):2199-206).
  • PGE2 affords neuroprotection is through EP2 or EP4 receptors, as they both increases cAMP, followed by a protein kinase A (PKA)-dependent pathway (Echeverria et al.
  • PKA protein kinase A
  • Stimulation of these receptors with PGE2 by administration of a compound that inhibits, reduces, and/or antagonizes 15-PGDH activity can promote neuroprotection in a subject from axonal degeneration, neuronal cell death, and/or glia cell damage after injury, augment neuronal signaling underlying learning and memory, stimulate neuronal regeneration after injury, and/or treat diseases, disorders, and/or conditions of the nervous system.
  • a method of treating and/or preventing a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder comprising administering one or more of the compositions described herein to a subject in need thereof.
  • the disease, disorder, and/or condition of the nervous system which can be treated with hydroxyprostaglandin dehydrogenase inhibitors provided herein, can include at least one of a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder.
  • the neurological disorder can include at least one of traumatic or toxic injuries to peripheral or cranial nerves, spinal cord or brain, such as traumatic brain injury, stroke, cerebral aneurism, and spinal cord injury.
  • the neurological disorder can also include at least one of Alzheimer's disease, dementias related to Alzheimer's disease, Parkinson's, Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de Ia Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob- Creutzfieldt disease.
  • the neural injury can be caused by or associated with at least one of epilepsy, cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, mental disorders, diseases of the nervous system, diseases of the sense organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the genitourinary system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, congenital anomalies, or conditions originating in the perinatal period.
  • epilepsy cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, mental disorders,
  • the hydroxyprostaglandin dehydrogenase inhibitors can be administered to a subject or neurons of the subject to promote the survival, growth, development and/or function of the neurons, particularly, the central nervous system (CNS), brain, cerebral, and hippocampal neurons.
  • CNS central nervous system
  • the hydroxyprostaglandin dehydrogenase inhibitors can be used stimulate hippocampal neurogenesis, for the treatment of neuropsychiatric and neurodegenerative diseases, including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine, and ***e.
  • neuro-active drugs such as alcohol, opiates, methamphetamine, phencyclidine, and ***e.
  • a method of treating and/or preventing fibrotic or adhesion disease, disorder or condition comprising administering one or more of the compositions described herein to a subject in need thereof.
  • inhibitors of short-chain dehydrogenase activity such as 15-PGDH inhibitors
  • 15-PGDH inhibitors can be administered to a subject in need thereof to decrease fibrotic symptoms, such as collagen deposition, collagen accumulation, collagen fiber formation, inflammatory cytokine expression, and inflammatory cell infiltration, and treat and/or prevent various fibrotic diseases, disorders, and conditions characterized, in whole or in part, by the excess production of fibrous material, including excess production of fibrotic material within the extracellular matrix, or the replacement of normal tissue elements by abnormal, non-functional, and/or excessive accumulation of matrix-associated components (Markowitz et.
  • Fibrotic diseases, disorders and conditions characterized, in whole or in part, by excess production of fibrotic material can include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma(including morphea, generalized morphea, or linear scleroderma), sclerodermatous graft- vs-host-disease fate kidney fibrosis (including glomerular sclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g.
  • pulmonary fibrosis glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy/radiation induced pulmonary fibrosis
  • oral fibrosis endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue in varying degrees, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure; myelofibrosis (bone marrow fibrosis), drug induced ergotism, myelodysplastic syndrome, myeloproliferative syndrome, collagenous colitis, acute fibrosis, organ specific fibrosis, and the like.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent a fibrotic disease, disorder or condition.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent kidney fibrosis, including kidney fibrosis resulting from dialysis following kidney failure, catheter placement, a nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end stage renal disease or renal failure, or combinations thereof.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent liver fibrosis, including liver fibrosis resulting from a chronic liver disease, viral induced hepatic cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH associated cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha- 1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins, or combinations thereof.
  • liver fibrosis including liver fibrosis resulting from a chronic liver disease, viral induced hepatic cirrhosis, hepatitis B virus infection, hepatitis
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent heart fibrosis such as cardiac fibrosis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and kidney fibrosis.
  • heart fibrosis such as cardiac fibrosis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and kidney fibrosis.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent systemic sclerosis.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce in intensity, severity, or frequency, and/or delay onset of one or more symptoms or features of a fibrotic disease, disorder or condition, or other related diseases, disorders or conditions.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to decrease or reduce collagen secretion, or collagen deposition, or collagen fiber accumulation, in a tissue or organ, such as the lung, the liver, the intestines, the colon, the skin or the heart, or a combination thereof.
  • the hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to treat or prevent lung fibrosis, including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors, drug-induced intersti
  • lung fibrosis including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis
  • provided herein is a method of reducing and/or preventing scar formation, comprising administering one or more of the compositions described herein to a subject in need thereof.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can used for reducing or preventing scar formation in a subject.
  • the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation on skin or scleroderma.
  • a method of treating and/or preventing muscle disorder, muscle injury and/or muscle atrophy comprising administering one or more of the compositions described herein to a subject in need thereof.
  • PGE2 degrading enzymes such as 15-PGDH
  • 15-PGDH hydroxyprostaglandin dehydrogenase
  • the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat muscle disorder, muscle injury and/or muscle atrophy in a subject.
  • said subject suffering from a muscle disorder, muscle injury and/or muscle atrophy may have Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), an inherited myopathy, myotonic muscular dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonia congenita, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress induced urinary incontinence, urethral sphinc
  • the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat sarcopenia.
  • the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat diaphragmatic atrophy or limb muscle atrophy due to the use of a mechanical ventilator.
  • the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat genetic disorders or neuromuscular disorders such as Spinal Muscular Atrophy (SMA).
  • SMA Spinal Muscular Atrophy
  • the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat ptosis, rotator cuff muscle atrophy, immobilization related muscle atrophy, surgical procedure related muscle atrophy, sarcopenia, or a combination thereof.
  • Pharmaceutical Compositions [0218] The inhibitors of hydroxyprostaglandin dehydrogenase can be formulated into pharmaceutical compositions to treat diseases and disorders described herein.
  • a pharmaceutical composition may comprise a therapeutically effective amount of one or more inhibitors of hydroxyprostaglandin dehydrogenase provided herein.
  • composition described herein may be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, micronized compositions, granules, elixirs, tinctures, suspensions, ointments, vapors, liposomal particles, nanoparticles, syrups and emulsions.
  • the pharmaceutical composition may also be administered in intravenous (bolus or infusion), subcutaneous injection, suppository, intraperitoneal, topical (e.g., dermal epidermal, transdermal), ophthalmicaly such as ocular eyedrop, intranasally, subcutaneous, inhalation, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • a compound provided herein can be administered as part of a therapeutic regimen that comprises administering one or more second agents (e.g.1, 2, 3, 4, 5, or more second agents), either simultaneously or sequentially with the compound provided herein.
  • the compound provided herein When administered sequentially, the compound provided herein may be administered before or after the one or more second agents.
  • the compound provided herein and the one or more second agents When administered simultaneously, the compound provided herein and the one or more second agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising a compound provided herein and one or more second agents).
  • a combination treatment according to the disclosure may be effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • the exact dosage will depend upon the agent selected, the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • EXAMPLES [0222] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. Synthesis and Characterization of Compounds [0223] The following synthetic schemes are provided for purposes of illustration, not limitation.
  • synthesis schemes may be partial schemes for producing inhibitors provided herein.
  • Described herein are exemplary synthesis schemes that can be used to synthesize the inhibitors described herein. The following abbreviations are used: [0227] Example 1.
  • Step-1 Synthesis of 6-chloro-5-nitronicotinic acid, general procedure for ester hydrolysis with LiOH: To a stirred solution of methyl 6-chloro-5-nitronicotinate, (SM-1) (5g, 23.09 mmol, 1.0 eq) in THF: water (1:1, 20 mL) at 0 °C, LiOH.H2O (2.8g, 69.27 mmol, 3 eq) was added at 0 °C.
  • Step-2 Synthesis of (6-chloro-5-nitropyridin-3-yl)(4,4-difluoropiperidin-1-yl) methanone (Int-2) (General procedure for acid-amine coupling using HATU): To the stirred solution of 6-chloro- 5-nitronicotinic acid, Int-1 (3g, 14.81 mmol, 1.0 eq.) in DMF (20 mL) at 0 o C, HATU (6.75g, 17.77 mmol, 1.2 eq), 4,4-difluoropiperidine hydrochloride (2.80g, 17.17mmol, 1.2 eq) were added.
  • N N’-diisopropylethylamine (7.76 mL, 44.43 mmol, 3 eq) was added at 0 °C and then continued for stirring at RT for 16 h. The progress of the reaction was monitored with TLC and LCMS. After consumption of starting material, the mixture was diluted with ice cold water (10 mL) and extracted with EtOAc (3x30 mL). The combined extracts were washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • Step-3 Synthesis of methyl 4-((5-(4,4-difluoropiperidine-1-carbonyl)-3-nitropyridin-2-yl) amino) benzoate (Int-3) (General procedure for Buchwald coupling): To a stirring solution of (6- chloro-5-nitropyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone (Int-2) (1 g, 3.27 mmol, 1.0 eq) in dioxane (30 mL) in a sealed tube under inert atmosphere, Cs2CO3 (3.18 g, 9.83 mmol, 3 eq), methyl 4- aminobenzoate (SM-2) (593 mg, 3.93 mmol, 1.2 eq) were added at RT.
  • SM-2 6- chloro-5-nitropyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone
  • Step-4 Synthesis of methyl 4-((3-amino-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl) amino)benzoate (Int-4), general procedure for reduction of aryl nitro compounds: To a stirred solution of compound methyl 4-((3-amino-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2- yl)amino)benzoate Int-3 (500mg, 1.19 mmol, 1.0 eq.) in ethanol (5 mL) was added Fe (5.0 eq ) followed by ammonium chloride (10 eq.) in water (5 mL) and the reaction mixture was heated at 80 °C for 3 h.
  • Step-5 Synthesis of methyl 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5- b]pyridin-3-yl) benzoate (Int-5): To a solution of methyl 4-((3-amino-5-(4,4-difluoropiperidine-1- carbonyl)pyridin-2-yl) amino) benzoate (Int-4) (110mg, 0.282 mmol, 1eq) dissolved in 1, 4-dioxane (5mL) was added NaNO 2 (38.91 mg, 0.564 mmol, 2 eq) at 0 o C followed by catalytic amount of HCl (conc).
  • Step-6 Synthesis of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridine -3-yl) benzoic acid (C-1): methyl 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)benzoate, (Int-5) (55mg, 0.137mmol, 1eq) was converted to 4-(6-(4,4- difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridine -3-yl) benzoic acid (C-1) using general procedure for ester hydrolysis with LiOH to afford 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridine -3-yl) benzoic acid (
  • Step-7 Synthesis of methyl 4-((3-acetamido-5-(4,4-difluoropiperidine-1-carbonyl) pyridin-2- yl) amino)benzoate (Int-6): To a stirred solution of methyl 4-((3-amino-5-(4,4-difluoropiperidine-1- carbonyl)pyridin-2-yl)amino)benzoate, (Int-4) (165mg, 0.422 mmol, 1eq) in anhydrous DCM (5 mL) cooled to 0 o C was added trimethylamine (0.115 mL, 0.84 mmol, 2 eq) followed by acetyl chloride (0.036 mL, 0.50 mmol, 1.2 eq ).
  • Step-8 Synthesis of methyl 4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-methyl-3H-imidazo [4,5-b]pyridin-3-yl)benzoate (Int-7), general procedure for cyclization to make imidazole: To a stirred solution methyl 4-((3-acetamido-5-(4,4-difluoropiperidine-1-carbonyl) pyridin-2-yl) amino)benzoate, (Int-6) (116mg, 0.26 mmol, 1eq) in toluene (5 mL) was added PTSA (20 mg, 0.133 mmol, 0.5 eq) followed by 4A0 molecular sieves.
  • Step-2 Synthesis of Int-2a, Int-2b and Int-2c: (4,4-difluoropiperidin-1-yl)(4-fluoro-3- nitrophenyl) methanone, Int-1 using the general procedure for SNAr reaction described earlier using appropriate amines to afford Int-2a, Int2b and Int2c.
  • Step-3 Synthesis of Int-3a, Int-3b and Int-3c: Int-2a, Int-2b, and Int-2c was subjected to the general procedure for aryl nitro reduction with Fe. The crude was purified by combiflash column chromatography using 60% EtOAc/ heptane to obtain Int-3a, Int-3b and Int-3c.
  • Step-4 Synthesis of Int-4a, Int-4b and Int-4c: Int-3a, Int-3b and Int-3c, was converted to Int- 4a, Int-4b and Int-4c using the general procedure for imidazole cyclisation with PTSA and trimethyl orthoformate to afford Int-4a, Int-4b and Int-4c
  • Step-5 Synthesis of Int-5a and Int-5b: Int-4a and Int-4b was converted to Int-5a and Int-5b using the general procedure for the oxidation of nitriles to afford crude Int-5a and Int-5b. The crude obtained was triturated with n-pentane filtered and dried in vacuo.
  • Step-5A Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d]imidazol-1-yl) benzoic acid, C-17: methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] imidazol-1- yl)benzoate, Int-4c (280 mg, 0.701 mmol, 1 eq) using the general procedure for ester hydrolysis with LiOH to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d]imidazol-1-yl) benzoic acid, C-17 (52mg
  • Step-6 Synthesis of (E)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] imidazol-1- yl)-N-((dimethylamino)methylene)picolinamide, Int-6a and (E)-4-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d]imidazol-1-yl)-N-((dimethylamino) methylene) benzamide, Int-6b: Int-5a and Int-5b was converted to (E)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] imidazol-1-yl)-N- ((dimethylamino)methylene)picolinamide, Int-6a and (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d]
  • Step-7 Synthesis of (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl) (4,4-difluoropiperidin-1-yl)methanone, MH-DH-650 and (1-(4-(1H-1,2,4-triazol-5-yl) phenyl)-1H- benzo [d] imidazol-5-yl) (4,4-difluoropiperidin-1-yl)methanone, C-16: Int-6a and Int-6b was converted to (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl) (4,4-difluoropiperidin- 1-yl)methanone, C-15 and (1-(4-(1H-1,2,4-triazol-5-yl) phenyl
  • Step-2 Synthesis of methyl 5-amino-6-((6-cyanopyridin-3-yl)amino)nicotinate (Int-2) methyl 6-((6-cyanopyridin-3-yl)amino)-5-nitronicotinate (Int-1) (2.2g, 7.35 mmol, 1.0 eq) was converted to methyl 5-amino-6-((6-cyanopyridin-3-yl)amino)nicotinate (Int-2) using the general procedure for reduction of nitro compounds using Fe/NH 4 Cl.
  • Step-3 Synthesis of methyl 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylate (Int-3) (General procedure for triazolo formation with NaNO 2 ): To a solution of methyl 5-amino-6-((6-cyanopyridin-3-yl) amino) nicotinate (Int-2) (1.2 g, 4.46 mmol, 1 eq) dissolved in water (36 mL) was added NaNO 2 (992 mg, 13.38 mmol, 3 eq) at 0 o C followed by catalytic amount of conc. HCl (3.6 mL).
  • Step-4 Synthesis of 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carboxylic acid (Int-4): methyl 3-(6-cyanopyridin-3-yl)-3H-[1, 2, 3] triazolo [4,5-b]pyridine-6-carboxylate, (Int-3) (1.1g, 3.93 mmol, 1.0 eq) was converted to 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylic acid using general procedure for ester hydrolysis with LiOH.
  • Step-5 Synthesis of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl) picolinonitrile (Int-5): 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylic acid (Int-4) (1g, 3.76 mmol, 1.0 eq.) was converted to 5-(6-(4,4-difluoropiperidine-1- carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl) picolinonitrile (Int-5) using general procedure for acid- amine coupling with HATU/4,4-difluoropiperidine hydrochloride (886mg, 5.63 mmol, 1.5 eq.).
  • Step-6 Synthesis of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl) picolinimidohydrazide (Int-6) (General procedure for imidohydrazide formation using hydrazine ): To a stirred solution of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5- b]pyridin-3-yl) picolinonitrile (300 mg, 0.812 mmol, 1.0 eq) in ethanol (3 mL) was added hydrazine monohydrate (6 mL).
  • Step-7 Synthesis of (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b] pyridin-6-yl) (4,4-difluoropiperidin-1-yl)methanone (C-5) (General procedure for triazole formation using triethylorthoformate): To a stirred solution of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl) picolinimidohydrazide (Int-6) (170 mg, 0.423 mmol, 1.0 eq) in 1,4- dioxane (5 mL), was added triethylorthoformate (0.251 mL, 2.11 mmol, 5.0 eq) and p-toluenesulfonic acid monohydrate (14.5 mg
  • Step-7 Synthesis of (4,4-difluoropiperidin-1-yl)(3-(6-(1-methyl-1H-1,2,4-triazol-5-yl) pyridin-3-yl) -3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl) methanone (C-8) (General procedure for methylation of amine using NaH): To a stirred solution of (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3H- [1,2,3] triazolo [4,5-b] pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone (C-8) (100 mg, 0.243 mmol, 1 eq) in DMF (5 mL), NaH (60% in mineral oil) (19 mg, 0.486 mmol, 2 eq) was added at 0 o C, slowly brought to RT and stir
  • Step-1 methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate (Int-1): methyl 6-chloro-5- nitronicotinate (SM-1) (2.6g, 12 mmol, 1.0 eq), was converted to methyl 6-((4-cyanophenyl)amino)-5- nitronicotinate (Int-1) using general procedure for S N Ar reaction using NaH (as described above) to afford methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate, Int-1 ( 1.5g, 42%) as a brown oil.
  • SM-1 methyl 6-chloro-5- nitronicotinate
  • NaH as described above
  • Step-2 Synthesis of methyl 5-amino-6-((4-cyanophenyl)amino)nicotinate (Int-2): methyl 6- ((4-cyanophenyl) amino)-5-nitronicotinate (Int-1) (1.5g, 5.03 mmol, 1.0 eq) was converted to methyl 5- amino-6-((4-cyanophenyl)amino)nicotinate (Int-2) using the general procedure for reduction of nitro compounds using Fe/NH 4 Cl.
  • Step-3 Synthesis of methyl 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylate (Int-3): methyl 5-amino-6-((4-cyanophenyl)amino)nicotinate (Int-2) (1.1g, 4.10 mmol, 1eq) was converted to methyl 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carboxylate using the general procedure for triazole formation using NaNO 2 /conc.
  • Step-4 Synthesis of 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carboxylic acid (Int-4) : methyl 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carboxylate, (Int-3) (1g, 3.58 mmol, 1.0 eq) was converted to 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b] pyridine-6-carboxylic acid (Int-4) using the general procedure for ester hydrolysis with LiOH.
  • Step-5 Synthesis of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl) benzonitrile (Int-5): 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carboxylic acid (Int-4) (900mg, 3.39 mmol, 1.0 eq.) was converted to 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)benzonitrile (Int-5) using general procedure for acid-amine coupling with HATU/4,4-difluoropiperidine hydrochloride (886mg, 5.63 mmol, 1.5 eq.).
  • Step-6 Synthesis of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl) benzamide (Int-6), general procedure for amide formation using H2O2: .
  • Step-7 Synthesis of (E)-4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl)-N-((dimethylamino)methylene)benzamide (Int-7) (General procedure for enamine formation with DMF-DMA): A solution of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)benzamide (Int-6) (400mg, 1.04 mmol, 1.0 eq) and N,N- dimethylformamide dimethyl acetal (DMF-DMA) (10mL) were stirred at 100 o C under nitrogen atmosphere for 1h.
  • DMF-DMA N,N- dimethylformamide dimethyl acetal
  • Step-8 (3-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)(4,4- difluoropiperidin-1-yl) methanone (MH-DH-613) (General procedure for triazole formation using hydrazine acetate): To a stirred solution of (E)-4-(6-(4,4-difluoropiperidine-1-carbonyl) -3H-[1, 2, 3] triazolo [4, 5-b] pyridin-3-yl)-N-((dimethylamino)methylene) benzamide, (Int-7) (100mg, 0.226 mmol, 1.0 eq) dissolved in acetic acid (0.5 mL) was added hydrazine acetate (104mg, 1.13 mmol, 5.0 eq) at room temperature.
  • the resultant mixture was stirred at 95°C for 2h. The progress of the reaction was monitored with TLC. After consumption of starting material, the mixture was quenched with saturated NaHCO3 (10 mL). The solution was extracted with EtOAc (2 X 20 mL) and washed with water (5 mL) and brine (5mL). The organic layer was dried over Na2SO4, filtered and concentrated.
  • Step-1 Synthesis of (4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanone (Int-1): 4-fluoro-3-nitrobenzoic acid, SM-1 (2 g, 10.80 mmol, 1.0 eq.) was converted to (4,4-difluoropiperidin-1- yl)(4-fluoro-3-nitrophenyl)methanone (Int-1) using general procedure for acid-amine coupling with HATU/4,4-difluoropiperidine hydrochloride (2.04 g, 12.97 mmol, 1.2 eq).
  • Step-2 Synthesis of 5-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) picolinonitrile (Int-2): (4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanone, (Int-1) (1.2g, 4.16 mmol, 1.0 eq) was converted to 5-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino)picolinonitrile (Int-2) using general procedure for S N Ar reaction using NaH.
  • Step-3 Synthesis of 5-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl) amino) picolinonitrile (Int-3): methyl 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzoate (Int-2) (800mg, 3.34 mmol, 1.0 eq) was converted to 5-((2-amino-4-(4,4-difluoropiperidine-1- carbonyl)phenyl)amino)picolinonitrile (Int-3) using the general procedure for reduction of nitro compounds with Fe/NH4Cl.
  • Step-4 Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3]triazol-1- yl) picolinonitrile (Int-4): 5-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl) amino) picolinonitrile (Int-3) (500 mg, 1.40 mmol, 1eq) was converted to 5-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl)picolinonitrile using general procedure for triazolo formation to afford 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl) picolinonitrile, Int-4 (300 mg, 58.30%) as a yellow solid.
  • Step-5 Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3]triazol-1- yl) picolinimidohydrazide (Int-5): 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3] triazol- 1-yl)picolinonitrile (300 mg, 0.814 mmol, 1.0 eq) was converted to 5-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl)picolinimidohydrazide, (Int-5), using the general procedure for imidohydrazide formation using hydrazine to afford 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl)picolinimid
  • Step-7 Synthesis of (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d] [1,2,3]triazol-5-yl) (4,4-difluoropiperidin-1-yl)methanone (C-9): 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d][1,2,3]triazol-1-yl)picolinimidohydrazide (Int-5) (180 mg, 0.450 mmol, 1.0 eq) was converted to (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl) (4,4-difluoropiperidin-1-
  • Step-2 Synthesis of 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzonitrile (Int-2): (4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanone, (Int-1) (1g, 3.47 mmol, 1.0 eq) was converted 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzonitrile (Int-2) using general procedure for SNAr reaction with NaH.
  • Step-3 Synthesis of 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl)phenyl) amino) benzonitrile (Int-3):4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzonitrile (Int-2) (850mg, 3.34 mmol, 1.0 eq) was converted to 4-((2-amino-4-(4,4-difluoropiperidine-1- carbonyl)phenyl)amino)benzonitrile (Int-3) using the general procedure for reduction of nitro compounds with Fe/NH 4 Cl.
  • Step-4 Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl) picolinonitrile (Int-4): 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl)phenyl) amino) benzonitrile (Int-3) (370 mg, 1.04 mmol, 1eq) was converted to 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d][1,2,3]triazol-1-yl)benzonitrile (Int-4) using general procedure for triazolo formation with NaNO 2 to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzonitrile, Int-4 (310 mg, 81.50%) as a yellow solid.
  • Step-5 Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl) benzamide (Int-5): .4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzonitrile (Int-4) (250mg, 0.680 mmol, 1.0 eq) was converted to 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d][1,2,3]triazol-1-yl)benzamide using general procedure for amide formation with H 2 O 2 to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1
  • Step-6 Synthesis of (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol- 1-yl)-N-((dimethylamino) methylene)benzamide (Int-6): 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d] [1,2,3]triazol-1-yl)benzamide (Int-5) (180 mg, 1.04 mmol, 1.0 eq) was converted to (E)-4-(5- (4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl)-N-((dimethylamino)methylene) benzamide (Int-6) using the general procedure for enamine formation with DMF-DMA.
  • Step-7 Synthesis of (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(4,4- difluoropiperidin-1-yl)methanone (C-10): (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl) -1H- benzo[d][1,2,3]triazol-1-yl)-N-((dimethylamino)methylene) benzamide, (Int-6) (150 mg) was converted to (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(4,4-difluoropiperidin -1-yl) methanone using general procedure for triazole formation using hydrazine acetate.
  • Step-2 Synthesis of methyl 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzoate (Int-2): 4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanone, (Int-1) (2g, 6.94 mmol, 1.0 eq) was converted to methyl 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzoate (Int-2) using general procedure for S N Ar reaction with NaH.
  • Step-3 Synthesis of methyl 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl) amino) benzoate (Int-3):- methyl 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzoate (Int-2) (1.4, 3.34 mmol, 1.0 eq) was converted to methyl 4-((3-amino-5-(4,4-difluoropiperidine- 1-carbonyl)pyridin-2-yl) amino)benzoate (Int-3) using the general procedure for reduction of nitro compounds using Fe/NH4Cl.
  • Step-4 Synthesis of methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3] triazol-1-yl)benzoate (Int-4): methyl 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl) amino) benzoate (Int-3) (250mg, 0.642 mmol, 1eq) was converted to methyl 4-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl) benzoate using general procedure for triazolo formation to afford methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3]triazol-1-yl)benzoate, Int-4 (200mg, 77.8%) as a yellow solid.
  • Step-5 Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3] triazol-1- yl) benzoic acid (C-11): methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3] triazol-1- yl)benzoate, (Int-4) (200 mg, 0.499 mmol, 1eq) was converted to 4-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl) benzoic acid (C-11) using general procedure for hydrolysis with LiOH to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-
  • Step-2A Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrazolo[3,4-b] pyridin- 1-yl) benzoic acid,
  • Step-2B Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-indazol-1-yl) benzoic acid, C-14 and 4-(5-(4,4-difluoropiperidine-1-carbonyl)-2H-indazol-2-yl) benzoic acid: To a stirred solution of tert-butyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-indazol-1-yl)benzoate (Int-5b) (180 mg, 0.407 mmol, 1 eq) in DCM (6 mL), TFA (2 mL) was added at 0 o C.
  • Step-6 Synthesis of Int-6a/Int-6b: Int-6a/Int-6b was synthesized from Int-5a/Int-5b using general procedure for oxidation of nitrile using K2CO3 (2.0 eq) and H2O2 (5.0 eq) in DMSO (10 v) to obtain Int-6a/Int-6b as an off-white solids.
  • Step-8 Synthesis of (S)-(3-(4-(4H-1,2,4-triazol-3-yl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin- 6-yl)(3-methylpiperidin-1-yl)methanone (C-18) / (S)-(3-(6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3H- [1,2,3]triazolo[4,5-b]pyridin-6-yl)(3-methylpiperidin-1-yl)methanone (C-19) (General procedure for triazole synthesis using hydrazine acetate) : To a stirred solution of Int-7a/Int-7b (1.0 eq) in acetic acid (10 v), was added hydrazine acetate (5.0 eq) and heated to 80 o C, for 1h.
  • Step-2 General procedure for Ullmann coupling (Int2a-d): To a stirred solution of Int-2 (1 eq) in Dioxane (100 mL), heteroaryl bromide (1.2 eq), K 3 PO 4 ( 2.0 eq), CuI (0.2 eq), trans- dimethylcyclohexane-1,2-diamine (0.2 eq) were added at room temperature. Reaction mixture was purged with argon gas for 15 min and then continued the reaction at 100 °C for 16 h. The reaction was monitored by TLC and after completion of the reaction, quenched with sat.NH 4 Cl solution (10 mL), and stirred at room temperature for 1h.
  • Step-3 General procedure for oxidation of nitriles (Int-3a-d): To a stirred solution (Int-2a-d) (1eq) in DMSO (10 V) was added H2O2 (30%, 2.0 eq) and potassium carbonate (1.0 eq), the resultant mixture was stirred at 60 °C for 2h. The progress of the reaction was monitored by TLC.
  • Step-4 General procedure for synthesis of Int-4a-4dusing DMF-DMA: A solution of amide (Int-3a-3d) (1.0 eq) and N,N-dimethylformamide dimethyl acetal (DMF-DMA) (10 V) were stirred at 100 o C under nitrogen atmosphere for 1h. The progress of the reaction was monitored by TLC. The mixture was evaporated under reduced pressure, solid obtained was triturated with n-pentane, filtered and dried in vacuo to afford Int-4a, Int-4b, Int-4c, and Int-4d.
  • DMF-DMA N,N-dimethylformamide dimethyl acetal
  • Step-5A General procedure for 1H-1, 2, 4-triazole formation using hydrazine acetate, C-4, C-6, C-12, C-13: To a stirred solution of appropriate Int-4 (1.0 eq) dissolved in acetic acid (0.5 V) was added hydrazine acetate (5.0 eq) at room temperature. The resultant mixture was stirred at 95°C for 2h. The progress of the reaction was monitored with TLC. After completion of the reaction, the mixture was quenched with saturated NaHCO 3 (10 mL). The solution was extracted with EtOAc (2 X 20 mL) and washed with water (5 mL) and brine (5mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • Step-2 Int-2a/ Int-2b/ Int-2c: These were prepared from Int-1 using the general procedure for Ullman coupling.
  • Step-3 Int-3a/ Int-3b/ Int-3c: Int-2 was converted to Int-3 using the general procedure for oxidation of nitrile with H2O2.
  • Step-4 General procedure for synthesis of Int-4a/ Int-4b/ Int-4c) using DMF-DMA: A solution of amide Int-3 (1.0 eq) and N,N-dimethylformamide dimethyl acetal (DMF-DMA) (10 V) were stirred at 100 o C under nitrogen atmosphere for 1h.
  • Step-5 General procedure for 1H-1, 2, 4-triazole formation using hydrazine acetate, C-20, C-21, and C-22: To a stirred solution of appropriate Int-4 (1.0 eq) dissolved in acetic acid (0.5 V) was added hydrazine acetate (5.0 eq) at room temperature. The resultant mixture was stirred at 95°C for 2h. The progress of the reaction was monitored with TLC. After completion of the reaction, the mixture was quenched with saturated NaHCO3 (10 mL). The solution was extracted with EtOAc (2 X 20 mL) and washed with water (5 mL) and brine (5 mL).
  • Step 1 To a mixture of (4,4-difluoropiperidin-1-yl)(1H-pyrazolo[3,4-b]pyridin-5-yl)methanone (150 mg, 563 ⁇ mol, 1.00 eq.), 3-(3-iodophenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (240 mg, 676 ⁇ mol, 1.20 eq.), CuI (21.5 mg, 113 ⁇ mol, 0.2 eq.), K3PO4 (239 mg, 1.13 mmol, 2.00 eq.), dimethylcyclohexane-1
  • reaction mixture was diluted with H 2 O (20 mL) and EtOAc (10 mL), then filtered to give a filtrate and extracted with EtOAc (15 mL ⁇ 3). The combined organic layers were washed with brine (20 mL ⁇ 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a mixture of (4,4-difluoropiperidin-1-yl)(1-(3-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4- triazol-3-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone (200 mg, 405 ⁇ mol, 1.00 eq.) in MeOH (2 mL) was added p-TsOH (83.7 mg, 486 ⁇ mol, 1.20 eq.) and the mixture was stirred at 50 °C for 2 hours.
  • p-TsOH 83.7 mg, 486 ⁇ mol, 1.20 eq.
  • reaction mixture was diluted with H 2 O (20 mL) and quenched with NaHCO 3 at 0°C to adjust pH to neutral, and then extracted with EtOAc (20 mL ⁇ 3). The combined organic layers were washed with brine (20 mL ⁇ 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a mixture of [(2R)-2-methylmorpholin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-5- yl)methanone (200 mg, 812 ⁇ mol, 1.00 eq.), 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (346 mg, 975 ⁇ mol, 1.20 eq.), CuI (30.9 mg, 162 ⁇ mol, 0.20 eq.), K 3 PO 4 (345 mg, 1.62 mmol, 2.00 eq.) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (23.1 mg, 162 ⁇ mol, 0.20 eq.) in DMA (4.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 90 °C for 3 hours under N 2 atmosphere (15 psi).
  • reaction mixture was filtered and diluted with H 2 O (20.0 mL), then extracted with EtOAc (20.0 mL ⁇ 3). The combined organic layers were washed with brine (20.0 mL ⁇ 1), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 3 To a mixture of [(2R)-2-methylmorpholin-4-yl]-[1-[3-(4-tetrahydropyran-2-yl-1,2,4- triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]methanone (100 mg, 211 ⁇ mol, 1.00 eq.) in MeOH (2.00 mL) was added TsOH (43.6 mg, 253 ⁇ mol, 1.20 eq.). Then the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with saturated NaHCO3 (10.0 mL) and extracted with EtOAc (10.0 mL ⁇ 3).
  • Step 2 To a solution of (1-(3-chloro-5-(4-(tetrahydro-2H-pyran-2-yl)- 4H-1,2,4-triazol-3- yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(thiomorpholino)methanone (200 mg, 392 ⁇ mol, 1.00 eq.) in MeOH (2 mL) was added TsOH (81.0 mg, 471 ⁇ mol, 1.20 eq.). The mixture was stirred at 50 °C for 2 hours.
  • Example 15 Synthesis of 4-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridin-3- yl)benzoic acid (D-1) / 5-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridin-3-yl)picolinic acid (D-2) [0352] Scheme 15
  • Step-1 Synthesis of methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate (Int-2): [0354] To a stirred solution of methyl imidazo[1,2-a]pyridine-7-carboxylate (SM-1) (1.0 g, 5.6 mmol, 1.0 eq) in methanol (10 mL) at 0 o C, sodium acetate (0.56 g, 6.8 mmol, 1.2 eq) and Bromine ( 0.32 mL, 6.2 mmol, 1.1 eq) were added. The reaction was stirred at RT for 1h. The progress of the reaction was monitored by TLC.
  • SM-1 methyl imidazo[1,2-a]pyridine-7-carboxylate
  • methanol 10 mL
  • Bromine 0.32 mL, 6.2 mmol, 1.1 eq
  • Step-3 Synthesis of (3-bromoimidazo[1,2-a]pyridin-7-yl)(4,4-difluoropiperidin-1- yl)methanone (Int-3): (3-bromoimidazo[1,2-a]pyridin-7-yl)(4,4-difluoropiperidin-1-yl)methanone (Int- 3) was synthesized from 3-bromoimidazo[1,2-a]pyridine-7-carboxylic acid (Int-2) (1.1 g, 4.5 mmol, 1.0 eq) using the general procedure for amide coupling with HATU to afford (3-bromoimidazo[1,2-a]pyridin- 7-yl)(4,4-difluoropiperidin-1-yl)methanone (Int-3) (1.42 g, 91.61%, MS :345.2 [M+1] + ) as an off-white solid.
  • Step-4 Synthesis of Int-4: In a sealed tube, to the stirred solution of (3-bromoimidazo[1,2- a]pyridin-7-yl)(4,4-difluoropiperidin-1-yl)methanone (Int-3) (1.0 eq) in 1,4- dioxane : water (8:2, 10 v), degassed with argon. The respective boronic acid (1.3 eq) and sodium carbonate (3.0 eq) was added. After 15 min, Pd(dppf)Cl2 DCM adduct (0.1 eq) was added and stirred at 90 o C, for 8h. The progress of the reaction was monitored by the TLC.
  • Step-1 Synthesis of 5-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridin-3- yl)picolinonitrile (Int-4): In a sealed tube, to the stirred solution of (3-bromoimidazo[1,2-a]pyridin-7- yl)(4,4-difluoropiperidin-1-yl)methanone (Int-3) (0.6 g, 1.74 mmol, 1.0 eq) in 1,4- Dioxane:water (8:2, 10 v), degassed with argon.
  • Step-2 Synthesis of 5-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridin-3- yl)picolinimidohydrazide (Int-5): To a stirred solution of 5-(7-(4,4-difluoropiperidine-1- carbonyl)imidazo[1,2-a]pyridin-3-yl)picolinonitrile Int-4 (0.15 g, 0.42 mmol, 1.0 eq) in ethanol (10 v) Hydrazine hydrate (2 mL) was added and stirred at 80 o C for 1h. The progress of the reaction was monitored by TLC and LCMS.
  • Step-3 Synthesis of (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)imidazo[1,2-a]pyridin-7-yl)(4,4- difluoropiperidin-1-yl)methanone (D-3): To Int-5 (0.13 g, 0.32 mmol, 1.0 eq) in Dioxane (10 v) was added p-TSA (0.012g, 0.06 mmol, 0.2 eq) and trimethyl orthoformate ( 0.17g, 0.16 mmol, 5.0 eq) and heated to 90 o C for 3h.
  • p-TSA 0.012g, 0.06 mmol, 0.2 eq
  • trimethyl orthoformate 0.17g, 0.16 mmol, 5.0 eq
  • Example B-1 hPGDH Inhibitor Screening Biochemical Assay
  • a hydroxyprostaglandin dehydrogenase inhibition screening biochemical assay can be performed to assess the synthesized inhibitors provided herein.
  • Provided herein is an exemplary biochemical assay for hPGDH inhibitor screening.
  • the in vitro biochemical assay can be performed in white, 384 plates in total 20 ⁇ l reaction volume consisting of 10 nM of 15-PGDH/HPGD (R&D System# 5660-DH), 15 ⁇ M Prostaglandin E2 (Sigma, Cat # P5640-10MG) and 0.25 mM ⁇ -Nicotinamide adenine dinucleotide sodium salt (Sigma, Cat# N0632-5G) made in reaction buffer (50 mM Tris-HCl, pH 7.5, 0.01% Tween 20) at 10-point dose response curve for test/tool compounds.
  • reaction buffer 50 mM Tris-HCl, pH 7.5, 0.01% Tween 20
  • Example B-2. Additional Biochemical Assays 15-PGDH is highly expressed in resting human lung adenocarcinoma cells (A549) (Tong et al., 2006), and this cell line was used to assess 15-PGDH inhibition by MF-300Na in vitro. [0371] In this assay, A549 cells are treated with interleukin (IL) 1 ⁇ , which induces the expression of cycloxygenase-2 and the synthesis of PGE2 (Tong et al., 2006).
  • IL interleukin

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Abstract

L'invention concerne des composés inhibiteurs de la 15-hydroxyprostaglandine déshydrogénase. De tels composés peuvent être administrés à des sujets qui peuvent bénéficier de la modulation des niveaux de prostaglandine.
PCT/US2022/038515 2021-07-28 2022-07-27 Inhibiteurs de pgdh bicycliques et leurs procédés de fabrication et d'utilisation WO2023009618A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100324011A1 (en) * 2009-04-22 2010-12-23 Haiyan Bian Azetidinyl diamides as monoacylglycerol lipase inhibitors
WO2020160151A1 (fr) * 2019-01-31 2020-08-06 Kyorin Pharmaceutical Co., Ltd. Inhibiteurs de 15-pgdh
WO2020252146A1 (fr) * 2019-06-11 2020-12-17 The Board Of Trustees Of The Leland Stanford Junior University Méthodes de rajeunissement de tissus âgés par l'inhibition de la 15-hydroxyprostaglandine déshydrogénase (15-pgdh)
WO2022082009A1 (fr) * 2020-10-15 2022-04-21 Epirium Bio Inc. Formulations inhalées d'inhibiteurs de pgdh et leurs procédés d'utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100324011A1 (en) * 2009-04-22 2010-12-23 Haiyan Bian Azetidinyl diamides as monoacylglycerol lipase inhibitors
WO2020160151A1 (fr) * 2019-01-31 2020-08-06 Kyorin Pharmaceutical Co., Ltd. Inhibiteurs de 15-pgdh
WO2020252146A1 (fr) * 2019-06-11 2020-12-17 The Board Of Trustees Of The Leland Stanford Junior University Méthodes de rajeunissement de tissus âgés par l'inhibition de la 15-hydroxyprostaglandine déshydrogénase (15-pgdh)
WO2022082009A1 (fr) * 2020-10-15 2022-04-21 Epirium Bio Inc. Formulations inhalées d'inhibiteurs de pgdh et leurs procédés d'utilisation

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