WO2024108090A1 - Méthodes de traitement d'états inflammatoires - Google Patents

Méthodes de traitement d'états inflammatoires Download PDF

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WO2024108090A1
WO2024108090A1 PCT/US2023/080224 US2023080224W WO2024108090A1 WO 2024108090 A1 WO2024108090 A1 WO 2024108090A1 US 2023080224 W US2023080224 W US 2023080224W WO 2024108090 A1 WO2024108090 A1 WO 2024108090A1
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compound
peripheral
inflammatory condition
disease
systemic inflammatory
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PCT/US2023/080224
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Robert Taylor
Jewel JOHNSTON
Hans J. MOEBIUS
Andree-Anne Berthiaume
Kevin Church
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Athira Pharma, Inc.
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Publication of WO2024108090A1 publication Critical patent/WO2024108090A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present disclosure relates generally to compounds, compositions, and methods for treating diseases, such as peripheral and/or systemic inflammatory conditions.
  • Hepatocyte growth factor is a pleiotropic protein factor involved in numerous biological processes including embryonic and organ development, regeneration, and inflammation. HGF is a key contributor to cortical, motor, sensory, sympathetic, and parasympathetic neuronal development and maturation. HGF is translated and secreted as inactive pro-HGF, but following cleavage, the resultant a and P-subunits are joined by a disulfide linkage to form the active heterodimer. Expression of HGF predominantly occurs in mesenchymal cells such as fibroblasts, chondroblasts, adipocytes, and the endothelium. Expression has also been demonstrated in the central nervous system (CNS) including neurons, astrocytes, and ependymal cells (Nakamura and Mizuno, 2010).
  • CNS central nervous system
  • HGF a transmembrane receptor tyrosine kinase that serves as the sole known receptor for HGF.
  • MET has known involvement in a variety of biological processes, with demonstrated roles in development, regeneration, and response to injury.
  • homo-dimerization of the MET protein leads to auto-phosphorylation of the intracellular domain.
  • Phosphorylation of MET intracellular domains leads to recruitment and phosphorylation of a variety of effector proteins including Gabi, GRB2, Phospholipase C, and Stat3 (Gherardi et al., 2012; Organ and Tsao, 2011).
  • HGF is a key regulator of inflammation and autoimmunity. HGF activity reduces the expression of the pro-inflammatory cytokine IL-6 and promotes expression of the antiinflammatory 11-10 in monocytes (Molnarfi et al., 2015). Additionally, HGF increases tolerogenic dendritic cells and attenuates cytotoxic T-cell activity (Ilangumaran et al., 2016). These effects of HGF activity on inflammation and immune function would likely be beneficial in inflammatory conditions.
  • Nonlimiting exemplary embodiments include:
  • a method of treating a peripheral and/or systemic inflammatory condition in a subject in need thereof comprising administering an effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein:
  • R la and R lb are independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halo, or Ce-Cio arylalkyl;
  • R 2 is H, oxo, or thioxo
  • R 6 is H, Ci-Ce alkyl, or oxo
  • R 7 is H or oxo; m is 1 or 2; and n is an integer from 0 to 3; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl,
  • R la and R lb are each independently H, methyl, fluoro, 2-methylbutyl, -CH2F, methoxy, -CH2CO2H,
  • R la and R lb are each independently H or C1-C3 alkyl.
  • C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C6 cycloalkylalkyl, Ce-Cio arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl is optionally substituted with one to five substituents selected from hydroxyl, halo, amino, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, cyano, -(C O)NH2, nitro, -SO2(Ci-Ce alkyl), and -CO2H.
  • R 3 is C2 alkyl substituted by 1-3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2, and -SO2(Ci-C3 alkyl).
  • R 4 is Ce-Cio aryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy.
  • R 4 is phenyl substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluoro, and chloro.
  • R 4 is 5- to 10-membered heteroaryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy.
  • R 4 is pyridyl or indolyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy.
  • R 4 is 5- to 10-membered heterocyclyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy.
  • R la and R lb are independently H or C1-C3 alkyl optionally substituted with -CO2H;
  • R 3 is C4-C5 alkyl, C4-C5 alkenyl, or C1-C3 alkyl substituted with C3-C5 cycloalkyl;
  • R 4 is phenyl or pyridyl substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluoro, and chloro.
  • a method of treating a peripheral and/or systemic inflammatory condition in a subject in need thereof comprising administering an effective amount of Compound A19: or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • a method of treating a peripheral and/or systemic inflammatory condition in a subject in need thereof comprising administering an effective amount of a compound selected from the compounds of Table lA and Compound A19: and pharmaceutically acceptable salts, isotopic forms, or stereoisomers thereof.
  • peripheral and/or systemic inflammatory condition is inflammatory bowel disease, Crohn’s disease, ulcerative colitis, coeliac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, noninfectious uveitis, opticus neuritis, Leber hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis.
  • the peripheral and/or systemic inflammatory condition is inflammatory bowel disease, Crohn’s disease, ulcerative colitis, coeliac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis,
  • peripheral and/or systemic inflammatory condition is inflammatory bowel disease.
  • peripheral and/or systemic inflammatory condition is ulcerative colitis.
  • peripheral and/or systemic inflammatory condition is coeliac disease.
  • peripheral and/or systemic inflammatory condition is type 2 diabetes.
  • peripheral and/or systemic inflammatory condition is obesity.
  • peripheral and/or systemic inflammatory condition is coronary heart disease.
  • peripheral and/or systemic inflammatory condition is gout.
  • the peripheral and/or systemic inflammatory condition is fatty liver disease.
  • peripheral and/or systemic inflammatory condition is seasonal allergies.
  • peripheral and/or systemic inflammatory condition is COPD.
  • peripheral and/or systemic inflammatory condition is endometriosis.
  • peripheral and/or systemic inflammatory condition is systemic lupus erythematosus.
  • peripheral and/or systemic inflammatory condition is dermatomyositis.
  • peripheral and/or systemic inflammatory condition is polymyositis.
  • peripheral and/or systemic inflammatory condition is opticus neuritis.
  • peripheral and/or systemic inflammatory condition is macular degeneration.
  • peripheral and/or systemic inflammatory condition is myasthenia gravis.
  • peripheral and/or systemic inflammatory condition is not caused by neuroinflammation or a disease or disorder of the central nervous system.
  • peripheral and/or systemic inflammatory condition is not caused by Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensorineural hearing and vision loss.
  • peripheral and/or systemic inflammatory condition is not associated with neuroinflammation or a disease or disorder of the central nervous system.
  • peripheral and/or systemic inflammatory condition is not associated with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensorineural hearing and vision loss.
  • any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
  • the terms “about” and “approximately” mean ⁇ 20%, ⁇ 10%, ⁇ 5%, or ⁇ 1% of the indicated range, value, or structure, unless otherwise indicated.
  • Amino refers to the -NH2 radical.
  • Carboxy or “carboxyl” refers to the -CO2H radical.
  • “Hydroxy” or “hydroxyl” refers to the -OH radical.
  • Niro refers to the -NO2 radical.
  • Alkyl refers to an unbranched or branched saturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (Ci- C12 alkyl), preferably one to eight carbon atoms (Ci-Cs alkyl), one to six carbon atoms (Ci-Ce alkyl), or one to three carbon atoms (C1-C3 alkyl) and which is attached to the rest of the molecule by a single bond, c.g, methyl, ethyl, //-propyl, 1 -methylethyl (/ o-propyl), //-butyl, //-pentyl, 1,1 -dimethylethyl (/-butyl), 3 -methylhexyl, 2-methylhexyl and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.
  • alkenyl refers to an unbranched or branched unsaturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carboncarbon double bonds, having from two to twelve carbon atoms (C2-C12 alkenyl), preferably two to eight carbon atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl), and which is attached to the rest of the molecule by a single bond, c.g, ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.
  • Alkynyl refers to an unbranched or branched unsaturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carboncarbon triple bonds, having from two to twelve carbon atoms (C2-C12 alkynyl), preferably two to eight carbon atoms (C2-C8 alkynyl) or two to six carbon atoms (C2-C6 alkynyl), and which is attached to the rest of the molecule by a single bond, c.g, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.
  • Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above containing one to twelve carbon atoms.
  • Preferred alkoxy groups have one to six carbon atoms (z.e., Ci-Ce alkoxy) or one to three carbon atoms (z.e., C1-C3 alkoxy) in the alkyl radical. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.
  • Aromatic ring refers to a cyclic planar portion of a molecule (z.e., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms.
  • Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl. Unless stated otherwise specifically in the specification, an aromatic ring includes all radicals that are optionally substituted.
  • Aryl refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms and at least one aromatic ring (z.e., Ce-Cis aryl), preferably having 6 to 10 carbon atoms (z.e., Ce-Cio aryl).
  • the aryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, phenyl, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.
  • Arylalkyl refers to a radical of the formula -Rb-Rc where Rb is an alkylene chain and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like.
  • An arylalkyl group may contain a C1-C10 alkylene chain connected to a Ce-Cio aryl radical (z.e., Ce-Cio arylalkyl). Unless stated otherwise specifically in the specification, an arylalkyl group is optionally substituted.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms (z.e., C3-C15 cycloalkyl), preferably having from three to ten carbon atoms (z.e., C3-C10 cycloalkyl) or three to six carbon atoms (z.e., C3-C6 cycloalkyl), and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl also includes “spiro cycloalkyl” when there are two positions for substitution on the same carbon atom.
  • Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.
  • Cycloalkylalkyl refers to a radical of the formula -Rb-Rc where Rb is an alkylene chain and R c is one or more cycloalkyl radicals as defined above, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and the like.
  • a cycloalkylalkyl group may contain a C1-C10 alkylene chain connected to a C3-C12 cycloalkyl radical (ie., C3- C12 cycloalkylalkyl) or a C1-C10 alkylene chain connected to a C3-C6 cycloalkyl radical (z.e., C3-C6 cycloalkylalkyl). Unless stated otherwise specifically in the specification, a cycloalkylalkyl group is optionally substituted.
  • fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the disclosure.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring is replaced with a nitrogen atom.
  • Halo or “halogen” refers to bromo, chloro, fluoro, or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • a preferred haloalkyl group includes an alkyl group having one to six carbon atoms and that is substituted by one or more halo radicals (z.e., Ci-Ce haloalkyl).
  • the halo radicals may be all the same or the halo radicals may be different. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.
  • Haloalkoxy refers to a radical of the formula -ORa where Ra is a haloalkyl radical as defined herein containing one to twelve carbon atoms.
  • a preferred haloalkoxy group includes an alkoxy group having one to six carbon atoms (z.e., Ci-Ce haloalkoxy) or having one to three carbon atoms (C1-C3 haloalkoxy) and that is substituted by one or more halo radicals.
  • the halo radicals may all be the same or the halo radicals may all be different. Unless stated otherwise specifically in the specification, a haloalkoxy group is optionally substituted.
  • Heteroaryl refers to an aromatic group (e.g., a 5-14 membered ring system) having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 10 ring carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur within the ring.
  • Preferred heteroaryl groups have a 5- to 10-membered ring system containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur (z.e., a 5- to 10- membered heteroaryl) and a 5- to 6-membered ring system containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur (z.e., a 5- to 6-membered heteroaryl).
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems.
  • heteroaryl groups include pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).
  • a heteroaryl may comprise one or more N-oxide (N-O-) moieties, such as pyridine-N- oxide. Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.
  • Heteroaryl alkyl refers to a radical of the formula -Rb-Rc where Rb is an alkylene chain and Rc is one or more heteroaryl radicals as defined above.
  • a heteroarylalkyl group may contain a Ci-Cio alkylene chain connected to a 5- to 10-membered heteroaryl group (z.e., 5- to 10-membered heteroarylalkyl) or a Ci-Cio alkylene chain connected to a 5- to 6-membered heteroaryl group (z.e., 5- to 6-membered heteroarylalkyl). Unless stated otherwise specifically in the specification, a heteroarylalkyl group is optionally substituted.
  • Heterocyclyl refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the term “heterocyclyl” includes heterocycloalkenyl groups (z.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro- heterocyclyl groups.
  • any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (z.e., can be bound through a carbon atom or a heteroatom).
  • heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 1 to 10 ring carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, and 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • Preferred heterocyclyls have five to 10 members in the ring system including one to four heteroatoms selected from nitrogen and oxygen (z.e., 5- to 10-membered heterocyclyl) or five to eight members in the ring system including one to four heteroatoms selected from nitrogen and oxygen (z.e., 5- to 8-membered heterocyclyl).
  • heterocyclyl groups include dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-
  • Heterocyclylalkyl refers to a radical of the formula -Rb-Rc where Rb is an alkylene chain and Rc is one or more heterocyclyl radicals as defined above.
  • a heterocyclylalkyl group may contain a Ci-Cio alkylene chain connected to a 5- to 10-membered heterocyclyl radical (z.e., 5- to 10-membered heterocyclylalkyl) or a Ci-Cio alkylene chain connected to a 5- to 8- membered heterocyclyl radical (z.e., 5- to 8-membered heterocyclylalkyl). Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.
  • each choice for L, R la , R lb , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is optionally substituted as described above unless specifically stated otherwise, and provided that all valences are satisfied by the substitution.
  • each choice for L, R la , R lb , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is optionally substituted unless specifically stated otherwise, and provided such substitution results in a stable molecule (e.g., groups such as H and halo are not optionally substituted).
  • Peripheral inflammation and systemic inflammation refer to the activation of the innate or adaptive immune system and the release of inflammatory cytokine signaling molecules in response to various pathological stimuli outside of the central nervous system.
  • Tissues that generate or respond to peripheral inflammatory signaling include muscle and connective tissue, the gastrointestinal tract and enteric nervous system, thoracic organs, blood, skin, and lymphatic tissue.
  • Effective amount or “therapeutically effective amount” of a compound or a composition refers to that amount of the compound or the composition that results in an intended result as desired based on the disclosure herein. Effective amounts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals including, without limitation, by determining the ED50 (the dose therapeutically effective in 50% of the population) and the LDso (the dose lethal to 50% of the population). In some embodiments, an effective amount of a compound results in reduction or inhibition of symptoms or a prolongation of survival in a subject (z.e., a human patient). The results may require multiple doses of the compound.
  • Treating” or “treatment” of a disease in a subject refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a subject.
  • treatment is a reduction of pathological consequence of the disease or disorder. The methods of the invention contemplate any one or more of these aspects of treatment.
  • the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal. Examples include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, the mammal is a human.
  • a therapeutic 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; causing partial or complete regression of a disease or condition; or any combination thereof.
  • co-administration 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.
  • “Pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy ethane
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are iso
  • pharmaceutically acceptable salts include quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide).
  • therapeutic agent refers to a biological, pharmaceutical, or chemical compound or other moiety.
  • Non-limiting examples include a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound.
  • Various compounds can be synthesized, for example, small molecules and oligomers e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures.
  • various natural sources can provide compounds for screening, such as plant or animal extracts, and the like.
  • the term “zzz vzvo” refers to an event that takes place in a subject’s body.
  • Embodiments of the disclosure are also meant to encompass all pharmaceutically acceptable compounds of Formula (I) being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number (z.e., an “isotopic form” of a compound of Formula (I)).
  • isotopes that can be incorporated into the compounds of Formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
  • Certain isotopically-labeled compounds of Formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, z.e., 3 H, and carbon-14, z.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood, or other biological samples. [0056] “ Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • solvate refers to an aggregate that comprises one or more molecules of a compound of Formula (I) with one or more molecules of solvent.
  • the solvent is water, in which case the solvate is a hydrate.
  • the solvent is an organic solvent.
  • the compounds of Formula (I) may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of Formula (I) is a true solvate, while in other cases, the compound of the disclosure merely retains adventitious water or is a mixture of water plus some adventitious solvent.
  • “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc. are not intended for inclusion herein.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms. Such impermissible substitution patterns are well known to the skilled artisan.
  • a “pharmaceutical composition” or “pharmaceutically acceptable composition” refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt or isotopic form thereof may contain one or more centers giving rise to geometric asymmetry and may thus provide enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.
  • R la and R lb are independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halo, or Ce-Cio arylalkyl;
  • R 2 is H, oxo, or thioxo
  • R 3 is C2-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C6 cycloalkylalkyl, Ce- C10 arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl, wherein the 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl contains 1-3 heteroatoms selected from nitrogen and oxygen;
  • R 4 is Ce-Cio aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from nitrogen and oxygen; each R 5 is independently Ci-Ce alkyl, oxo, or halo;
  • R 6 is H, Ci-Ce alkyl, or oxo
  • each R a and R b is independently H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, each R a and R b is independently H, C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl. In some embodiments, R a and R b are each H. In some embodiments, R a is H. In some embodiments, R a is Ci-Ce alkyl, such as methyl, ethyl, or propyl. In some embodiments, R a is C2-C6 alkenyl, such as vinyl or propenyl.
  • R a is C2-C6 alkynyl, such as ethynyl or propynyl.
  • R b is H.
  • R b is Ci-Ce alkyl, such as methyl, ethyl, or propyl.
  • R b is C2-C6 alkenyl, such as vinyl or propenyl.
  • R b is C2- Ce alkynyl, such as ethynyl or propynyl.
  • R la and R lb are independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halo, or Ce-Cio arylalkyl.
  • R la is H.
  • R la is Ci-Ce alkyl, such as methyl, ethyl, or propyl.
  • R la is C2-C6 alkenyl, such as vinyl or propenyl.
  • R la is C2-C6 alkynyl, such as ethynyl or propynyl.
  • R la is Ci-Ce alkoxy, such as methoxy, ethoxy, or propoxy. In some embodiments, R la is halo, such as fluoro, chloro, or bromo. In some embodiments, R la is Ce-Cio arylalkyl, such as benzyl. In some embodiments, R lb is H. In some embodiments, R lb is Ci-Ce alkyl, such as methyl, ethyl, or propyl. In some embodiments, R lb is C2-C6 alkenyl, such as vinyl or propenyl.
  • R lb is C2-C6 alkynyl, such as ethynyl or propynyl.
  • R lb is Ci-Ce alkoxy, such as methoxy, ethoxy, or propoxy.
  • R lb is halo, such as fluoro, chloro, or bromo.
  • R lb is Ce-Cio arylalkyl, such as benzyl.
  • R la is Ci-Ce alkyl substituted with 1-3 halo, such as fluoro or chloro.
  • R la is Ci-Ce alkyl substituted with 1-3 -CO2H groups.
  • R la is Ce- C10 arylalkyl substituted by 1-3 halo, such as fluoro, chloro, or bromo. In some embodiments, R la is Ce-Cio arylalkyl substituted by 1-3 amino. In some embodiments, R lb is Ci-Ce alkyl substituted with 1-3 halo, such as fluoro or chloro. In some embodiments, R lb is Ci-Ce alkyl substituted with 1-3 -CO2H groups. In some variations, R lb is C1-C3 alkyl substituted with 1-2 -CO2H groups, such as -CH2CO2H or -CH2CH2CO2H.
  • R lb is Ce-Cio arylalkyl substituted by 1-3 amino.
  • R la and R lb are each independently H or C1-C3 alkyl.
  • R la is methyl and R lb is H.
  • R la and R lb are each H.
  • one of R la and R lb is H and the other is C1-C3 alkyl, such as methyl.
  • R 2 is H, oxo, or thioxo. In some embodiments, R 2 is H. In some embodiments, R 2 is oxo. In some embodiments, R 2 is thioxo.
  • R 3 is C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C6 cycloalkylalkyl, Ce-Cio arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl, wherein the 5- to 10-membered heteroarylalkyl or 5- to 10- membered heterocyclylalkyl contains 1-3 heteroatoms selected from nitrogen and oxygen.
  • R 3 is C3-C6 alkyl, such as propyl, butyl, pentyl, or hexyl. In some embodiments, R 3 is C4-C6 alkyl. In some embodiments, R 3 is C3-C6 alkenyl. In some embodiments, R 3 is C4-C6 alkenyl. In some embodiments, R 3 is C3-C6 alkynyl. In some embodiments, R 3 is C4-C6 alkynyl. In some embodiments, R 3 is C3-C12 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 3 is C3-C6 cycloalkyl. In some embodiments, R 3 is C3-C6 cycloalkylalkyl, such as -(CH2)i-3(C3-Ce cycloalkyl). In some embodiments, R 3 is Ce-Cio arylalkyl, such as benzyl. In some embodiments, R 3 is 5- to 10-membered heteroarylalkyl, such as -(CH2)I-3(5- to 10-membered heteroaryl) or -(CH2)I-3(5- to 6-membered heteroaryl). In some embodiments, the 5- to 10- membered heteroarylalkyl contains 1-2 nitrogen atoms.
  • R 3 is 5- to 10- membered heterocyclylalkyl, such as -(CH2)I-3(5- to 10-membered heterocyclyl) or -(CH2)I-2(5- to 6-membered heterocyclyl).
  • the 5- to 10-membered heterocyclylalkyl contains 1-2 nitrogen atoms.
  • R 3 is C2 alkyl substituted by 1-3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2, and -SO2(Ci-C3 alkyl).
  • R 3 is:
  • R 3 is 2-m ethylbutyl.
  • R 4 is Ce-Cio aryl, 5- to 10-membered heteroaryl, or 5- to 10- membered heterocyclyl, wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from nitrogen and oxygen.
  • R 4 is Ce-Cio aryl, such as phenyl.
  • R 4 is 5- to 10- membered heteroaryl containing 1-2 nitrogen atoms.
  • R 4 is 5- to 10- membered heterocyclyl.
  • R 4 is 5- to 9-membered heterocyclyl containing 1-2 nitrogen atoms.
  • R 4 is 5- to 9-membered heterocyclyl containing 1-2 oxygen atoms.
  • R 4 is 5- to 9-membered heterocyclyl containing 1 nitrogen atom and 1 oxygen atom.
  • R 4 is Ce-Cio aryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy.
  • R 4 is phenyl substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluoro, and chloro.
  • R 4 is:
  • R 4 is 5- to 10-membered heteroaryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy.
  • R 4 is pyridyl or indolyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy.
  • R 4 is .
  • R 4 is pyridyl substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy.
  • R 4 is In some embodiments, R 4 is 5- to 10-membered heterocyclyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy. In some embodiments, R 4 is indolinyl.
  • -L-R 4 is -CH2(phenyl) or -C(O)(phenyl), wherein the phenyl is substituted by 1-3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy.
  • -L-R 4 is -CH pyridyl) or -C(O)(pyridyl), wherein the pyridyl is substituted by 1-3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy.
  • -L-R 4 is:
  • each R 5 is independently Ci-Ce alkyl, oxo, or halo.
  • R 5 is Ci-Ce alkyl, such as methyl, ethyl, or propyl.
  • R 5 is oxo.
  • R 5 is halo, such as fluoro, chloro, or bromo.
  • R 5 is oxo or halo.
  • R 5 is oxo or fluoro.
  • R 6 is H, Ci-Ce alkyl, or oxo. In some embodiments, R 6 is H. In some embodiments, R 6 is Ci-Ce alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 6 is oxo.
  • R 7 is H or oxo. In some embodiments, R 7 is H. In some embodiments, R 7 is oxo.
  • n is 1. In other embodiments, m is 2.
  • n is 0. In other embodiments, n is an integer from 1 to 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • each Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, Ce-Cio aryl, Ce-Cio arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclyl alkyl is optionally substituted with one to three substituents selected from hydroxyl, halo (such as fluoro, chloro, or bromo), amino, Ci-Ce haloalkyl (such as -CF3 or -CHF2), Ci-Ce alkoxy (such as methoxy or ethoxy), Ci-Ce haloalkoxy (such as -OCHF2 or -OCF3), and -(C O)
  • the compound of Formula (I) is a compound of Formula (II), (Ila), (lib), (lie), (lid), or (lie): or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein L, R la , R lb , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as described for Formula (I).
  • the compound is of Formula (II) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (Ila) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (lib) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (lie) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (lid) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (lie) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound of Formula (I) is a compound of Formula (Illa), (Illb), (inc), or (Illd):
  • R la , R lb , R 3 , R 5 , R 6 , and n are as described for Formula (I), and R represents one or more optional substituents, such as hydroxyl, halo, amino, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, as described for Formula (I).
  • the compound is of Formula (Illa) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (Illb) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (IIIc) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of Formula (Illd) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound of Formula (I) is a compound of Formula (IVa), (IVb), (IVc), or (IVd):
  • the compound is of Formula (IVa) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (IVb) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is of Formula (IVc) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of Formula (IVd) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound of Formula (I) is a compound of Formula (V): or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein L, R la , R lb , R 3 , and R 4 are as described for Formula (I).
  • R la and R lb are independently H or C1-C3 alkyl optionally substituted with -CO2H;
  • R 3 is C4-C5 alkyl, C4-C5 alkenyl, or C1-C3 alkyl substituted with C3-C5 cycloalkyl;
  • R 4 is phenyl or pyridyl substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluoro, and chloro.
  • one of R la and R lb is H and the other is C1-C3 alkyl, such as methyl.
  • every description, variation, embodiment, or aspect of a moiety may be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed.
  • every description, variation, embodiment, or aspect provided herein with respect to L of Formula (I) may be combined with every description, variation, embodiment, or aspect of R la , R lb , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n the same as if each and every combination were specifically and individually listed.
  • a compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is provided.
  • certain compounds described in the present disclosure, including in Table 1 are presented as specific stereoisomers and/or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 1, are herein described.
  • the compound of Formula (I) is not Compound 3a, 3b, 9, 10,
  • a compound selected from the compounds in Table lA or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is provided.
  • certain compounds described in the present disclosure, including in Table 1 A are presented as specific stereoisomers and/or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 1 A, are herein described.
  • Table 1A or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the compound is pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • Fosgonimeton is a prodrug that is rapidly converted to the active drug ATH-1001 (Dihexa; see US2014/0094413) in the plasma after subcutaneous injection.
  • the active drug ATH-1001 acts as a positive modulator of the hepatic growth factor (HGF) receptor and its tyrosine kinase, MET, receptor system.
  • HGF hepatic growth factor
  • Fosgonimeton is a pharmaceutically acceptable salt of the Compound A19:
  • Nonlimiting exemplary pharmaceutically acceptable salts of Compound Al 9 include:
  • fosgonimeton refers to the monosodium salt of Compound Al 9, shown below:
  • Compound A19 and pharmaceutically acceptable salts, isotopic forms, or stereoisomers thereof, including fosgonimeton, may be synthesized and characterized using methods known to those of skill in the art, such as those described in PCT Publication No. WO 2017/210489 Al.
  • fosgonimeton is formulated for subcutaneous administration.
  • Compounds of Formula (I), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, can be prepared by using organic chemistry synthesis methods known in the art.
  • starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure’ 5th edition (Wiley, December 2000)) or prepared as described herein.
  • General Reaction Scheme 1
  • General Reaction Scheme 1 provides an exemplary method for preparation of compounds of Formula (I).
  • R la , R lb , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L, and n in General Reaction Scheme 1 are as defined herein.
  • X is a reactive moiety selected to facilitate the desired reaction (e.g., halo).
  • Pi and P2 are suitable protecting groups.
  • L' is selected such that a desired L moiety results from the reaction between L'-R 4 and the secondary amine.
  • Compounds of structure Al are purchased or prepared according to methods known in the art.
  • Reaction of Al with A2 under appropriate coupling conditions yields the product of the coupling reaction between Al and A2, A3.
  • A3 is then reacted with A4 under suitable coupling conditions (e.g., T3P and base) to afford compound A5.
  • Compound A5 is then cyclized (e.g., using formic acid) and deprotected (e.g., using piperidine) to afford compound A6.
  • Compound A6 is then reacted with compound A7 to afford the final compound of Formula (I) as shown.
  • R la , R lb , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L, and n in General Reaction Scheme 2 are as defined herein.
  • P2 is a suitable protecting group.
  • Each X is a reactive moiety selected to facilitate the desired reaction (e.g., halo).
  • L' is selected such that a desired L moiety results from the reaction between L'-R 4 and the secondary amine.
  • Intermediate A5 is prepared with a removable protecting group P 3 (e.g. para-methoxybenzyl) as the R 3 group giving intermediate A8.
  • A8 is then cyclized (e.g., using formic acid) and deprotected (e.g., using piperidine) to afford compound A9.
  • Compound A9 is then reacted with A7 to give compound A10.
  • Compound A10 is then deprotected (e.g., with ceric ammonium nitrate) to give compound Al 1.
  • Compound Al 1 is then reacted with A12 to provide the final compound of Formula (I).
  • Suitable protecting groups may include hydroxy, amino, and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, /-butyldimethyl silyl, Z-butyldiphenylsilyl or trimethyl silyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino and amidino include /-butoxy carbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters.
  • Protecting groups are optionally added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999)’ 3rd Ed., Wiley.
  • the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
  • compositions comprising any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for injection.
  • the pharmaceutical compositions comprise a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and an additional therapeutic agent.
  • additional therapeutic agent Non-limiting examples of such therapeutic agents are described herein below.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.
  • the compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compound described herein is administered topically.
  • the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are 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 are used in some embodiments.
  • An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon 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.
  • a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is administered in a single dose.
  • administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly.
  • other routes are used as appropriate.
  • a single dose of a compound of the disclosure may also be used for treatment of an acute condition.
  • a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is administered in multiple doses.
  • dosing is about once, twice, three times, four times, five times, six times, or more than six times per day.
  • dosing is about once a month, once every two weeks, once a week, or once every other day.
  • a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and another therapeutic agent are administered together about once per day to about 6 times per day.
  • the administration of a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and a therapeutic agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • Administration of the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof may continue as long as necessary.
  • a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects (e.g., peripheral or systemic inflammatory conditions).
  • chronic effects e.g., peripheral or systemic inflammatory conditions.
  • the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound may be found by routine experimentation in light of the instant disclosure.
  • the compounds Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated into pharmaceutical compositions.
  • pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • compositions comprising a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • methods for administering a pharmaceutical composition comprising a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • the compounds are administered as pharmaceutical compositions in which compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are mixed with other therapeutic agents, as in combination therapy.
  • the pharmaceutical compositions include one or more compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • a pharmaceutical composition refers to a mixture of a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated.
  • the mammal is a human.
  • therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.
  • one or more compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated in an aqueous solution.
  • the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
  • one or more compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated for transmucosal administration.
  • transmucosal formulations include penetrants that are appropriate to the barrier to be permeated (e.g., the blood-brain barrier).
  • appropriate formulations include aqueous or nonaqueous solutions.
  • such solutions include physiologically compatible buffers and/or excipients.
  • compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated for oral administration.
  • Compounds are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients.
  • the compounds Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more of the compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are optionally added.
  • Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
  • concentrated sugar solutions are used for coating the dosage form.
  • the sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, Carbopol® gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
  • therapeutically effective amounts of at least one of the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated into other oral dosage forms.
  • Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • push-fit capsules contain the active ingredients in admixture with one or more fillers. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • soft capsules contain one or more active compounds that is/are dissolved or suspended in a suitable liquid.
  • suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
  • stabilizers are optionally added.
  • therapeutically effective amounts of at least one of the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, described herein are formulated for buccal or sublingual administration.
  • Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.
  • the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage forms (e.g., in ampoules) or in multi-dose containers.
  • Preservatives are, optionally, added to the injection formulations.
  • the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles.
  • Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • a suspension of an active compound or compounds e.g., compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are administered topically.
  • the compounds are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.
  • Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.
  • transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • transdermal delivery of the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof is accomplished by means of iontophoretic patches and the like.
  • transdermal patches provide controlled delivery of the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the rate of absorption is slowed by using ratecontrolling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers are used to increase absorption.
  • Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated for administration by inhalation.
  • Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders.
  • compositions of any of the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide, or other suitable gas).
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount.
  • capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator is formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable.
  • Pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one compound of Formula (I) or Compound A 19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, described herein as an active ingredient.
  • the active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein.
  • the compounds Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • compositions comprising the compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • Semi-solid compositions include, but are not limited to, gels, suspensions, and creams.
  • the form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • compositions comprising at least one compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, illustratively takes the form of a liquid where the agents are present in solution, in suspension or both.
  • a liquid composition includes a gel formulation.
  • the liquid composition is aqueous.
  • useful aqueous suspensions contain one or more polymers as suspending agents.
  • Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as crosslinked carboxyl-containing polymers.
  • Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected, for example, from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate, and dextran.
  • Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
  • useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases, and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.
  • compositions optionally include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.
  • compositions include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10 and octoxynol 40.
  • compositions include one or more antioxidants to enhance chemical stability where required.
  • Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
  • aqueous suspension compositions are packaged in singledose non-reclosable containers.
  • multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days.
  • the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • polysorbate 20 (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
  • the concentration of the compound of Formula (I) or Compound Al 9 provided in the pharmaceutical compositions of the present disclosure is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.
  • the concentration of the compound of Formula (I) or Compound Al 9 provided in the pharmaceutical compositions of the present disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%,
  • the concentration of the compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical compositions ranges from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, or approximately 1% to approximately 10% w/w, w/v or v/v.
  • the concentration of the compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical compositions ranges from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, or approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
  • the amount the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical compositions is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g,
  • the amount of the compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical compositions of the present disclosure is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04
  • the amount of the compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical compositions ranges from 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
  • the method includes administering Compound A19 or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof by subcutaneous injection.
  • the method includes administering the HGF/MET positive modulator by oral dosage form.
  • the method includes administering Compound 2a or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof by oral dosage form.
  • the method includes administering Compound la or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof by oral dosage form.
  • the method includes administering Compound 5a or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof by oral dosage form.
  • the method includes administering Compound 6a or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof by oral dosage form.
  • the method includes administering Compound 7a or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof by oral dosage form.
  • kits and articles of manufacture are also provided.
  • such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • the articles of manufacture provided herein contain packaging materials.
  • Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.
  • kits include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein.
  • the container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • materials include, but not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vials, and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
  • a set of instructions will also typically be included.
  • a label is optionally on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, or a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application.
  • the label indicates directions for use of the contents, such as in the methods described herein.
  • the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
  • the pack for example contains metal or plastic foil, such as a blister pack.
  • a pack or dispenser device may be accompanied by instructions for administration.
  • a pack or dispenser may be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • compositions containing a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Embodiments of the present disclosure provide a method for modulating hepatocyte growth factor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as disclosed herein (e.g., a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof).
  • a compound described herein activates hepatocyte growth factor.
  • a compound as described herein positively modulates hepatocyte growth factor activity. Modulation (e.g., inhibition or activation) of hepatocyte growth factor can be assessed and demonstrated by a wide variety of ways known in the art. Kits and commercially available assays can be utilized for determining whether and to what degree hepatocyte growth factor has been modulated (e.g., inhibited or activated).
  • provided herein are compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, for use in positively modulating hepatocyte growth factor in a subject in need thereof.
  • a method for modulating hepatocyte growth factor in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • a method for activating hepatocyte growth factor in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • a method for positively modulating hepatocyte growth factor activity in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • the positive modulation comprises treating, or reducing the symptoms of, a disease, condition, or injury.
  • the disease, condition, or injury is a peripheral and/or systemic inflammatory condition.
  • the peripheral and/or systemic inflammatory condition may be gastrointestinal, dermatological, ophthalmological, related to metabolic diseases, or pulmonological.
  • the peripheral and/or systemic inflammatory condition may be inflammatory bowel disease, Crohn’s disease, ulcerative colitis, coeliac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, noninfectious uveitis, opticus neuritis, Leber hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis.
  • inflammatory bowel disease Crohn’s disease
  • ulcerative colitis coeliac disease
  • rheumatoid arthritis psoriasis
  • systemic lupus erythematosus dermatomyositis
  • polymyositis noninfectious uveitis
  • provided herein are methods of treating inflammatory bowel disease, Crohn’s disease, ulcerative colitis, coeliac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, noninfectious uveitis, opticus neuritis, Leber hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating inflammatory bowel disease in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating Crohn’s disease in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating ulcerative colitis in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating psoriasis in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating noninfectious uveitis in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating type 2 diabetes in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating obesity in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating coronary heart disease in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • methods of treating gout in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating fatty liver disease in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating seasonal allergies in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating COPD in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating endometriosis in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating systemic lupus erythematosus in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating dermatomyositis in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating polymyositis in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • methods of treating opticus neuritis in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating LHON in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating macular degeneration in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating retinal degeneration in a subject.
  • the method includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating myasthenia gravis in a subject includes administering an effective amount of a compound in Table 1, a compound in Table la, Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating inflammatory bowel disease, Crohn’s disease, ulcerative colitis, coeliac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, noninfectious uveitis, opticus neuritis, leber hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating inflammatory bowel disease in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating Crohn’s disease in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating ulcerative colitis in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating coeliac disease in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating rheumatoid arthritis in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating psoriasis in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating noninfectious uveitis in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating type 2 diabetes in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • methods of treating obesity in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating coronary heart disease in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating gout in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating fatty liver disease in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating seasonal allergies in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating COPD in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating endometriosis in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating systemic lupus erythematosus in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • methods of treating dermatomyositis in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating polymyositis in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating opticus neuritis in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating LHON in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating macular degeneration in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • provided herein are methods of treating retinal degeneration in a subject.
  • the method includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • kits for treating myasthenia gravis in a subject includes administering an effective amount of Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof to the subject.
  • the peripheral and/or systemic inflammatory condition is not caused by neuroinflammation or a disease or disorder of the central nervous system. In some embodiments, the peripheral and/or systemic inflammatory condition is not caused by a dementia. In some embodiments, the peripheral and/or systemic inflammatory condition is not caused by a neurodegenerative disease. In some embodiments, the peripheral and/or systemic inflammatory condition is not caused by Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensorineural hearing and vision loss. In some embodiments, the subject being treated for the peripheral and/or systemic inflammatory condition is not suffering from a dementia.
  • the subject being treated for the peripheral and/or systemic inflammatory condition is not suffering from a neurodegenerative disease. In some embodiments, the subject being treated for the peripheral and/or systemic inflammatory condition is not suffering from Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, and/or sensorineural hearing and vision loss.
  • the peripheral and/or systemic inflammatory condition is not associated with neuroinflammation or a disease or disorder of the central nervous system. In some embodiments, the peripheral and/or systemic inflammatory condition is not associated with a dementia. In some embodiments, the peripheral and/or systemic inflammatory condition is not associated with a neurodegenerative disease. In some embodiments, the peripheral and/or systemic inflammatory condition is not associated with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensorineural hearing and vision loss. In some embodiments, the subject being treated for peripheral and/or systemic inflammatory condition is not suffering from a dementia.
  • the disclosure provides methods of modulating protein activity (e.g., hepatocyte growth factor activity) in a subject including but not limited to rodents and mammal (e.g., human) by administering into the subject an effective amount of a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • modulation of hepatocyte growth factor is activation of hepatocyte growth factor.
  • the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the percentage of inhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the disclosure provides methods of modulating hepatocyte growth factor activity in a cell by contacting said cell with an amount of a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor.
  • the disclosure provides methods of modulating hepatocyte growth factor activity in a tissue by contacting said tissue with an amount of a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the tissue.
  • the disclosure provides methods of modulating hepatocyte growth factor activity in an organism by contacting said organism with an amount of a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the organism. In some embodiments, the disclosure provides methods of modulating hepatocyte growth factor activity in an animal by contacting the animal with an amount of a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the animal.
  • the disclosure provides methods of modulating hepatocyte growth factor activity in a mammal by contacting the mammal with an amount of a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the mammal.
  • the disclosure provides methods of modulating hepatocyte growth factor activity in a human by contacting the human with an amount of a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the human.
  • the present disclosure provides methods of treating a disease mediated by hepatocyte growth factor activity in a subject in need of such treatment.
  • modulation of hepatocyte growth factor by a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof involves activation of hepatocyte growth factor.
  • a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level in the subject of at least one proinflammatory molecule.
  • the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected G- CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-la, IL-ip, IL-4, IL-10, IL-12p70, IL-17A, TNFa, and IFNy.
  • the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected from IL-ip, IL-4, IL-6, TNF-a, and IFNy. In some embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected from BAFF, G-CSF, ENA-78 (CXCL5), Eotaxin (CCL11), IL-2R, LIF, MIP-lBeta (CCL4) and MIP-1 Alpha (CCL3).
  • a compound of Table 1, Table 1 A or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level in the subject of at least one proinflammatory molecule.
  • the compound of Table 1, Table lA or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected G- CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-la, IL-ip, IL-4, IL-10, IL-12p70, IL-17A, TNFa, and IFNy.
  • the compound of Table 1, Table 1A or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected from IL-ip, IL-4, IL-6, TNF-a, and IFNy.
  • the compound of Table 1, Table lA or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected from BAFF, G-CSF, ENA-78 (CXCL5), Eotaxin (CCL11), IL-2R, LIF, MIP-lBeta (CCL4) and MIP-1 Alpha (CCL3).
  • Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level in the subject of at least one proinflammatory molecule.
  • Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected G- CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-la, IL-ip, IL-4, IL-10, IL-12p70, IL-17A, TNFa, and IFNy.
  • Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected from IL-ip, IL-4, IL-6, TNF-a, and IFNy.
  • Compound la, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof decreases the level of at least one proinflammatory molecule selected from BAFF, G-CSF, ENA-78 (CXCL5), Eotaxin (CCL11), IL-2R, LIF, MIP-lBeta (CCL4) and MIP-1 Alpha (CCL3).
  • proinflammatory molecule selected from BAFF, G-CSF, ENA-78 (CXCL5), Eotaxin (CCL11), IL-2R, LIF, MIP-lBeta (CCL4) and MIP-1 Alpha (CCL3).
  • Other embodiments provide methods for combination therapies in which a therapeutic agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.
  • such therapy includes but is not limited to the combination of one or more compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, with therapeutic agents, therapeutic antibodies, and other forms of treatment, to provide a synergistic or additive therapeutic effect.
  • a subject having a peripheral and/or systemic inflammatory condition is also treated with another antiinflammatory agent, such as a steroid.
  • the compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are formulated or administered in conjunction with liquid or solid tissue barriers also known as lubricants.
  • tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm®, and hyaluronic acid.
  • the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof can be used in combination with the therapeutic agents disclosed herein depending on the condition being treated. Hence, in some embodiments the one or more compounds of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, will be coadministered with other therapeutic agents as described above.
  • the compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof are administered with the second therapeutic agent simultaneously or separately. This administration in combination can include simultaneous administration in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.
  • a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and any of the therapeutic agents described above can be formulated together in the same dosage form and administered simultaneously.
  • a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and any of the therapeutic agents described above can be simultaneously administered, wherein both are present in separate formulations.
  • a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof can be administered just followed by and any of the therapeutic agents described above, or vice versa.
  • a compound of Formula (I) or Compound Al 9, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and any of the therapeutic agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.
  • Example Bl Reduction of inflammatory pain-related behaviors and inflammation biomarkers following treatment in a rodent CEA inflammatory pain model
  • Response to peripheral inflammatory stimulus can be modeled by administering complete Freund’s adjuvant (CFA), a suspension of desiccated mycobacterium in paraffin oil and mannide monooleate, by subcutaneous injection into the rat’s footpad.
  • CFA complete Freund’s adjuvant
  • the introduction of CFA to peripheral tissues leads to a rapid, sustained, inflammatory reaction in the exposed tissue within 24 hours.
  • Subcutaneous administration of CFA in the plantar region of the paw induces inflammatory pain-related behaviors that persist for at least 8 days.
  • CFA treatment also leads to the accumulation of inflammatory cytokines in paw tissue at the site of injury.
  • the extent of inflammatory response to CFA can be assessed by quantification of inflammatory cytokines in paw skin homogenate, and inflammatory pain-related behaviors by tests of mechanical allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test).
  • Compound 2a was tested for its ability to reduce inflammatory pain- related behaviors in the CFA inflammation model.
  • 50 pg of CFA was administered subcutaneously in the plantar of the right hind paw. Animals were treated daily with Compound 2a in solution via oral gavage (PO) at doses of 1, 0.1, and 0.025 mg/kg. Treatment began before CFA injection on study day -1 and continued through study day 8.
  • PO oral gavage
  • Thermal hyperalgesia was measured using the Hargreaves method. A temperature ramp was applied to the right hind paw via a directed light beam and the paw withdrawal latency (PWL) was recorded as a measure of sensitivity to thermal stimulation. One hour postdose testing was performed on study days 1, 3, and 7, and pre-dose testing was performed on day 7. Statistical analysis was performed using a 1-way ANOVA with Tukey post-test. A p- value below 0.05 was considered statistically significant. Results are summarized in Table 2. Control animals stimulated with CFA but treated with only vehicle had a high sensitivity to thermal stimulation compared to normal control animals. Treatment with Compound 2a at a dose of 1 mg/kg resulted in reduced thermal sensitivity on day 3 and in pre-dose testing on day 7.
  • NS no statistically significant change in sensitivity compared to CFA alone
  • Intraplantar CFA injection occurred at day 0.
  • Treatment with Compounds la, 5a, and 6a occurred daily from day -1 to day 8.
  • the rats were terminated and cytokine levels were measured in paw skin. Tissue from paw bone, joint, and muscle were obtained for H&E staining and analysis. Cytokine levels in CFA-stimulated test compound-treated animals were compared to CFA-stimulated vehicle-treated animals. Analytes included interleukin 4 (IL-4), tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-y) Statistical analysis consisted of 1-way ANOVA followed by Dunnett’s multiple comparisons post-test.
  • IL-4 interleukin 4
  • TNF-a tumor necrosis factor alpha
  • IFN-y interferon gamma
  • PWT refers to lower paw withdrawal threshold where a higher value corresponds to a higher pain threshold.
  • PWL refers to lower paw withdrawal latency where a higher value corresponds to a higher pain threshold.
  • test compounds reduced the expression of the assessed cytokines in at least one tested dose, except for compound 6a which had no effect on IFN-y expression (Table 4). These results suggest that the test compounds produce a meaningful anti-inflammatory effect in response to CFA-stimulated peripheral inflammation.
  • NS no statistically significant change in expression compared to CFA alone
  • Example B2 Reduction of inflammation following pulmonary LPS challenge.
  • Acute pulmonary inflammation can be effectively modeled in rats by intratracheal administration of bacterial lipopolysaccharides (LPS).
  • LPS bacterial lipopolysaccharides
  • the severity of inflammatory response can be measured by quantifying the amount of immune cell infiltration and secretion of cytokine signaling proteins in bronchoalveolar lavage fluid (BALF).
  • BALF bronchoalveolar lavage fluid
  • Activation of the HGF/MET signaling system by HGF/MET positive modulators is expected to reduce the inflammatory response.
  • Two test compounds, Compound la and Compound 5a were evaluated for their ability to reduce acute pulmonary inflammation in an intranasal LPS model.
  • mice Four hours post-LPS administration, animals were euthanized by intraperitoneal injection of thiopentone and 20 mL of cold Hanks Balanced Salt Solution, pH 7.2, was infused into the lungs through tracheal cannulation. BALF was then collected.
  • Immune cell infiltration in BALF was quantified as an assessment of an inflammatory response, with the results shown in Table 5. Immune cell infiltration was performed by counting total leukocytes using a MUSE® mini flow cytometer, and by manual counting of neutrophil cells in cytospin smears stained with Leishman’s staining reagent. Treatment with Compound la and Compound 5a reduced both total leukocyte counts and neutrophil counts compared to LPS-only controls.
  • Cytokine expression in BALF supernatant was quantified by multiplex immunoassay using a MAGPIX multiplexing unit with a cytokine multiplex kit (Merck-Millipore, Cat# RECYMAG65K27PMX).
  • the panel of tested cytokines included growth factors (G-CSF, GM- CSF, EGF, VEGF, TNF-a), chemokines (CCL2, CCL3, CCL5, CCL11, CXCL 1, CXCL 2, CXCL5, CXCL10, CX3CL1), interleukins (IL-la, IL-ip, IL-2, IL-4, IL-5, IL-6, IL-10, IL- 12p70, IL-13, IL-17A), and interferon gamma (IFNy).
  • the results of this analysis are shown in Table 6.
  • Statistically significant change from LPS-only animals was determined by Student’s T- test, with p ⁇ 0.05 indicating statistically significant change in cytokine expression levels.
  • Treatment with Compound la lead to significant changes in expression of G-CSF, CXCL2, CXCL10, IFN-y, and IL-ip.
  • Treatment with Compound 5a led to significant changes in expression of CCL3, CXCL1, IFN-y, IL-la, IL-ip, IL- 10, IL-12p70, and IL- 17 A.
  • These results indicate that treatment with test compounds had a meaningful impact on acute pulmonary inflammation response to LPS by decreasing the levels of proinflammatory molecules.
  • the normal process of inflammation is regulated and promoted by expression, secretion, and distribution of inflammatory signaling proteins.
  • Therapeutics intended to reduce inflammation are commonly identified by their ability to change the expression levels of inflammatory signaling molecules, either by disruption of the inflammatory pathway directly, or resolution of the inflammatory signaling cascade.
  • the compounds provided herein are expected to be capable of interrupting inflammatory signaling based on their demonstrated impact on the expression of noteworthy inflammatory cytokines.
  • Example B3 Reduction of pro-inflammatory cytokine expression in macrophage-like cell cultures.
  • Inflammation plays a crucial role in disease progression and is a complex phenomenon involving various cells that affect many extra- and intracellular signaling pathways and cytokine production.
  • Macrophages are tissue-resident or infiltrated immune cells critical for innate immunity, normal tissue development, homeostasis, and repair of damaged tissue.
  • Activated macrophages participate in developing systemic and peripheral inflammation, responding to toxic exogenous substances (like LPS) or endogenous substances.
  • THP-1 cells as an in-vitro cell model to evaluate mechanisms relevant to systemic and peripheral inflammation. Differentiation with PMA causes THP-1 monocyte cells to acquire functional and morphological resemblance to macrophages.
  • THP-1 differentiated macrophage through the toll-like receptor 4, triggering the inflammatory response and stimulating pro-inflammatory cytokine release and eventually leading to cellular death.
  • test compounds have anti-inflammatory effects on LPS-challenged macrophage cultures.
  • THP-1 -differentiated macrophages were treated with test compounds for 20 minutes, followed by 24 hrs of LPS challenge. Culture supernatants were then collected and analyzed for the presence of pro-inflammatory cytokines: interleukin ip (IL-ip), interleukin 6 (IL-6) and tumor necrosis factor a (TNF-a).
  • IL-ip interleukin ip
  • IL-6 interleukin 6
  • TNF-a tumor necrosis factor a
  • Cytokine quantification in cell culture supernatants was accomplished by homogeneous time-resolved fluorescence (HTRF) kits to assess levels of IL-ip (Human IL-ip kit, #62HIL1BPEG, Cisbio) and IL-6 (Human IL-6 kit, 62HIL06PET, Cisbio), and by ELISA to determine the levels of TNF-a (Human TNF-a ELISA kit, KHC3011, ThermoFisher).
  • HTRF time-resolved fluorescence
  • Table 7 Significant reduction in pro-inflammatory cytokine expression by THP-1 immune cells in vitro
  • Example B4 Reduction in Streptozotocin-Induced Inflammatory Cytokines in Response to Compound Treatment.
  • Cytokines were quantified using a bead-capture detection system (ProcartaPlex, ThermoFisher, Catalog #: PPX-090MXKA44V) using a Luminex multiplex detection system. Each analyte was quantified in relation to a standard curve and the abundance in plasma was measured in pg/ml. Interferon gamma (IFN-y) and interleukin-4 (IL-4) were strongly upregulated by STZ stimulation and also reduced in response to test compound treatment. IFN-y is expressed in response to other inflammatory cytokines and promotes inflammation by activation of the JAK/STAT signaling pathway.
  • IFN-y Interferon gamma
  • IL-4 interleukin-4
  • IL-4 is a pro-inflammatory cytokine that activates several types of inflammatory macrophage cells. Thus, reduction in the expression of either of these analytes represents a reduction in inflammatory response to disease induction.
  • Statistical analysis was conducted by one-way ANOVA followed by Dunnett’s multiple comparisons post-test against untreated disease control.
  • Example B5 Reduction of pro-inflammatory cytokine expression in a mouse model of LPS-induced inflammation.
  • LPS bacterial lipopolysaccharides
  • Animals from groups 1 and 2 served as control groups and received vehicle (saline - 0.9% NaCl). Starting from Day (D) 0, animals from both groups were treated once a day (QD) via subcutaneous (SC) route at 10 mL/kg. All animals from group 1 were treated for 4 consecutive days, while the first 16 animals from group 2 received a single dose, the next 8 animals were treated for two consecutive days, and the remaining 8 animals were treated for 4 consecutive days. Prior to dosing, the animals were weighed, and the amount of vehicle administered adjusted according to individual weights.
  • the test article, Compound A19 was dissolved in saline (0.9% NaCl), pH 7.4-7.7, and prepared to achieve final concentrations of 0.125, 0.5 and 1.25 mg/kg for groups 3-5, respectively.
  • saline (0.9% NaCl)
  • pH 7.4-7.7 pH 7.4-7.7
  • final concentrations 0.125, 0.5 and 1.25 mg/kg for groups 3-5, respectively.
  • DO 0.125, 0.5 or 1.25 mg/kg of Compound Al 9, respectively, once a day (QD) via subcutaneous (SC) route at 10 mL/kg.
  • the first 16 animals from each group received a single dose, the next 8 animals were treated for two consecutive days, and the remaining 8 animals were treated for 4 consecutive days. Prior to dosing, animals were weighed, and the amount administered adjusted according to individual weights.
  • Cytokines were quantified by multiplex analysis using an Invitrogen Immune Monitoring 48-Plex Mouse ProcartaPlexTM Panel kit according to the manufacturer’s instructions and amounts were calculated by interpolation from the standard curve. The panels determine levels of certain cytokines, chemokines, growth factors/regulators and soluble receptors. The panel include pro-inflammatory and anti-inflammatory molecules and other molecules.
  • Cytokines BAFF, G-CSF (CSF-3), GM-CSF, IFN alpha, IFN gamma, IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12p70, IL-13, IL-15/IL-15R, IL-17A (CTLA-8), IL- 18, IL- 19, IL-22, IL-23, IL-25 (IL-17E), IL-27, IL-28, IL-31, IL-33, LIF, M-CSF, RANKL, and TNF alpha; Chemokines: ENA-78 (CXCL5), Eotaxin (CCL11), GRO alpha (CXCL1), IP-10 (CXCL10), MCP-1 (CCL2), MCP-3 (CCL7), M
  • mice treated with Compound Al 9 at 1.5 mg/kg had significantly lower levels of the inflammatory mediators BAFF, G-CSF, ENA-78, Eotaxin, IL-2R, LIF, MIP-lBeta and MIP-lAlpha compared to vehicle- treated LPS animals.
  • Mice treated with Compound A19 at 0.125 mg/kg also exhibited a significant decrease in levels of G-CSF and ENA-78 at this timepoint.
  • levels of BAFF, ENA-78, and IL-2R remained lowered compared to LPS-treated vehicle mice.
  • the LPS challenge resulted in a nominal but not significant increase in levels of inflammatory mediators relative to the group 1 controls, but Compound Al 9 was able to significantly reduce these levels. These events are denoted by an asterisk in Table 10. These results show that treatment with Compound A19 can mitigate increases in inflammatory mediators following LPS challenge, suggesting immunomodulatory capabilities of Compound Al 9.

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Abstract

L'invention concerne des composés et des compositions à base de ceux-ci pour moduler des facteurs de croissance des hépatocytes. Dans certains modes de réalisation, les composés et les compositions sont destinés au traitement de maladies, notamment de maladies inflammatoires périphériques et/ou systémiques.
PCT/US2023/080224 2022-11-18 2023-11-17 Méthodes de traitement d'états inflammatoires WO2024108090A1 (fr)

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WO2017210489A1 (fr) 2016-06-01 2017-12-07 M3 Biotechnology, Inc. Composés
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WO2002092010A2 (fr) * 2001-05-16 2002-11-21 Molecumetics, Ltd. Mimetiques de coudes inverses et methodes associees
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US20140094413A1 (en) 2012-04-02 2014-04-03 Washington State University Hepatocyte growth factor (hgf) mimics as therapeutic agents
WO2017210489A1 (fr) 2016-06-01 2017-12-07 M3 Biotechnology, Inc. Composés
WO2022094400A1 (fr) 2020-11-02 2022-05-05 Athira Pharma, Inc. Composés bicycliques et leurs utilisations pour le traitement de maladies
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