WO2024258897A1 - Alcoxypyridinyle et composés apparentés et leur utilisation en thérapie - Google Patents

Alcoxypyridinyle et composés apparentés et leur utilisation en thérapie Download PDF

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WO2024258897A1
WO2024258897A1 PCT/US2024/033492 US2024033492W WO2024258897A1 WO 2024258897 A1 WO2024258897 A1 WO 2024258897A1 US 2024033492 W US2024033492 W US 2024033492W WO 2024258897 A1 WO2024258897 A1 WO 2024258897A1
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cancer
disease
combination
therapeutic agent
additional therapeutic
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Jorge Garcia Fortanet
Jonathan Michael GOODWIN
Christophe QUÉVA
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Dem Biopharma Inc
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Dem Biopharma Inc
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms
    • C07D231/34—Oxygen atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention provides alkoxypyridinyl and related compounds, pharmaceutical compositions, their use for agonizing G protein-coupled receptor 84 (GPR84), and their use in the treatment of a disease or condition, such as a cancer.
  • GPR84 G protein-coupled receptor 84
  • the invention also provides combination therapy using a GPR84 agonist to treat a disease or condition, such as a cancer.
  • Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease.
  • Solid tumors such as prostate cancer, colon, rectum, skin cancer, breast cancer, and lung cancer remain highly prevalent among the world population.
  • Existing therapies for treating cancer include localized therapies, such as surgery, radiation therapy, cryotherapy, and systemic therapies (e.g., chemotherapy, hormonal therapy, immune therapy, and targeted therapy) used alone or in combination.
  • Support therapies are also used in some contexts, where supportive therapies are additional treatments that do not directly treat cancer but are used to reduce side effects and address patient quality of life.
  • current treatment options for cancer are not effective for all patients and/or can have substantial adverse side effects.
  • New therapies are needed to address this unmet need in cancer therapy.
  • G protein-coupled receptors are a class of membrane protein receptors and have over three- hundred human gene code-related proteins, which are involved in many cell physiological functions.
  • GPR84 is a membrane protein receptor. Human GPR84 is expressed in bone marrow and peripheral blood leukocytes (including neutrophils, eosinophils and basophils). GPR84 has been reported to have important beneficial effects against cancer, including a role as an important metabolic sensing switch to orchestrate anti-tumorigenic macrophage polarization. See, for example, Xin et al. In Journal for ImmunoTherapy of Cancer (2022) vol. 10, Issue Suppl 2. GPR84 is also implicated in inflammatory diseases.
  • GPR84 functions as an enhancer of inflammatory signaling in macrophages once inflammation is established. See, for example, Recio et al. In Front Immunol. (2016) vol. 9, 1419. Molecules having activity towards GPR84 are described in, for example, international patent application WO 2022/076446 and U.S. Patent Application Publication No 2018/0237399. New molecules having GPR84 agonist activity are needed to address diseases responsive to GPR84 agonism.
  • the invention provides alkoxypyridinyl and related compounds, pharmaceutical compositions, their use for agonizing G protein-coupled receptor 84 (GPR84), and their use in the treatment of a disease or condition, such as a cancer.
  • GPR84 G protein-coupled receptor 84
  • the invention also provides combination therapy using a GPR84 agonist to treat a disease or condition, such as a cancer.
  • one aspect of the invention provides a collection of alkoxypyridinyl and related compounds, such as a compound represented by Formula 1: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of alkoxypyridinyl and related compounds are described in the detailed description.
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a method of treating a disease or condition responsive to GPR84 agonism.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disease or condition, as further described in the detailed description.
  • Another aspect of the invention provides a method of treating cancer.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the cancer, as further described in the detailed description
  • Another aspect of the invention provides a method of agonizing the activity of GPR84.
  • the method comprises contacting a GPR84 with an effective amount of a compound described herein, such as a compound of Formula I, to agonize the activity of said GPR84, as further described in the detailed description.
  • Another aspect of the invention provides a method for treating a disease or condition responsive to GPR84 agonism.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of (i) a GPR84 agonist and (ii) an additional therapeutic agent, such as an additional therapeutic agent that binds to a target selected from CCR4, CD 19, CD20, CD22, CD30, CD33, CD38, CD47, CD52, CD79b, Claudin 18.2, CTLA-4, EGFR, FGFR2, GD2, HER2, LAG3, MET, Nectin-4, PDGFRa, PD-L1, RANKL, SLAMF7, TF, TROP2, VEGF, VEGFR, VEGFR2, or epidermal growth factor receptor with exon 20 insertion mutations, to treat the disease or condition, as further described in the detailed description.
  • an additional therapeutic agent such as an additional therapeutic agent that binds to a target selected from CCR4, CD 19, CD20, CD22, CD30, CD33,
  • Another aspect of the invention provides a method for treating a disease or condition responsive to GPR84 agonism.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of (i) a GPR84 agonist and (ii) CAR-T therapy, to treat the disease or condition, as further described in the detailed description.
  • FIG. 1A is a bar graph showing the extent of TTI-622-induced ADCP of A375 melanoma cells in a dose-response assay in the presence or absence of 1-4 at the indicated concentrations.
  • FIG. IB is a bar graph showing selected data from FIG. 1A, including the condition producing the maximal ADCP response, with statistical significance indicated.
  • FIG. 2A is a bar graph showing the extent of TTI-622-induced ADCP of HCT116 colon adenocarcinoma tumor cells in a dose-response assay in the presence or absence of 1-4 at the indicated concentrations.
  • FIG. 2B is a bar graph showing selected data from FIG. 2A, including the condition producing the maximal ADCP response, with statistical significance indicated.
  • FIG. 3A is a bar graph showing the extent of magrolimab-induced ADCP of A375 melanoma cells in a dose-response assay in the presence or absence of 1-4 at the indicated concentrations.
  • FIG. 3B is a bar graph showing selected data from FIG. 3A, including the condition producing the maximal ADCP response, with statistical significance indicated.
  • FIG. 4A is a bar graph showing the extent of cetuximab-induced ADCP of HCT 116 colon adenocarcinoma tumor cells in a dose-response assay in the presence or absence of 1-4 at the indicated concentrations.
  • FIG. 4B is a bar graph showing selected data from FIG. 4A, including the condition producing the maximal ADCP response, with statistical significance indicated.
  • FIG. 5A is a bar graph showing the extent of rituximab-induced ADCP of Ramos lymphoma cells in a dose-response assay in the presence or absence of 1-4 at the indicated concentrations.
  • FIG. 5B is a bar graph showing selected data from FIG. 5A, including the condition producing the maximal ADCP response, with statistical significance indicated.
  • FIG. 6A is a bar graph showing the extent of daratumumab-induced ADCP of MM. IS multiple myeloma cells in a dose-response assay in the presence or absence of 1-4 at the indicated concentrations.
  • FIG. 6B is a bar graph showing selected data from FIG. 6A, including the condition producing the maximal ADCP response, with statistical significance indicated.
  • FIG. 7 is a bar graph showing the extent of ADCP of Ramos lymphoma cells in the presence or absence of 1-4, with ADCP induced by rituximab, magrolimab, or TTI-622 as indicated.
  • the invention provides alkoxypyridinyl and related compounds, pharmaceutical compositions, their use for agonizing G protein-coupled receptor 84 (GPR84), and their use in the treatment of a disease or condition, such as a cancer.
  • GPR84 G protein-coupled receptor 84
  • the invention also provides combination therapy using a GPR84 agonist to treat a disease or condition, such as a cancer.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, eds., 1991-1992); Handbook of Experimental Immunology (D.M.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • aliphatic groups contain 1 -4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bicyclic ring or “bicyclic ring system” refers to any bicyclic ring system, i.e. , carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.
  • a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include:
  • lower alkyl refers to a straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaterized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • the term “-(C 0 alkylene)-“ refers to a bond. Accordingly, the term “-(C 0-3 alkylene)-” encompasses a bond (i.e., C0) and a -(C 1-3 alkylene)- group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent.
  • Suitable substituents include those described below for a substituted aliphatic group.
  • halogen or “halo” means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • phenylene refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it.
  • phenylene is a bivalent phenyl group when it has two groups attached to it (e.g ); “phenylene” is a trivalent phenyl group when it has three groups attached to it (e.g.,
  • arylene refers to a bivalent aryl group.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/7-quinolizinyl. carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • a heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “hetero aromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heteroarylene refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it.
  • heteroarylene is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.
  • pyridinylene refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it.
  • pyridinylene is a bivalent pyridine radical when it has two groups
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4- dihydro-277-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in A-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydro thiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, hctcroaryl, or cycloaliphatic rings, such as indolinyl, 3/H-indolyl. chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono- or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • oxo-heterocyclyl refers to a heterocyclyl substituted by an oxo group.
  • heterocyclylene refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; which may be substituted with R°; which may be substituted with which may be substituted with ridyl which may be substituted with C(NH)NR° 2 ; –P(O) 2 R°; -P(O)R° 2 ; -OP(O)R° 2 ; –OP(O)(OR°) 2 ; SiR° 3 ; –(C 1–4 straight or branched alkylene)O–N(R°) 2 ; or –(C 1–4 straight or branched alkylene)C(O)O–N(R°) 2 .
  • R * is C1–6 aliphatic
  • R * is optionally substituted with halogen, –R o , -(haloR o ), -OH, –OR o , –O(haloR o ), –CN, –C(O)OH, –C(O)OR o , –NH 2 , –NHR o , –NR o 2 , or –NO 2
  • each R o is independently selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R o is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O)2R ⁇ , -S(O)2NR ⁇ 2, –C(S)NR ⁇ 2, –C(NH)NR ⁇ 2, or –N(R ⁇ )S(O)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstitute
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the invention includes compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the term “about” refers to within ⁇ 10% of the stated value.
  • the invention encompasses embodiments where the value is within ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, or ⁇ 1% of the stated value.
  • the terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C 1 -C 12 alkyl, C 1 -C 10 alkyl, and C 1 -C 6 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C 3 -C 6 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • exemplary haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
  • haloalkylene refers to a bivalent haloalkyl group.
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • Exemplary haloalkoxyl groups include -OCH 2 F, - OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 3 , and the like.
  • hydroxyalkoxyl refers to an alkoxyl group that is substituted with at least one hydroxyl.
  • exemplary hydroxyalkoxyl groups include -OCH 2 CH 2 OH, -OCH 2 C(H)(OH)CH 2 CH 2 OH, and the like.
  • alkoxylene refers to a bivalent alkoxyl group.
  • the symbol “ ” indicates a point of attachment.
  • any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solidvate encompasses both solution-phase and isolatable solvates.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and, most preferably, include humans.
  • the term “compound” refers to a quantity of molecules that is sufficient to be weighed, tested for its structural identity, and to have a demonstrable use (e.g., a quantity that can be shown to be active in an assay, an in vitro test, or in vivo test, or a quantity that can be administered to a patient and provide a therapeutic benefit).
  • IC50 is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.
  • the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result).
  • an effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate-buffered saline solution, water, emulsions (e.g., such as oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified.
  • R 1 is C 2-12 alkoxyl, -[-O-(C 1-2 alkylene)] n -H, -(C 1-6 alkylene)-[-O-(C 1-2 alkylene)] n -H, -C 4-12 alkyl, -C(O)-(C 4-12 alkyl), -(C 1-10 alkylene)-R 6 , -O-(C 1-10 alkylene)-R 6 , -N(R 4 )([(C 1-2 alkylene)-O- ]n-(C 1-6 alkyl)), or -N(R 4 )(R 5 ); R 2 is hydroxyl, C 1-4 alkoxyl, or hydrogen; R 3 is hydroxyl, C1-4 haloalkyl, or hydrogen; R 4
  • variables in Formula I above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I.
  • R 1 is C2-12 alkoxyl, -[-O-(C 1-2 alkylene)]n-H, -(C 1-6 alkylene)- [-O-(C 1-2 alkylene)] n -H, -C 4-12 alkyl, -C(O)-(C 4-12 alkyl), -(C 1-10 alkylene)-R 6 , -O-(C 1-10 alkylene)- R 6 , -N(R 4 )([(C 1-2 alkylene)-O-]n-(C 1-6 alkyl)), or -N(R 4 )(R 5 ).
  • R 1 is C2-12 alkoxyl.
  • R 1 is C6-10 alkoxyl. In certain embodiments, R 1 is C8 alkoxyl. In certain embodiments, R 1 is -[-O-(C 1-2 alkylene)] n -H. In certain embodiments, R 1 is -(C 1-6 alkylene)-[-O-(C 1-2 alkylene)]n-H. In certain embodiments, R 1 is -C 4-12 alkyl. In certain embodiments, R 1 is -C7-10 alkyl. In certain embodiments, R 1 is -C10 alkyl. In certain embodiments, R 1 is -C(O)-(C 4-12 alkyl). In certain embodiments, R 1 is -C(O)-(C 8-12 alkyl).
  • R 1 is -(C 1-10 alkylene)-R 6 . In certain embodiments, R 1 is -(C 4-6 alkylene)-R 6 . In certain embodiments, R 1 is -O-(C 1-10 alkylene)-R 6 . In certain embodiments, R 1 is -N(R 4 )([(C 1-2 alkylene)-O-]n-(C 1-6 alkyl)). In certain embodiments, R 1 is -N(R 4 )(R 5 ). In certain embodiments, R 1 is -C(O)-(C 4-12 alkyl) or -O-(C 1-10 alkylene)-R 6 .
  • R 1 is -N(R 4 )([(C 1-2 alkylene)-O-] n -(C 1-6 alkyl)) or -N(R 4 )(R 5 ).
  • R 1 is selected from the groups depicted in the compounds in Table 1 below.
  • R 2 is hydroxyl, C1-4 alkoxyl, or hydrogen.
  • R 2 is hydroxyl.
  • R 2 is C 1-4 alkoxyl.
  • R 2 is hydrogen.
  • R 2 is selected from the groups depicted in the compounds in Table 1 below.
  • R 3 is hydroxyl, C 1-4 haloalkyl, or hydrogen. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 3 is C 1-4 haloalkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 1 below. [0087] As defined generally above, R 4 is C 1-6 alkyl. In certain embodiments, R 4 is C 1-4 alkyl. In certain embodiments, R 4 is C 1-2 alkyl. In certain embodiments, R 4 is selected from the groups depicted in the compounds in Table 1 below. [0088] As defined generally above, R 5 is C 4-12 alkyl.
  • R 5 is C 6-10 alkyl. In certain embodiments, R 5 is C8-10 alkyl. In certain embodiments, R 5 is C6-8 alkyl. In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 1 below. [0089] As defined generally above, R 6 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-6 alkyl and halo.
  • R 6 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-6 alkyl and halo. In certain embodiments, R 6 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-6 alkyl.
  • R 6 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo.
  • R 6 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-6 alkyl and halo.
  • R 6 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-6 alkyl .
  • R 6 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo.
  • R 6 is pyridinyl, pyrazolyl, or oxazolyl, each of which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1-6 alkyl and halo. In certain embodiments, R 6 is selected from the groups depicted in the compounds in Table 1 below. [0090] As defined generally above, A 1 is (i) a 6-membered heteroarylene containing 1 or 2 heteroatoms selected from nitrogen or (ii) a 5-membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, A 1 is (i) a 6-membered heteroarylene containing 1 or 2 heteroatoms selected from nitrogen.
  • a 1 is (ii) a 5-membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a 1 is pyridinylene.
  • a 1 is pyrazolylene, oxazolylene, or 1,2,4-triazolylene.
  • n is 5. In certain embodiments, n is 6. In certain embodiments, n is selected from the groups depicted in the compounds in Table 1 below. [0092] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments. [0093] In certain embodiments, the compound of Formula I is further defined by Formula Ia or a pharmaceutically acceptable salt thereof: Ia. [0094] In certain embodiments, the compound of Formula I is further defined by Formula Ia. [0095] In certain embodiments, the compound of Formula I is further defined by Formula Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof: Ib Ic Id.
  • the compound of Formula I is further defined by Formula Ib, Ic, or Id.
  • Another aspect of the invention provides a compound in Table 1 below, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound in Table 1. TABLE 1.
  • Methods for preparing compounds described herein are illustrated in the following synthetic scheme. The scheme is provided for the purpose of illustrating the invention, and is not intended to limit the scope or spirit of the invention. Starting materials shown in the scheme can be obtained from commercial sources or can be prepared based on procedures described in the literature. [0099] In the schemes, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed.
  • one aspect of the invention provides a method of treating a disease or condition responsive to GPR84 agonism.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disease or condition.
  • the compound is a compound of Formula Ia, Ib, Ic or defined by one of the embodiments described above. Further description of exemplary diseases or conditions responsive to GPR84 agonism is provided herein below.
  • Another aspect of the invention provides a method of agonizing the activity of GPR84.
  • the method comprises contacting a GPR84 with an effective amount of a compound described herein, such as a compound of Formula I, to agonize the activity of said GPR84.
  • the compound is a compound of Formula Ia, Ib, Ic or defined by one of the embodiments described above.
  • Exemplary Diseases or Conditions Responsive to GPR84 Agonism [0105]
  • the disease or condition responsive to GPR84 agonism is an infectious disease or condition, a neurological or neurodegenerative disease or condition, or cancer.
  • the disease or condition responsive to GPR84 agonism is cancer.
  • the cancer is a solid tumor.
  • the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, or a neuroendocrine cancer.
  • the cancer is a solid tumor.
  • the cancer is a sarcoma or carcinoma.
  • the cancer is prostate cancer, breast cancer, lung cancer, liver cancer, bladder cancer, urinary tract cancer, or eye cancer.
  • the cancer is prostate cancer.
  • the cancer is breast cancer.
  • the cancer is lung cancer.
  • the cancer is liver cancer.
  • the cancer is bladder cancer.
  • the cancer is urinary tract cancer.
  • the cancer is eye cancer.
  • the cancer is a B-cell non-Hodgkin’s Lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), mature B- cell acute leukemia (B-AL), chronic lymphocytic leukemia (CLL), follicular lymphoma, multiple myeloma, head and neck cancer, colorectal cancer, a squamous cell carcinoma, HER2 overexpressing breast cancer, gastric junction adenocarcinoma, gastro-esophageal junction adenocarcinoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, urothelial cancer, renal cancer, giant cell bone cancer, bone metastasis, neuroblastoma, mycosis fungoides, or Sézary syndrome.
  • DLBCL diffuse large B-cell lymphoma
  • BL Burkitt lymphoma
  • BLL Burkitt-like
  • the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas (e.g., Burkitt’s lymphoma and Non- Hodgkin’s lymphoma); benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas,
  • the cancer is a neuroblastoma, craniopharyngioma, glioma, glioblastoma, schwannoma, astrocytoma, oligodendroglioma, medulloblastoma, pinealoma, hemangioblastoma, retinoblastoma, ependymoma, chordoma, meningioma, medullary carcinoma, small cell lung carcinoma, papillary adenocarcinoma, papillary carcinoma, mesothelioma, nasopharyngeal carcinoma, acoustic neuroma, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, melanoma, sweat gland carcinoma, sebaceous gland carcinoma, squamous cell carcinoma, basal cell carcinoma, bile duct and gallbladder cancers, liver cancer, he
  • the cancer is a hematological cancer. In certain embodiments, the cancer is lymphoma, leukemia, or myeloma. [0114] In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is Burkitt’s lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, non- Hodgkin’s lymphoma, lymphoid malignancies of T-cell or B-cell origin, peripheral T-cell lymphoma, adult T-cell leukemia-lymphoma, or Waldenström’s macroglobulinemia. [0115] In certain embodiments, the cancer is a leukemia.
  • DLBCL diffuse large B-cell lymphoma
  • follicular lymphoma non- Hodgkin’s lymphoma
  • non- Hodgkin non- Hodgkin
  • lymphoid malignancies of T-cell or B-cell origin peripheral T-cell lymphoma
  • the cancer is acute leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, myelogenous leukemia, B-cell leukemia, T-cell leukemia, acute myelogenous leukemia, acute T-cell leukemia, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, polycythemia vera, multiple myeloma, or erythroleukemia.
  • the cancer is a myelodysplastic and/or myeloproliferative syndrome. In certain embodiments, the cancer is a myelodysplastic syndrome.
  • the cancer is a myeloproliferative syndrome.
  • the cancer is a cancer or related myeloproliferative disorder selected from histiocytosis, essential thrombocythemia, myelofibrosis, heavy chain disease, and other malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus.
  • the cancer is a malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, epithelioid sarcoma, renal medullary carcinoma, pancreatic undifferentiated rhabdoid carcinoma, schwannoma, epithelioid malignant peripheral nerve sheath tumor, or diffuse intrinsic glioma.
  • the cancer is retinoblastoma multiforme, metastatic castration- resistant prostate cancer, prostate small cell neuroendocrine carcinoma, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, bladder cancer, or urinary tract cancer.
  • the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastom
  • the cancer is a neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, acute myeloblastic leukemia, acute myeloblastic leukemia with complex karyotype, Hodgkin’s lymphoma, non- Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B- Cell lymphoma, low grade follicular lymphoma
  • the cancer an ADCP-resistant cancer. In certain embodiments, the cancer comprises U266 cells. [0122] In certain embodiments, the cancer is a metastatic cancer. In certain embodiments, the cancer is a relapsed and/or refractory cancer.
  • the cancer is ovarian cancer, uterine cancer, gestational trophoblastic disease, endometrial cancer, cervical cancer, embryonal carcinoma, choriocarcinoma, prostate cancer (including hormone insensitive and castrate resistant prostate cancers), testicular tumors (including germ cell testicular cancer / seminoma), cystadenocarcinoma, breast cancer (including estrogen-receptor positive breast cancer), brain tumors (including neuroblastoma, craniopharyngioma, glioma, glioblastoma, schwannoma, astrocytoma, oligodendroglioma, medulloblastoma, and pinealoma), hemangioblastoma, retinoblastoma, ependymoma, chordoma, meningioma, medullary carcinoma, lung cancer (including small cell lung carcinoma, papillary adenocarcinomas, and papillary carcinoma
  • the disease or condition responsive to GPR84 agonism is an infectious disease or condition.
  • the infectious disease or condition is Human granulocytic anaplasmosis; brucellosis; melioidosis; pneumonia; bronchitis; meningitis; Q fever; ehrlichiosis; tularemia; Legionnaire’s disease; Listeriosis; tuberculosis; Rocky Mountain spotted fever; salmonellosis; HIV infection; or Helicobacter pylori infection.
  • the disease or condition responsive to GPR84 agonism is a neurodegenerative disease or condition.
  • the neurodegenerative disease or condition is a disease involving amyloid beta deposit formation or a disease of frontal neuronal degeneration.
  • the disease involving amyloid beta deposit formation is Alzheimer disease; multiple sclerosis; Huntington's disease; or Parkinson's disease.
  • the disease of frontal neuronal degeneration is frontotemporal dementia.
  • the disease or condition responsive to GPR84 agonism is selected from those listed in Table 2.
  • the disease or condition is septicemia.
  • the disease or condition is obesity.
  • the subject is a human. In certain embodiments, the subject is an adult human.
  • the subject is a pediatric human. In certain embodiments, the subject is a geriatric human.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease or condition described herein, such as cancer.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I or other compounds in Section I) for treating a disease or condition, such as cancer. III.
  • Combination Therapy [0133] Another aspect of the invention provides for combination therapy.
  • an alkoxypyridinyl or related compound described herein may be used in combination with an additional therapeutic agent to treat diseases or conditions, such as cancer.
  • a GPR84 agonist is used in combination with an additional therapeutic agent that binds to a target selected from CCR4, CD19, CD20, CD22, CD30, CD33, CD38, CD47, CD52, CD79b, Claudin 18.2, CTLA-4, EGFR, FGFR2, GD2, HER2, LAG3, MET, Nectin-4, PDGFRa, PD-L1, RANKL, SLAMF7, TF, TROP2, VEGF, VEGFR, VEGFR2, or epidermal growth factor receptor with exon 20 insertion mutations, to treat a disease or condition, such as cancer.
  • the present invention provides a method of treating a disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • One or more additional therapeutic agents may be administered separately from a first compound or composition, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a first compound in a single composition.
  • one or more other therapeutic agent and first compound may be administered simultaneously, sequentially or within a period of time from one another.
  • the compounds of the disclosure can be administered with one or more of a second therapeutic agent, sequentially or concurrently, either by the same route or by different routes of administration. When administered sequentially, the time between administrations is selected to benefit, among others, the therapeutic efficacy and/or safety of the combination treatment.
  • the compound of the disclosure can be administered first followed by a second therapeutic agent, or alternatively, the second therapeutic agent administered first followed by the compound of the disclosure.
  • the compound of the disclosure can be administered for the same duration as the second therapeutic agent, or alternatively, for a longer or shorter duration as the second therapeutic compound.
  • the compounds of the disclosure can be administered separately at the same time as the second therapeutic agent, by the same or different routes, or administered in a single composition by the same route.
  • the compound of the disclosure is prepared as a first pharmaceutical composition, and the second therapeutic agent prepared as a second pharmaceutical composition, where the first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously, sequentially, or separately.
  • the amount and frequency of administration of the second therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent.
  • One aspect of the invention provides a method for treating a disease or condition responsive to GPR84 agonism, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of (i) a compound described herein (e.g., a compound of Formula I or other compound in Section 1) and (ii) an additional therapeutic agent, to treat the disease or condition.
  • a compound described herein e.g., a compound of Formula I or other compound in Section 1
  • an additional therapeutic agent to treat the disease or condition.
  • Another aspect of the invention provides a method for treating a disease or condition responsive to GPR84 agonism, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of (i) a GPR84 agonist and (ii) an additional therapeutic agent that binds to a target selected from CCR4, CD19, CD20, CD22, CD30, CD33, CD38, CD47, CD52, CD79b, Claudin 18.2, CTLA-4, EGFR, FGFR2, GD2, HER2, LAG3, MET, Nectin-4, PDGFRa, PD-L1, RANKL, SLAMF7, TF, TROP2, VEGF, VEGFR, VEGFR2, or epidermal growth factor receptor with exon 20 insertion mutations, to treat the disease or condition.
  • a GPR84 agonist binds to a target selected from CCR4, CD19, CD20, CD22, CD30, CD33, CD38, CD47, CD52, CD79b, Claudin 18.
  • the target is CCR4, CD19, CD20, CD22, CD30, CD33, CD38, CD47, CD52, or CD79b.
  • the target is Claudin 18.2 or CTLA-4.
  • the target is EGFR, FGFR2, or epidermal growth factor receptor with exon 20 insertion mutations.
  • the target is GD2, HER2, LAG3, MET, Nectin-4, PDGFRa, or PD-L1.
  • the target is RANKL, SLAMF7, TF, or TROP2.
  • the target is VEGF or VEGFR.
  • the target is CCR4.
  • the target is CD19.
  • the target is CD20. In certain embodiments, the target is CD22. In certain embodiments, the target is CD30. In certain embodiments, the target is CD33. In certain embodiments, the target is CD38. In certain embodiments, the target is CD47. In certain embodiments, the target is CD52. In certain embodiments, the target is CD79b. In certain embodiments, the target is Claudin 18.2. In certain embodiments, the target is CTLA-4. In certain embodiments, the target is EGFR. In certain embodiments, the target is FGFR2. In certain embodiments, the target is GD2. In certain embodiments, the target is HER2. In certain embodiments, the target is LAG3. In certain embodiments, the target is MET.
  • the target is Nectin-4. In certain embodiments, the target is PDGFRa. In certain embodiments, the target is PD-L1. In certain embodiments, the target is RANKL. In certain embodiments, the target is SLAMF7. In certain embodiments, the target is TF. In certain embodiments, the target is TROP2. In certain embodiments, the target is VEGF. In certain embodiments, the target is VEGFR. In certain embodiments, the target is VEGFR2. In certain embodiments, the target is epidermal growth factor receptor with exon 20 insertion mutations. [0140] In certain embodiments, the additional therapeutic agent is an inhibitor. In certain embodiments, the additional therapeutic agent is an agonist.
  • the additional therapeutic agent is an antibody.
  • the additional therapeutic agent is Alemtuzumab, Amivantamab-vmjw (Amivantamab), Avelumab, Bemarituzumab, Bevacizumab, Cetuximab, Cosibelimab, Daratumumab, Denosumab, Dinutiximab, Elotuzumab, Ibritumomab tiuxetan, Isatuximab-irfc (Isatuximab), Magrolizumab, Margetuximab-cmkb (Margetuximab), Mogamulizumab-kpkc (Mogamulizumab), Naxitamab-gqgk (Naxitamab), Necitumumab, Obinutuzumab, Ofatumumab, Olaratumab, Panitumumab, Pertuzumab
  • the additional therapeutic agent is Alemtuzumab, Amivantamab-vmjw, Avelumab, Bemarituzumab, Bevacizumab, Cetuximab, Cosibelimab, Daratumumab, Denosumab, Dinutiximab, Elotuzumab, Ibritumomab tiuxetan, Isatuximab-irfc, Magrolizumab, Margetuximab- cmkb, Mogamulizumab-kpkc, Naxitamab-gqgk, Necitumumab, Obinutuzumab, Ofatumumab, Olaratumab, Panitumumab, Pertuzumab, Ramucirumab, Rituximab, Tafasitamab-cxix, Trastuzumab, TTI-622, evorpacept, a SIRP ⁇ Fc
  • the additional therapeutic agent is an antibody-drug-conjugate.
  • the additional therapeutic agent is Brentuximab vedotin, Enfortumab vedotin, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Inotuzumab ozogamicin, Loncastuximab tesirine, Moxetumomab pasudotox, Polatuzumab vedotin, Sacituzumab govitecan, Tisotumab vedotin, Trastuzumab deruxtecan, or Trastuzumab emtansine.
  • the additional therapeutic agent is a SIRP ⁇ Fc fusion protein (such as described in U.S. Patent No. 10,906,954, which is herein incorporated by reference in its entirety).
  • the additional agent is a fusion of a CD47-binding domain of human SIRP ⁇ linked to the Fc region of human IgG 4 .
  • the additional therapeutic agent is Alemtuzumab.
  • the additional therapeutic agent is Amivantamab-vmjw.
  • the additional therapeutic agent is Avelumab.
  • the additional therapeutic agent is Bemarituzumab.
  • the additional therapeutic agent is Bevacizumab.
  • the additional therapeutic agent is Cetuximab. In certain embodiments, the additional therapeutic agent is Cosibelimab. In certain embodiments, the additional therapeutic agent is Daratumumab. In certain embodiments, the additional therapeutic agent is Denosumab. In certain embodiments, the additional therapeutic agent is Dinutiximab. In certain embodiments, the additional therapeutic agent is Elotuzumab. In certain embodiments, the additional therapeutic agent is Ibritumomab tiuxetan. In certain embodiments, the additional therapeutic agent is Isatuximab-irfc. In certain embodiments, the additional therapeutic agent is Magrolizumab. In certain embodiments, the additional therapeutic agent is Margetuximab-cmkb.
  • the additional therapeutic agent is Mogamulizumab-kpkc. In certain embodiments, the additional therapeutic agent is Naxitamab-gqgk. In certain embodiments, the additional therapeutic agent is Necitumumab. In certain embodiments, the additional therapeutic agent is Obinutuzumab. In certain embodiments, the additional therapeutic agent is Ofatumumab. In certain embodiments, the additional therapeutic agent is Olaratumab. In certain embodiments, the additional therapeutic agent is Panitumumab. In certain embodiments, the additional therapeutic agent is Pertuzumab. In certain embodiments, the additional therapeutic agent is Ramucirumab. In certain embodiments, the additional therapeutic agent is Rituximab.
  • the additional therapeutic agent is Tafasitamab-cxix. In certain embodiments, the additional therapeutic agent is Trastuzumab. In certain embodiments, the additional therapeutic agent is TTI- 622. In certain embodiments, the additional therapeutic agent is evorpacept. In certain embodiments, the additional therapeutic agent is a SIRP ⁇ Fc fusion proteins. In certain embodiments, the additional therapeutic agent is Zolbetuximab. In certain embodiments, the additional therapeutic agent is an antibody-drug-conjugate.
  • the additional therapeutic agent is Brentuximab vedotin, Enfortumab vedotin, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Inotuzumab ozogamicin, Loncastuximab tesirine, Moxetumomab pasudotox, Polatuzumab vedotin, Sacituzumab govitecan, Tisotumab vedotin, Trastuzumab deruxtecan, or Trastuzumab emtansine.
  • the additional therapeutic agent is Brentuximab vedotin. In certain embodiments, the additional therapeutic agent is Enfortumab vedotin. In certain embodiments, the additional therapeutic agent is Gemtuzumab ozogamicin. In certain embodiments, the additional therapeutic agent is Ibritumomab tiuxetan. In certain embodiments, the additional therapeutic agent is Inotuzumab ozogamicin. In certain embodiments, the additional therapeutic agent is Loncastuximab tesirine. In certain embodiments, the additional therapeutic agent is Moxetumomab pasudotox. In certain embodiments, the additional therapeutic agent is Polatuzumab vedotin.
  • the CAR-T therapy is idecabtagene vicleucel or lisocabtagene maraleucel.
  • the CAR-T therapy is idecabtagene vicleucel, and the disease or condition is multiple myeloma, such as a relapsed or refractory multiple myeloma (RR-MM) after four or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
  • RR-MM refractory multiple myeloma
  • the CAR-T therapy is lisocabtagene maraleucel
  • the disease or condition is a large B-cell lymphoma, such as a relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.
  • the methods may be further characterized according to the identity of the disease or condition to be treated.
  • the disease or condition is cancer.
  • the cancer is a solid tumor.
  • the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.
  • the cancer is a B-cell non-Hodgkin’s Lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), mature B-cell acute leukemia (B-AL), chronic lymphocytic leukemia (CLL), follicular lymphoma, multiple myeloma, head and neck cancer, colorectal cancer, a squamous cell carcinoma, HER2 overexpressing breast cancer, gastric junction adenocarcinoma, gastro-esophageal junction adenocarcinoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, urothelial cancer, renal cancer, giant cell bone cancer, bone metastasis, neuroblastoma, mycosis fungoides, or Sézary syndrome.
  • DLBCL diffuse large B-cell lymphoma
  • BL Burkitt lymphoma
  • BLL Burkitt-like
  • the disease or condition is an autoimmune and/or inflammatory disorder. In certain embodiments, the disease or condition is rheumatoid arthritis.
  • the method is further characterized according to the identity of both the additional therapeutic agent used (e.g., the inhibitor of a protein) and the disease or condition to be treated. Exemplary combinations of additional therapeutic agent used (e.g., the inhibitor of a protein) and the disease or condition to be treated are set forth in Table 2 below. TABLE 2.
  • the additional therapeutic agent is a combination of two, three, or four therapeutic agents or treatments. In certain embodiments, the additional therapeutic agent is a combination of two therapeutic agents or treatments.
  • the additional therapeutic agent is a combination of three therapeutic agents or treatments. In certain embodiments, the additional therapeutic agent is a combination of four therapeutic agents or treatments. In certain embodiments, the treatment is radiation therapy. [0149] In certain embodiments, the additional therapeutic agent is Rituximabin in combination with CHOP. In certain embodiments, the additional therapeutic agent is Rituximab in combination with CVP. In certain embodiments, the additional therapeutic agent is Rituximab in combination with fludarabine and cyclophosphamide. In certain embodiments, the additional therapeutic agent is Rituximab in combination with BTKi. In certain embodiments, the additional therapeutic agent is Rituximab in combination with venetoclax.
  • the additional therapeutic agent is Rituximab in combination with CAR-T. In certain embodiments, the additional therapeutic agent is Rituximab in combination with venetoclast. In certain embodiments, the additional therapeutic agent is Rituximab in combination with Ibrutinib. In certain embodiments, the additional therapeutic agent is Rituximab in combination with acalabrutinib. In certain embodiments, the additional therapeutic agent is Rituximab in combination with zanubrutinib. In certain embodiments, the additional therapeutic agent is Rituximab in combination with tirabrutinib. In certain embodiments, the additional therapeutic agent is Rituximab in combination with orelabrutinib.
  • the additional therapeutic agent is Rituximab in combination with idelalisib. In certain embodiments, the additional therapeutic agent is Rituximab in combination with autologous stem cell transplantation (ASCT). In certain embodiments, the additional therapeutic agent is Rituximab in combination with Copanlisib. In certain embodiments, the additional therapeutic agent is Rituximab in combination with Tazemetostat. In certain embodiments, the additional therapeutic agent is Rituximab in combination with Axicabtagene ciloleucel. In certain embodiments, the additional therapeutic agent is Rituximab in combination with Tisagenlecleucel.
  • ASCT autologous stem cell transplantation
  • the additional therapeutic agent is Rituximab in combination with Copanlisib. In certain embodiments, the additional therapeutic agent is Rituximab in combination with Tazemetostat. In certain embodiments, the additional therapeutic agent is Rituximab in combination with Axicabtagene ciloleucel. In certain embodiments, the additional therapeutic agent
  • the additional therapeutic agent is Rituximab in combination with Mosunetuzumab- axgb. In certain embodiments, the additional therapeutic agent is Rituximab in combination with Lisocabtagene maraleucel. In certain embodiments, the additional therapeutic agent is Rituximab in combination with Polatuzumab vedotin-piiq. [0151] In certain embodiments, the additional therapeutic agent is Obinutuzumab in combination with chlorambucil. In certain embodiments, the additional therapeutic agent is Obinutuzumab in combination with acalabrutinib. In certain embodiments, the additional therapeutic agent is Obinutuzumab in combination with Venetoclax.
  • the additional therapeutic agent is Obinutuzumab in combination with ibrutinib. In certain embodiments, the additional therapeutic agent is Obinutuzumab in combination with bendamustine. [0152] In certain embodiments, the additional therapeutic agent is Tafasitamab-cxix in combination with Lenalidomide. [0153] In certain embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib, melphalan and prednisone (VMP). In certain embodiments, the additional therapeutic agent is Daratumumab in combination with lenalidomide and dexamethasone.
  • the additional therapeutic agent is Daratumumab in combination with bortezomib, thalidomide, and dexamethasone. In certain embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib and dexamethasone. In certain embodiments, the additional therapeutic agent is Daratumumab in combination with pomalidomide and dexamethasone. In certain embodiments, the additional therapeutic agent is Daratumumab in combination with carfilzomib and dexamethasone. In certain embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone.
  • the additional therapeutic agent is Daratumumab in combination with Elotuzumab, lenalidomide, dexamethasone, and Bortezomib. In certain embodiments, the additional therapeutic agent is Daratumumab in combination with bendamustine, dexamethasone, and either carfilzomib or bortezomib. In certain embodiments, the additional therapeutic agent is Daratumumab in combination with Idecabtagene autoleucel. In certain embodiments, the additional therapeutic agent is Daratumumab in combination with Ciltacabtagene autoleucel.
  • the additional therapeutic agent is Daratumumab in combination with Teclistamab-cqyv.
  • the additional therapeutic agent is Isatuximab-irfc in combination with carfilzomib and dexamethasone.
  • the additional therapeutic agent is Isatuximab-irfc in combination with pomalidomide and dexamethasone.
  • the additional therapeutic agent is Isatuximab-irfc in combination with bendamustine, dexamethasone, and either carfilzomib or bortezomib.
  • the additional therapeutic agent is Isatuximab-irfc in combination with Idecabtagene autoleucel. In certain embodiments, the additional therapeutic agent is Isatuximab- irfc in combination with Ciltacabtagene autoleucel. In certain embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with Teclistamab-cqyv. [0157] In certain embodiments, the additional therapeutic agent is Elotuzumab in combination with lenalidomide and dexamethasone. In certain embodiments, the additional therapeutic agent is Elotuzumab in combination with pomalidomide and dexamethasone.
  • the additional therapeutic agent is Elotuzumab in combination with bendamustine, dexamethasone, and either carfilzomib or bortezomib. In certain embodiments, the additional therapeutic agent is Elotuzumab in combination with Idecabtagene autoleucel. In certain embodiments, the additional therapeutic agent is Elotuzumab in combination with Ciltacabtagene autoleucel. In certain embodiments, the additional therapeutic agent is Elotuzumab in combination with Teclistamab-cqyv. [0159] In certain embodiments, the additional therapeutic agent is Cetuximab in combination with radiation therapy.
  • the additional therapeutic agent is Cetuximab in combination with platinum-based therapy with fluorouracil. In certain embodiments, the additional therapeutic agent is Cetuximab in combination with FOLFIRI. In certain embodiments, the additional therapeutic agent is Cetuximab in combination with irinotecan. [0160] In certain embodiments, the additional therapeutic agent is Cetuximab in combination with Regorafenib. In certain embodiments, the additional therapeutic agent is Cetuximab in combination with trifluridine and tipiracil. In certain embodiments, the additional therapeutic agent is Cetuximab in combination with trifluridine, tipiracil, and bevacizumab.
  • the additional therapeutic agent is Cetuximab in combination with a Her2 inhibitor. In certain embodiments, the additional therapeutic agent is Cetuximab in combination with a BrafV600E inhibitor. [0161] In certain embodiments, the additional therapeutic agent is Panitumumab in combination with FOLFOX. [0162] In certain embodiments, the additional therapeutic agent is Panitumumab in combination with Regorafenib. In certain embodiments, the additional therapeutic agent is Panitumumab in combination with trifluridine and tipiracil. In certain embodiments, the additional therapeutic agent is Panitumumab in combination with trifluridine, tipiracil, and bevacizumab.
  • the additional therapeutic agent is Panitumumab in combination with a Her2 inhibitor. In certain embodiments, the additional therapeutic agent is Panitumumab in combination with a BrafV600E inhibitor. [0163] In certain embodiments, the additional therapeutic agent is Necitumumab in combination with gemcitabine and cisplatin. [0164] In certain embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Nivo. In certain embodiments, the additional therapeutic agent is Amivantamab- vmjw in combination with Pembro. In certain embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Atezo.
  • the additional therapeutic agent is Amivantamab-vmjw in combination with Docetaxel. In certain embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Gemcitabine. [0165] In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with docetaxel and carboplatin. In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with paclitaxel.
  • the additional therapeutic agent is Trastuzumab in combination with cisplatin and capecitabine. In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with 5-fluorouracil. [0166] In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with Fam-trastuzumab deruxtecan-nxki. In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with Sacituzumab govitecan. In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with systemic chemotherapy. In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with a biomarker guided Rx.
  • the additional therapeutic agent is Trastuzumab in combination with a Her2 inhibitor. In certain embodiments, the additional therapeutic agent is Trastuzumab in combination with a BrafV600E inhibitor. [0167] In certain embodiments, the additional therapeutic agent is Pertuzumab in combination with trastuzumab and docetaxel. In certain embodiments, the additional therapeutic agent is Pertuzumab in combination with trastuzumab and chemotherapy. [0168] In certain embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with chemotherapy. In certain embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with capecitabine.
  • the additional therapeutic agent is Margetuximab-cmkb in combination with capecitabine. In certain embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with eribulin. In certain embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with gemcitabine. In certain embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with vinorelbine. [0169] In certain embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with lapatinib. In certain embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with tucatinib.
  • the additional therapeutic agent is Margetuximab-cmkb in combination with neratinib. [0170] In certain embodiments, the additional therapeutic agent is Zolbetuximab in combination with mFOLFOX6. [0171] In certain embodiments, the additional therapeutic agent is Zolbetuximab in combination with Regorafenib and trifluridine. In certain embodiments, the additional therapeutic agent is Zolbetuximab in combination with Regorafenib and tipiracil. In certain embodiments, the additional therapeutic agent is Zolbetuximab in combination with Regorafenib, Bevacizumab, and trifluridine.
  • the additional therapeutic agent is Zolbetuximab in combination with Regorafenib, Bevacizumab and tipiracil.
  • the additional therapeutic agent is Ramucirumab in combination with paclitaxel.
  • the additional therapeutic agent is Ramucirumab in combination with erlotinib.
  • the additional therapeutic agent is Ramucirumab in combination with docetaxel.
  • the additional therapeutic agent is Ramucirumab in combination with FOLFIRI.
  • the additional therapeutic agent is Ramucirumab in combination with Osimertinob.
  • the additional therapeutic agent is Olaratumab in combination with doxorubicine.
  • the additional therapeutic agent is Avelumab.
  • the additional therapeutic agent is Magrolizumab.
  • the additional therapeutic agent is TTI-622.
  • the additional therapeutic agent is Bevacizumab.
  • the additional therapeutic agent is Denosumab.
  • the additional therapeutic agent is Dinutiximab in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13- cis-retinoic acid (RA).
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-2 interleukin-2
  • RA 13- cis-retinoic acid
  • the additional therapeutic agent is Naxitamab-gqgk in combination with granulocyte-macrophage colony-stimulating factor (GMCSF).
  • GMCSF granulocyte-macrophage colony-stimulating factor
  • GPR84 Agonist The methods may be further characterized according to the identity of the GPR84 agonist.
  • the GPR84 agonist is a compound described in Section 1 herein.
  • the GPR84 agonist may comprise: medium chain fatty acid capric acid, ZQ-16, (octylamino) pyrimidine-2,4(lH,3H)- dione (6-n-octylaminouracil), 6-OAU), DL- 175 (ACS Chem. Biol.
  • the GPR84 agonist comprises medium chain fatty acid capric acid.
  • the GPR84 agonist is selected from the group consisting of ZQ-16, (octylamino) pyrimidine-2,4(lH,3H)-dione (6-n- octylaminouracil, 6-OAU), or a combination thereof.
  • the GPR84 agonist is one of the following:
  • the additional therapeutic agent is a leukotriene inhibitor, non- steroidal anti-inflammatory drug (NSAID), steroid, tyrosine kinase inhibitor, receptor kinase inhibitor, modulator of nuclear receptor family of transcription factor, HSP90 inhibitor, adenosine receptor (A 2 A) agonist, disease modifying antirheumatic drugs (DMARDS), phosphodiesterase (PDE) inhibitor, neutrophil elastase inhibitor, modulator of Axl kinase, an anti-cancer agent, anti- allergic agent, anti-nausea agent (or anti-emetic), pain reliever, cytoprotective agent, or a combination thereof.
  • NSAID non- steroidal anti-inflammatory drug
  • steroid steroid
  • tyrosine kinase inhibitor inhibitor
  • receptor kinase inhibitor modulator of nuclear receptor family of transcription factor
  • HSP90 inhibitor adenosine receptor (A 2 A) agonist
  • DARDS disease modifying anti
  • the additional therapeutic agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof.
  • the additional therapeutic agent is a leukotriene inhibitor. Examples of leukotriene inhibitors considered for use in combination therapies of the invention include but are not limited to montelukast, zafirlukast, pranlukast, zileuton, or combinations thereof.
  • the additional therapeutic agent is a an NSAID.
  • NSAIDs considered for use in combination therapies of the invention include but are not limited to acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naioxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, or combinations thereof.
  • the additional therapeutic agent is a steroid.
  • steroids considered for use in combination therapies of the invention include but are not limited to prednisone, prednisolone, methylprednisone, triacmcinolone, betamethasone, dexamethasone, and prodrugs thereof.
  • the additional therapeutic agent is a tyrosine kinase inhibitor. Examples of tyrosine kinase inhibitors considered for use in combination therapies of the invention include but are not limited to inhibitors of the following kinases, including, among others: JAK, Syk, JNK/SAPK, MAPK, PI-3K, and/or Ripk2.
  • the tyrosine kinase inhibitor is ruxolitinib, tofacitinib, oclactinib, filgotinib, ganotinib, lestaurtinib, momelotinib, pacritinib, upadacitinib, peficitinib, fedratinib, bentamapimod, D-JNKI-1 (XG-102, AM-111), ponatinib, WEHI-345, OD36, GSK583, idelalisib, copanlisib, taselisib, duvelisib, alpelisib, umbralisib, dactolisib, CUDC-907, entospletinib, fostamatinib, or combinations thereof.
  • the additional therapeutic agent is a receptor kinase inhibitor, including among others, an inhibitor of EGFR or HER2.
  • receptor kinase inhibitors considered for use in combination therapies of the invention include but are not limited to gefitinib, erlotinib, neratinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib, trastuzumab, neratinib, lapatinib, pertuzumab, or combinations thereof.
  • the additional therapeutic agent is a modulator of nuclear receptor family of transcription factors, including, among others, an inhibitor of PPAR, RXR, FXR, or LXR.
  • the inhibitor is pioglitazone, bexarotene, obeticholic acid, ursodeoxycholic acid, fexaramine, hypocholamide, or combinations thereof.
  • the additional therapeutic agent is an HSP90 inhibitor.
  • HSP90 inhibitors considered for use in combination therapies of the invention include but are not limited to ganetespib, 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17- dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, or combinations thereof.
  • the additional therapeutic agent is an adenosine receptor 2A (A2A) agonist.
  • A2A adenosine receptor 2A
  • adenosine receptor agonists considered for use in combination therapies of the invention include but are not limited to those disclosed in U.S. Pat. No. 9,067,963, which is incorporated herein by reference.
  • the adenosine receptor agonist is LNC- 3050, LNC-3015, LNC-3047, LNC-3052, or combinations thereof.
  • the additional therapeutic agent is selected from disease modifying antirheumatic drugs (DMARDS). Examples of DMARDS considered for use in combination therapies of the invention include but are not limited to tocilizumab, certolizumab, etanercept, adalimumab, anakinra, abatacept, infliximab, rituximab, golimumab, uteskinumab, or combinations thereof.
  • the additional therapeutic agent is a phosphodiesterase (PDE) inhibitor.
  • Examples of phosphodiesterase inhibitor considered for use in combination therapies of the invention include but are not limited to apremilast, crisaborole, piclimilast, drotaverine, ibudulast, roflumilast, sildenafil, tadalafil, vardenafil, or combinations thereof.
  • the additional therapeutic agent is a neutrophil elastase inhibitor.
  • neutrophil elastase inhibitors considered for use in combination therapies of the invention include but are not limited to sivelestat.
  • the additional therapeutic agent is a modulator of Axl kinase.
  • modulators of Axl kinase considered for use in combination therapies of the invention include but are not limited to bemcentinib (BGB324 or R428), TP-0903, LY2801653, amuvatinib (MP-470), bosutinib (SKI-606), MGCD 265, ASP2215, cabozantinib (XL184), foretinib (GSK1363089/XL880), and SGI-7079.
  • the modulator of Axl kinase is a monoclonal antibody targeting AXL (e.g., YW327.6S2) or an AXL decoy receptor (e.g., GL2I.T), or glesatinib, merestinib, or a dual Flt3-Axl inhibitor such as gilteritinib.
  • the additional therapeutic agent is an anti-cancer agent or chemo- therapeutic agent.
  • anti-cancer agents considered for use in combination therapies of the invention include but are not limited erlotinib, bortezomib, fulvestrant, sunitib, imatinib mesylate, letrozole, finasunate, platins such as oxaliplatin, carboplatin, and cisplatin, finasunate, fluorouracil, rapamycin, leucovorin, lapatinib, lonafamib, sorafenib, gefitinib, camptothecin, topotecan, bryostatin, adezelesin, anthracyclin, carzelesin, bizelesin, dolastatin, auristatins, duocarmycin, eleutherobin, taxols such as paclitaxel or docetaxel, cyclophosphamide, doxorubicin, vincristine, prednisone or pred
  • the additional therapeutic agent is selected from anastrozole (ARIMIDEX®), bicalutamide (CASODEX®), bleomycin sulfate (BLENOXANE®), busulfan (MYLERAN®), busulfan injection (BUSULFEX®), capecitabine (XELODA®), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (PARAPLATIN®), carmustine (BiCNU®), chlorambucil (LEUKERAN®), cisplatin (PLATINOL®), cladribine (LEUSTATIN®), cyclophosphamide (CYTOXAN® or NEOSAR®), cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposome injection (DEPOCYT®), dacarbazine (DTIC- Dome®), dactinomycin (act
  • the additional therapeutic agent is capable of inhibiting BRAF, MEK, CDK4/6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof.
  • the compounds of the present invention are combined with another therapeutic agent selected from vemurafinib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, verinostat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719 or CLR457, or a combination thereof.
  • the additional therapeutic agent is selected based on the disease or condition that is being treated.
  • the additional therapeutic agent is selected from aldesleukin (e.g., PROLEUKIN®), dabrafenib (e.g., TAFINLAR®), dacarbazine, recombinant interferon alfa-2b (e.g., INTRON® A), ipilimumab, trametinib (e.g., MEKINIST®), peginterferon alfa-2b (e.g., PEGINTRON®, SYLATRONTM), vemurafenib (e.g., ZELBORAF®)), and ipilimumab (e.g., YERVOY®).
  • aldesleukin e.g., PROLEUKIN®
  • dabrafenib e.g., TAFINLAR®
  • dacarbazine recombinant interferon alfa-2b (e.
  • the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), carboplatin (PARAPLATIN®), cyclophosphamide (CYTOXAN®, NEOSAR®), cisplatin (PLATINOL®, PLATINOL-AQ®), doxorubicin hydrochloride liposome (DOXIL®, DOX-SL®, EVACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).
  • doxorubicin hydrochloride Adriamycin®
  • carboplatin PARAPLATIN®
  • CYTOXAN® cyclophosphamide
  • PLATINOL-AQ® cisplatin
  • DOXIL® DOX-SL®
  • EVACET® EVACET®
  • LIPODOX® gemcitabine hydrochloride
  • the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®).
  • the additional therapeutic agent is selected from fluorouracil (e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®), bevacizumab (AVASTIN®), irinotecan hydrochloride (CAMPTOSTAR®), capecitabine (XELODA®), cetuximab (ERBITUX®), oxaliplatin (ELOXATIN®), leucovorin calcium (WELLCOVORIN®), regorafenib (STIVARGA®), panitumumab (VECTIBIX®), and ziv-aflibercept (ZALTRAP®).
  • fluorouracil e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®
  • bevacizumab AVASTIN®
  • irinotecan hydrochloride CAMPTOSTAR®
  • capecitabine XELODA®
  • cetuximab ERBITUX®
  • the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), paclitaxel (TAXOL®), paclitaxel albumin-stabilized nanoparticle formulation (ABRAXANE®), afatinib dimaleate (GILOTRIF®), pemetrexed disodium (ALIMTA®), bevacizumab (AVASTIN®), carboplatin (PARAPLATIN®), cisplatin (PLATINOL®, PLATINOL-AQ®), crizotinib (XALKORI®), erlotinib hydrochloride (TARCEVA®), gefitinib (IRESSA®), and gemcitabine hydrochloride (GEMZAR®).
  • methotrexate LPF e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE
  • the other therapeutic agent may be selected from fluorouracil (ADRUCIL®), EFUDEX®, FLUOROPLEX®), erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®), and mitomycin or mitomycin C (MITOZYTREXTM, MUTAMYCIN®).
  • the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®) and topotecan hydrochloride (HYCAMTIN®).
  • the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), bleomycin (BLENOXANE®), cetuximab (ERBITUX®), cisplatin (PLATINOL®, PLATINOL-AQ®) and docetaxel (TAXOTERE®).
  • methotrexate LPF e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®
  • fluorouracil ADRUCIL®, EFUDEX®, FLUOROPLEX®
  • BLENOXANE® cetuximab
  • cisplatin PATINOL®, PLATINOL-AQ®
  • docetaxel TXOTER
  • the additional therapeutic agent is selected from bosutinib (BOSULIF®), cyclophosphamide (CYTOXAN®, NEOSAR®), cytarabine (CYTOSAR-U®, TARABINE PFS®), dasatinib (SPRYCEL®), imatinib mesylate (GLEEVEC®), ponatinib (ICLUSIG®), nilotinib (TASIGNA®) and omacetaxine mepesuccinate (SYNRIBO®).
  • anti- allergic agents may be administered to minimize the risk of an allergic reaction.
  • Suitable anti- allergic agents include corticosteroids, such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate; e.g., ALA-CORT®, hydrocortisone phosphate, Solu-CORTEF®, HYDROCORT Acetate® and LANACORT®), prednisolone (e.g., DELTA-Cortel®, ORAPRED®, PEDIAPRED® and PRELONE®), prednisone (e.g., DELTASONE®, LIQUID RED®, METICORTEN® and ORASONE®),
  • corticosteroids such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g.,
  • anti-emetics may be administered in preventing nausea (upper stomach) and vomiting.
  • Suitable anti-emetics include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®. dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof.
  • EMEND® aprepitant
  • ZOFRAN® ondansetron
  • KYTRIL® granisetron HCl
  • lorazepam ATIVAN®.
  • DECADRON® dexamethasone
  • prochlorperazine COMPAZINE®
  • casopitant REZONIC® and Zunrisa®
  • Opioid analgesic drugs such as hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®) are also useful for moderate or severe pain.
  • hydrocodone/paracetamol or hydrocodone/acetaminophen e.g., VICODIN®
  • morphine e.g., ASTRAMORPH® or AVINZA®
  • oxycodone e.g., OXYCONTIN® or PERCOCET®
  • OPANA® oxymorphone hydrochloride
  • fentanyl e.g., DURAGESIC®
  • cytoprotective agents such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like
  • Suitable cytoprotective agents include amifostine (ETHYOL®), glutamine, dimesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
  • a compound of the present invention may be used in combination with known therapeutic processes, for example, with the administration of hormones or in radiation therapy.
  • a compound of the present invention may be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
  • the compound described herein e.g., a compound of Formula I or other compounds in Section I
  • the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disease or condition.
  • the compound described herein (e.g., a compound of Formula I or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disease or condition.
  • the compound described herein (e.g., a compound of Formula I or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
  • the compound described herein (e.g., a compound of Formula I or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • Another aspect of this invention is a kit comprising a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.
  • the kit further comprises instructions, such as instructions for treating a disease described herein. IV.
  • compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier.
  • therapeutically effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mann
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical- formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. [0238] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend upon the factors described above.
  • the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • the invention further provides a unit dosage form (such as a tablet or capsule) comprising a imidazopyrimidine compound or related compound described herein in a therapeutically effective amount for the treatment of a disease or condition described herein. IV.
  • kits comprising, for example, (i) a compound described herein, and (ii) instructions for use according to a method described herein.
  • EXAMPLES [0253] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the invention. [0254] The following abbreviations are used herein: Analytical Instrumentation and Purification [0255] NMR Instrument Details: Bruker Avance III HD 300MHz or 400MHz. [0256] LCMS Instrument Details: Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and ELS detectors. Softa model 400.
  • EXAMPLE 1 Synthesis of 6-(octyloxy)pyridine-2,4-diol (I-1) Step 1. Synthesis of (2-chloro-6-methoxypyridin-4-yl)methanol (1.1) [0257] Into a 250 mL 3-necked round-bottom flask were added methyl 2-chloro-6- methoxypyridine-4-carboxylate (10.0 g, 49.6 mmol, 1.00 equiv) and THF (100 mL) at room temperature. To the above mixture was added LiAlH 4 (1.41 g, 37.2 mmol, 0.75 equiv) in portions over 10 min at 0 °C.
  • Step 2 Synthesis of 2,4-bis((4-methoxybenzyl)oxy)-6-(octyloxy)pyridine (4.2) [0266] To a solution of octanol (203 mg, 1.56 mmol, 2.00 equiv) in DMA (3 mL) was added sodium hydride (28.0 mg, 1.17 mmol, 1.50 equiv, 60% in oil) at 0 o C. The mixture was stirred for 15 min. To the above solution was added 2-chloro-4,6-bis((4-methoxybenzyl)oxy)pyridine (4.1; 300 mg, 0.778 mmol, 1.00 equiv), and the mixture was warmed to 100 o C and stirred for 2 h.
  • the crude product was purified by Prep-HPLC with the following conditions: column: Sunfire Prep C18 OBD, 19*150mm, 5 ⁇ m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 30 mL/min; gradient: 30% to 65 % B in 8 min; wavelength: 254nm/220nm.
  • iodononane (11.0 g, 43.3 mmol, 1.00 equiv) dropwise over 10 min at 0 °C.
  • the resulting mixture was stirred for an additional 2 h at room temperature.
  • the reaction was quenched by the addition of sat. NH4Cl (aq.) (100 mL) at room temperature.
  • the resulting mixture was extracted with EtOAc (2x100 mL).
  • the combined organic layers were washed with brine (2x100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Chiral-Prep-HPLC with the following conditions: column, SunFire Prep C18 OBD, 19*150 mm, 5um; mobile phase: water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 . H 2 O) and ACN (12% ACN up to 24% in 7 min); detector: UV 220 nm, to afford 2-(difluoromethyl)-6-nonylpyridin-4-ol (I-7; 15 mg, 26%) as a white solid.
  • the crude product was purified by Prep-HPLC with the following conditions: column: XBridge Prep OBD C18, 30*150 mm, 5 ⁇ m; mobile phase A: water (0.05%NH 3 .H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 45% B in 10 min; wavelength: 254nm/220nm.
  • mobile phase A water (0.05%NH 3 .H 2 O)
  • mobile phase B ACN
  • flow rate 60 mL/min
  • gradient 15% B to 45% B in 10 min
  • wavelength 254nm/220nm.
  • the crude product (50.0 mg) was purified by Prep-HPLC with the following conditions: column, SunFire Prep C18 OBD, 19*150 mm, 5 um; mobile phase, water (10 mmol/L NH4HCO3+0.1%NH 3 . .H 2 O) and ACN (12% ACN up to 24% in 6 min); detector: UV 220 nm) to afford 6-(3-(2-ethoxyethoxy)propyl)pyridine-2,4-diol (I-14; 4.00 mg, 12.5%) as a white solid.
  • EXAMPLE 15 cAMP reporter assay
  • Exemplary compounds were evaluated for activity in an cAMP assay. Experimental procedures and results are provided below. Part I - Experimental Procedure [0303] Protocol 1: Intracellular cAMP levels were measured using the DiscoverX HitHunter® Assay at Eurofins DiscoverX Corp. in Fremont, CA. Briefly, CHO-K1 cells stably expressing the human GPR84 cells were incubated with sample in the presence of EC80 forskolin [25 ⁇ M] to induce a response. Media was aspirated from cells and replaced with 15 ⁇ L 2:1 HBSS/10mM Hepes: cAMP XS+ Ab reagent.
  • Protocol 2 Culture Flp-In-293-human GPR84 cells in Dulbecco’s Modified Eagle’s Medium (DMEM) high glucose containing 10% fetal bovine serum, 2mM GlutaMAX, 1% penicillin-streptomycin and 200 ⁇ g/ml hygromycin B at 37°C, 5% CO2 incubator. On the day of experiment, perform a 3-fold serial dilution of compounds in DMSO to obtain 10 concentration gradients.
  • DMEM Modified Eagle’s Medium
  • EXAMPLE 16 GPR84 Agonist Enhancement of TTI-622-Induced ADCP of A375 Melanoma Cells [0306]
  • This Example describes coculture assays using J774A.1 mouse macrophages and A375 melanoma cells to measure antibody-dependent cellular phagocytosis (ADCP) induced by TTI- 622. Experimental procedures and results are provided below.
  • J774A.1 mouse macrophages (ATCC TIB-67) cultured in complete HI-DMEM media (containing 10% heat-inactivated (HI) FBS, GlutaMAX, 100 units/ml penicillin, 100 ⁇ g/ml streptomycin) were plated in assay plates at 10,000 cells/well in 40 ⁇ l HI-DMEM + 100ng/ml LPS media.
  • HI-DMEM media containing 10% heat-inactivated (HI) FBS, GlutaMAX, 100 units/ml penicillin, 100 ⁇ g/ml streptomycin
  • A375 melanoma cells (ATCC CRL- 1619) cultured in complete RPMI media (containing 10% HI FBS, GlutaMAX, 100 units/ml penicillin, 100 ⁇ g/ml streptomycin) were harvested, counted, and stained with pHrodo-Red-SE dye for 20 minutes. After labeling, the tumor cells were washed and resuspended in 1 ml PBS per 10 6 cells in 0.4% DMSO.
  • Tumor cells were then opsonized with 5 ⁇ g/ml TTI-622 fusion protein (human SIRP ⁇ CD47-binding domain fused to IgG4 Fc, produced in-house) without and with I-4 at 50 nM, 16.5 nM, 5.5 nM, 1.85 nM, 0.6 nM, or 0.2 nM or with 5 ⁇ g/ml human IgG4 isotype control (IchorBio #ICH 2 257) alone in each experiment, for 30 minutes at 37°C.
  • TTI-622 fusion protein human SIRP ⁇ CD47-binding domain fused to IgG4 Fc, produced in-house
  • FIG.2A Selected data from FIG. 2A (hIgG4 control, TTI-622 fusion protein alone, and the highest-activity condition, TTI-622 fusion protein with 0.37 nM I-4) are shown in FIG. 2B, with statistical significance indicated (using unpaired t-test, p ⁇ 0.05 (*)).
  • GPR84 Agonist Enhancement of ADCP of Various Cancer Cells Induced by Various Agents may be evaluated using an assay based on that described in Example 16, except that the ADCP- inducing agent, the cancer cell line, the IgG isotype control, and the coculture E:T ratio may be, for example, as set forth in Table 4, and the final coculture concentration of the ADCP-inducing agent may be, for example, 0.1, 1, or 10 ⁇ g/ml.. TABLE 4.
  • Exemplary agents that may be evaluated for GPR84 agonist enhancement of ADCP of various cancer cells include any of compounds I-1 through I-25, a medium chain fatty acid capric acid, ZQ-16; (octylamino) pyrimidine-2,4(lH,3H)-dione (6-n-octylaminouracil) (6-OAU); DL- 175; a diindolemethane derivative; a 2-alkylpyrimidine-4,6-diol; a 6-alkylpyridine-2,4-diol; embelin; or another GPR84 agonist , e.g., another GPR84 agonist recited herein.
  • EXAMPLE 24 GPR84 Agonist Enhancement of ADCP of Various Cancer Cells Induced by Various Agents (Human Macrophage System) [0324] The GPR84 agonist enhancement of ADCP of various cancer cells induced by an agent may be evaluated using an assay based on that described in Example 16, except that human monocyte-derived macrophages may be used in place of J774A mouse macrophages.
  • CD14+ monocyctes from human donor samples may be cultured in complete HI-RPMI media (containing 10% heat-inactivated (HI) FBS, GlutaMAX, 100 units/ml penicillin, 100 ⁇ g/ml streptomycin) supplemented with 40ng/ml M-CSF for a period of 7 days. Data from the 4-hour timepoints may be processed and analyzed. EXAMPLE 25.
  • GPR84 Agonist Enhancement of Tumor Cell Depletion by ADCP induced by Various Agents may be evaluated using an assay based on that described in Example 16, except that macrophages may be plated at 30,000 cells/well in complete growth media the day prior to the coculture assay. Human macrophages may be derived as described in Example 24, and mouse macrophages may be treated as described in Example 16.
  • Tumor cell lines chosen from Table 3 may be additionally stained with CFSE (ThermoFisher #C34554, final concentration of 1uM) for 20 minutes at the time of labeling with pHrodo-Red-SE.
  • phagocytosis may be quantified as the %pHrodo-Red-SE positive of the CD11b-positive population.

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Abstract

L'invention concerne un alkoxypyridinyle et des composés apparentés, des compositions pharmaceutiques, leur utilisation pour l'agonisation du récepteur 84 couplé à la protéine G (GPR84), et leur utilisation dans le traitement d'une maladie ou d'une affection, telle qu'un cancer. L'invention concerne également une polythérapie utilisant un agoniste de GPR84 pour traiter une maladie ou une affection, telle qu'un cancer.
PCT/US2024/033492 2023-06-13 2024-06-12 Alcoxypyridinyle et composés apparentés et leur utilisation en thérapie Pending WO2024258897A1 (fr)

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