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WO2025194014A1 - Hetero aryl modulators of apmap and uses thereof - Google Patents

Hetero aryl modulators of apmap and uses thereof

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Publication number
WO2025194014A1
WO2025194014A1 PCT/US2025/019890 US2025019890W WO2025194014A1 WO 2025194014 A1 WO2025194014 A1 WO 2025194014A1 US 2025019890 W US2025019890 W US 2025019890W WO 2025194014 A1 WO2025194014 A1 WO 2025194014A1
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WO
WIPO (PCT)
Prior art keywords
cancer
disease
compound
optionally substituted
combination
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/019890
Other languages
French (fr)
Inventor
Jorge Garcia Fortanet
Gary Thomas ASMUSSEN
Jonathan Michael GOODWIN
Christophe QUÉVA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dem Biopharma Inc
Original Assignee
Dem Biopharma Inc
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Filing date
Publication date
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Publication of WO2025194014A1 publication Critical patent/WO2025194014A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Phagocytes are immune cells that play a critical role in both the early and late stages of immune responses. Their main role is to circulate and migrate through tissues to ingest and destroy microbes, abnormal cells, and cellular debris. Enhancing uptake by macrophages has been posited to engage the immunomodulatory potential of the myeloid compartment and more broadly stimulate a productive adaptive immune response.
  • Adipocyte plasma membrane associated protein is a paraoxonase-like enzyme that resides in the endoplasmic reticulum. See, for example, Albrektsen, et al. Biochem J. (2001) vol. 359, 393-402. APMAP has been identified as a cancer-intrinsic anti-phagocytic factor. See, for example, Mosser etal. Hum. Mol. Genet. (2015) vol. 24, 371-82 and Kamber et al. Nature (2021) vol. 597, 549-554.
  • agents that are inhibitors of APMAP can be used to treat particular diseases, disorders, and conditions, such as cancer.
  • the present disclosure provides, among other things, new compounds and compositions that are useful as APMAP inhibitors and for treatment of diseases, disorders, and conditions responsive to APMAP inhibition.
  • the present disclosure provides a compound represented by
  • Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , A, B, X 1 , X 2 , X 3 , and Ring Y are as described in classes and subclasses here, both singly and in combination.
  • the present disclosure provides a compound represented by
  • the present disclosure provides a compound represented by
  • Formula II-2 or a pharmaceutically acceptable salt thereof, wherein X 1 and R 1 arc as described in classes and subclasses herein, both singly and in combination, and the carbon atom a is a chirally pure carbon atom.
  • the present disclosure provides a compound represented by
  • the present disclosure provides a compound represented by
  • Formula II-4 or a pharmaceutically acceptable salt thereof wherein X 1 and R 1 are as described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound represented by
  • the present disclosure provides a compound represented by Formula III-2:
  • the present disclosure provides a compound represented by
  • the present disclosure provides a compound represented by
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein, e.g., a compound of any of Formula I-III-5.
  • the present disclosure provides a method for treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any of Formula I-III-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutical [0016]
  • the present disclosure provides a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any of Formula I-III-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof.
  • the present dislcosure provides a method of inhibiting the activity of APMAP in a subject to treat a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any of Formula I-III-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., a compound of any of Formula I-III-5
  • a pharmaceutically acceptable salt thereof e.g., a compound of any of Formula I-III-5
  • the present disclosure provides a method for treating an autoimmune and/or inflammatory disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any of Formula I-III-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., a compound of any of Formula I-III-5
  • a pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable salt thereof
  • Fig. 1 is a bar chart showing the extent of rituximab-induced antibody-dependent cellular phagocytosis (ADCP) of Ramos lymphoma cells by J774A.1 mouse macrophages in a dose-response assay in the presence or absence of Compound 4 at the indicated concentrations.
  • Fig. 2 is a bar chart showing the extent of cetuximab-induced ADCP of MDA-MB-231 breast cancer cells by J774A.1 mouse macrophages in the presence or absence of Compound 4 at the indicated concentration.
  • ADCP antibody-dependent cellular phagocytosis
  • Fig. 3 is a bar chart showing the extent of TTI-622-induced ADCP of A375 melanoma cells by J774A.1 mouse macrophages in the presence or absence of Compound 4 at the indicated concentration.
  • Fig. 4 is a bar chart showing the extent of cetuximab-induced ADCP of A375 melanoma cells by J774A.1 mouse macrophages in the presence or absence of Compound 4 at the indicated concentration.
  • Fig. 5 is a bar chart showing the extent of rituximab-induced ADCP of Ramos lymphoma cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
  • Fig. 7 is a bar chart showing the extent of trastuzumab-induced ADCP of SKOV-3 ovarian cancer cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
  • Fig. 8 is a bar chart showing the extent of trastuzumab-induced ADCP of BT-474 breast cancer cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
  • Fig. 9 is a bar chart showing the extent of avelumab-induced ADCP of RKO colon carcinoma cells by primary human macrophages isolated from three individual donors in the presence or absence of Compound 4 at the indicated concentration.
  • Figs. 10A-10D are bar charts showing the trastuzumab-induced cytokine/chemokine concentrations of TNFa (Fig. 10A), IL-6 (Fig. 10B), IL- 10 (Fig. 10C), and IFNy (Fig. 10D) observed in coculture during ADCP of SK-BR-3 breast cancer cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
  • Figs. 12A-12D are bar charts showing the rituximab-induced cytokine/chemokine concentrations of IL-10 (Fig. 12A), IP-10 (Fig. 12B), MCP-1 (Fig. 12C), and MIP-la (Fig. 12D) observed in coculture during ADCP of Ramos lymphoma cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration, in the presence of B6H12 at the indicated concentration, or using modified APMAP-knockout (APMAP KO) Ramos lymphoma cells.
  • Fig. 13 is a bar chart showing the extent of tumor cell depletion following ADCP of Ramos lymphoma cells by J774A.1 mouse macrophages in the presence or absence of each of rituximab and Compound 4 at the indicated concentration.
  • the present disclosure provides, among other things, compounds, and compositions useful as modulators of adipocyte plasma membrane associated protein (APMAP).
  • APMAP adipocyte plasma membrane associated protein
  • the provided compounds and compositions are useful as inhibitors of APMAP.
  • the presently provided compounds and compositions are useful in the treatment of diseases, disorders, and conditions associated with APMAP, including, for example, cancer, and inflammatory diseases.
  • the present disclosure provides a compound represented by
  • R 1 , A, B, X 1 , X 2 , X 3 , and Ring Y are as described in classes and subclasses here, both singly and in combination.
  • structures depicted herein are meant to include all stereoisomeric (c.g., enantiomeric or diastcrcomcric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure.
  • stereoisomeric c.g., enantiomeric or diastcrcomcric
  • geometric or conformational isomeric forms of the structure e.g., the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure.
  • the term "approximately” or “about” may encompass a range of values that are within (i.e., ⁇ ) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.
  • Administering typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated.
  • agents that are, or is included in, a composition to a target site or a site to be treated.
  • routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human.
  • administration may be ocular, oral, parenteral, topical, etc.
  • administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc.
  • administration may be parenteral.
  • administration may be oral.
  • administration may be intravenous.
  • administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime- and-boost protocol.
  • a prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine).
  • a prime-and-boost protocol can result in an increased immune response in a patient.
  • agonist generally refers to an agent whose presence or level correlates with elevated level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level).
  • an agonist is one whose presence or level correlates with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known agonist, e.g., a positive control).
  • Aliphatic refers to 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 or more than one points of attachment to the rest of the molecule.
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., Ci-e).
  • aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., CM). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but arc not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups and hybrids thereof. A preferred aliphatic group is Ci-e alkyl.
  • Alkyl refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, CM, CI- 3, or C1-2).
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2- ethyl-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • Alkylene refers to a bivalent alkyl group.
  • “alkylene” is a bivalent straight or branched alkyl group
  • an "alkylene chain” is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent.
  • Suitable substituents include those described below for a substituted that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-mcmbcrcd ring. The substituents can be on the same or different atoms.
  • the suffix “-ene” or “-enyl” when appended to certain groups herein are intended to refer to a bifunctional moiety of said group. For example, “-ene” or “-enyl”, when appended to “cyclopropyl” becomes “cyclopropylene” or
  • alkenyl refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-1, or C2-3).
  • exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Antagonist- generally refers to an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level).
  • an antagonist is one whose presence or level correlates with a target level or activity that is comparable to or less than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known antagonist, e.g., a positive control).
  • an antagonist may be a direct antagonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an antagonist may be an indirect antagonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.
  • APMAP Inhibitor refers to an agent that is an inhibitor, as that term is defined herein, of Adipocyte plasma membrane associated protein. Inhibitory activity of APMAP inhibitors described herein can be reported by their half- maximal inhibitor concentration (IC50), which indicates the amount of agent needed to inhibit biological processes by half.
  • Example APMAP inhibitors include compounds and compositions described herein, such as a compound or a composition comprising a compound of any one of Formula I - HI-5.
  • Aryl refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., Ce-Cu), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl groups are hydrocarbons.
  • an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include
  • Bicyclic 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 hctcroatoms 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 “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:
  • Exemplary bridged bicyclics include:
  • Biological sample typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample is or comprises biological tissue or fluid.
  • a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc.
  • a biological sample is or comprises cells obtained from an individual.
  • obtained cells are or include cells from an individual from whom the sample is obtained.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
  • processing e.g., by removing one or more components of and/or by adding one or more agents to
  • a primary sample For example, filtering using a semi-permeable membrane.
  • Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
  • carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • carriers are or include one or more solid components.
  • Combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality (ies)).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
  • composition may be used to refer to a discrete physical entity that comprises one or more specified components.
  • a composition may be of any form - e.g., gas, gel, liquid, solid, etc.
  • Cycloaliphatic refers to a monocyclic C3-8 hydrocarbon or a bicyclic Ce-io hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.
  • Cycloalkyl- refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohcptyl.
  • Dosage form or unit dosage form Those skilled in the ail will appreciate that the term
  • dosage form may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject.
  • an active agent e.g., a therapeutic or diagnostic agent
  • each such unit contains a predetermined quantity of active agent.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).
  • Dosing regimen or therapeutic regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).
  • 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.
  • Excipient refers to a non -therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.
  • Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Halogen means F, Cl, Br, or I.
  • heteroaliphatic or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
  • nitrogen also includes a substituted nitrogen.
  • heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2- CH2-O-CH2-CH2-O-CH3, and the like.
  • Heteroaryl The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 147t-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroaryl and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6,
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l ,2-a]pyrimidinyl, imidazo[l ,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl.
  • 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 the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4//-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl.
  • Heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 6- to 10-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-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, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.
  • bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxo lyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl.
  • a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • a bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.
  • Inhibitor refers to an entity (e.g., an agent) whose presence correlates with decreased level or activity of a target.
  • an inhibitor may act directly (in which case it exerts its influence directly upon its target, for example by binding to the target); in some embodiments, an inhibitor may act indirectly (in which case it exerts its influence by interacting with and/or otherwise altering a regulator of the target, so that level and/or activity of the target is reduced). Inhibitory activity can be measured, for example, reported by half-maximal inhibitor concentration (ICso), which indicates the amount of agent needed to inhibit biological processes by half.
  • Example inhibitors include compounds and compositions described herein, such as a compound or a composition comprising a compound of any of Formula I to III-5.
  • modulator- refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein).
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator.
  • a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein.
  • a modulator is an agonist.
  • a modulator is an antagonist.
  • a modulator can be an inhibitor of a particular target, as those terms are defined herein.
  • Example modulators include compounds and compositions described herein, such as a compound or a composition comprising a compound of any of Formula I to III-5.
  • Partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions
  • composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: 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; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., 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. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • 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, pectinate
  • Substituted or optionally substituted As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “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. “Substituted” applies to one or more
  • -rR 1 hydrogens that arc cither explicit or implicit from the structure (c.g., refers to at least
  • 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 provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • Suitable monovalent substituents on a substitutable carbon atom of an “optionally s bstit ted” gro p are independentl halogen; (CH ) R°; (CH ) OR°; 0(CH ) R° O
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )O 2 R*, alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CIM aliphatic, - CH 2 Ph, -0(CH 2 )O iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: wherein each independent occurrence of R* is selected from hydrogen, Ci e aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently CM aliphatic, -CH2PI1, -0(CH2)o iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R', taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently CIM aliphatic, -CH2PI1, -0(CH2)o ⁇ iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Small molecule means a low molecular weight organic and/or inorganic compound.
  • a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size.
  • a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD.
  • the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D.
  • a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer.
  • a small molecule does not include a polymeric moiety.
  • a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide).
  • a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide).
  • a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc?). In some embodiments, a small molecule is not a lipid.
  • a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent).
  • a small molecule is biologically active.
  • a small molecule is detectable (e.g., comprises at least one detectable moiety).
  • a small molecule is a therapeutic agent.
  • small molecule compounds have structures that can exist in one or more stereoisomeric forms.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.
  • small molecule compounds have structures that can exist in one or more tautomeric forms.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.
  • small molecule compounds have structures that permit isotopic substitution (e.g., 2 H or 3 H for H; n C, 13 C or 14 C for 12 C; 13 N or 15 N for 14 N; 17 O or 18 O for 16 O; 36 C1 for 35 C1 or 37 C1; 18 F for 19 F; 131 II ffoorr 127 I; etc.).
  • such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.
  • reference to a particular small molecule compound may relate to a specific form of that compound.
  • a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
  • a small molecule compound is one that exists or is found in nature
  • that compound may be provided and/or utilized in accordance with the present disclosure in a form different from that in which it exists or is found in nature.
  • a reference preparation of interest e.g., in a primary sample from a source of interest such as a biological or environmental source
  • a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.
  • the symbol > zvvv refers to a point of attachment between two atoms. Additionally, or alternatively, the symbol ⁇ /vvu refers to a point of attachment ring in a spirocyclic manner.
  • Treat As used herein, the terms “treat, ” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • present disclosure provides, among other things compounds and compositions useful as APMAP modulators, and uses thereof in the treatment of certain diseases, disorders, and conditions, as described herein.
  • present disclosure provides, among other things, compounds, and compositions useful as APMAP inhibitors, and uses thereof in the treatment of certain diseases, disorders, and conditions, as described herein.
  • the present disclosure provides a compound represented by
  • X 1 is CR X or N
  • X 2 is C or N;
  • X 3 is CR X or N;
  • Ring ⁇ is optionally substituted 4- to 6-mcmbcrcd hctcroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; each R x is independently selected from the group consisting of hydrogen, halogen, -CN, -OR, optionally substituted Ci-Ce aliphatic, and optionally substituted C3-C7 cycloaliphatic,
  • A is -L'-A 1 -*, where * represents a point of attachment to B;
  • L 1 is a bond, -O-, -S-, -N(R)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 -, or optionally substituted Ci-Ce aliphatic;
  • a 1 is selected from the group consisting of -optionally substituted Ci-Ce aliphatic, optionally substituted -C3-C12 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cw aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
  • B is selected from the group consisting of a bond, optionally substituted -Ci-Ce aliphatic, optionally substituted -C3-C7 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
  • a compound of formula I is non-racemic.
  • Reference to a “non- racemic” compound is intended to refer to a compound where (R) and (S) enantiomers are not present in an equal amount.
  • the present disclosure provides a compound represented by
  • the present disclosure encompasses an insight that particular enantiomers, or molecules having a particular configuration at a particular carbon atom, are particularly active as inhibitors of APMAP, whereas the other enantiomer is less active.
  • Reference to a compound of Formula I not being a racemate means that the compound is not an unresolved mixture of R/S enantiomers. Accordingly, in some such embodiments, the racemate is intended reported scope. For example, when a compound that is referred to as not being a racemate means that the following compound is excluded: s
  • X 1 is N or CR X . In some embodiments, X 1 is N. In some embodiments, X 1 is CR X . In some embodiments, X 1 is CH.
  • X 2 is N or C. In some embodiments, X 2 is N. In some embodiments, X 2 is C.
  • X 3 is N or CR X . In some embodiments, X 3 is N. In some embodiments, X 3 is CR X . In some embodiments, X 3 is CH.
  • X 1 is N, X 2 is N, and X 3 is N.
  • X 1 is CR X , X 2 is N, and X 3 is N.
  • X 1 is N, X 2 is C, and X 3 is N.
  • X 1 is N, X 2 is N, and X 3 is CR X .
  • X 1 is CR X , X 2 is C, and X 3 is N.
  • X 1 is CR X , X 2 is N, and X 3 is CR X .
  • X 1 is N, X 2 is C, and X 3 is CR X .
  • X 1 is CR X , X 2 is C, and X 3 is CR X .
  • X 1 is CR X , X 2 is C, and X 3 is CR X .
  • X 1 is CR X , X 2 is C, and X 3 is CR X
  • Ring Y is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Ring Y is an optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Ring Y is 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with -(CH2)IMR°. In some embodiments, Ring Y is 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with R°, where R° is optionally substituted Ci-Ce aliphatic.
  • Ring Y is unsubstituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Ring Y is an optionally substituted 5-membered heteroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S. In some embodiments, Ring Y is: wherein
  • X 4 is O, S, N, NR X , or CR X , as valency permits;
  • X 5 is O, S, N, NR X , or CR X , as valency permits;
  • X 6 is O, S, N, NR X , or CR X , as valency permits.
  • X 4 is O, S, N, N(R X ), or C(R X ), as valency permits. A selection of a value for X 4 is made from the perspective of a person having ordinary skill in the art understanding which options are available that provide a stable compound.
  • X 4 is O.
  • X 4 is S.
  • X 4 is N.
  • X 4 is N(R X ).
  • X 4 is N(H).
  • X 4 is N(CI-C6 aliphatic).
  • X 4 is N(CHs).
  • X 4 is C(R X ).
  • X 4 is C(H).
  • X 4 is QCHa).
  • X 4 is N or C(R X ).
  • X 5 is O, S, N, N(R X ), or C(R X ), as valency permits.
  • a selection of a value for X 5 is made from the perspective of a person having ordinary skill in the art understanding which options arc available that provide a stable compound.
  • X 5 is O.
  • X 5 is S.
  • X 5 is N.
  • X 5 is N(R X ).
  • X 5 is N(H).
  • X 5 is N(Ci-Ce aliphatic).
  • X 5 is N(CH3).
  • X 5 is C(R X ).
  • X 5 is C(H).
  • X 5 is ClCHa).
  • X 5 is N or C(R X ).
  • X 6 is O, S, N, N(R X ), or C(R X ), as valency permits.
  • a selection of a value for X 6 is made from the perspective of a person having ordinary skill in the art understanding which options are available that provide a stable compound.
  • X 6 is O.
  • X 6 is S.
  • X 6 is N.
  • X 6 is N(R X ).
  • X 6 is N(H).
  • X 6 is N(CI-C6 aliphatic).
  • X 6 is N(CHj).
  • X 6 is C(R X ).
  • X 1 is N
  • X 2 is N
  • X 3 is CR X
  • X 4 is N
  • X 5 is N
  • X 6 is N
  • X 1 is CR X
  • X 2 is N
  • X 3 is CR X
  • X 4 is N
  • X 5 is N
  • X 6 is N
  • X 1 is N
  • X 2 is C
  • X 3 is CR X
  • X 4 is NR X
  • X 5 is N
  • X 6 is N
  • X 1 is N
  • X 2 is C
  • X 3 is CR X
  • X 4 is N
  • X 5 is NR X
  • X 6 is N
  • X 1 is N
  • X 2 is C
  • X 3 is CR X
  • X 4 is N
  • X 5 is NR X
  • X 6 is N
  • X 1 is N
  • X 2 is C
  • X 3
  • X 1 is N
  • X 2 is N
  • X 3 is CR X
  • X 4 is N
  • X 5 is N
  • X 6 is N
  • X 1 is N
  • X 2 is N
  • X 3 is CR X
  • X 4 is N
  • X 5 is N
  • X 6 is N
  • X 1 is N
  • X 2 is N
  • X 3 is CR X
  • X 4 is N
  • X 5 is N
  • X 6 is N
  • X 1 is CR X
  • X 2 is N
  • X 3 is CR X
  • X 4 is N
  • X 5 is N
  • X 6 is N.
  • R x is selected from the group consisting of hydrogen, halogen, -CN, -OR, optionally substituted C1-C6 aliphatic, and optionally substituted C3-C7 cycloaliphatic.
  • R x is hydrogen or optionally substituted Ci-Ce aliphatic.
  • R x is hydrogen.
  • R x is optionally substituted Ci-Ce aliphatic.
  • R x is methyl.
  • a moiety is
  • a moiety is
  • a moiety is
  • moiety A is -iJ-A 1 -*, where * represents a point of attachment to moiety B
  • L 1 is a bond, -O-, -S-, -N(R)-, -OC(O)-, C(O)O-, - C(O)N(R)-, -N(R)C(O)-, S(O)-, S(O)2-, or optionally substituted Ci-Ce aliphatic.
  • L 1 is a bond, -O-, or -N(R)-.
  • a 1 is selected from the group consisting of -optionally substituted Ci-Ce aliphatic, optionally substituted -C3-C12 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • a 1 is optionally substituted Ci- Ce aliphatic, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • a 1 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • L 1 is a bond
  • a 1 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • L 1 is -O- or -N(R)- and A 1 is Ci-Ce aliphatic.
  • moiety B when L 1 is a bond and A 1 is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, moiety B is connected to moiety A at a chiral carbon atom on moiety A.
  • the connection between moiety B and moiety A is chirally pure (e.g., is non-racemic).
  • the connection between moiety B and moiety A is in a single stereochemical configuration (e.g., is non-racemic, or has an absolute configuration of (R) or (S)).
  • a “chirally pure” carbon atom refers to a carbon atom that is chiral, non-racemic, and has an absolute stereochemical configuration that is either is in (R) or (S) stereochemical configuration.
  • the particular stereochemical configuration is the (S) enantiomer.
  • the particular stereochemical configuration is the (R) enantiomer.
  • the connection between moiety B and moiety A is in the (S) a chirally pure carbon atom on moiety A refers to a chirally pure connection between moiety A and R 1 .
  • a bond between moiety A and R 1 is either in the (S) or (R) stereochemical configuration. In some embodiments, when B is a bond, then a bond between moiety A and R 1 is in the (S) stereochemical configuration. In some embodiments, when B is a bond, then a bond between moiety A and R 1 is in the R stereochemical configuration.
  • reference to a “chirally pure” composition refers to a composition comprising greater than 50% and typically comprises at least about 60%, 70%, 80%, 90%, or even more of a compound that is in a particular stereochemical configuration.
  • chirally pure compositions comprise at least from about 90% to about 99% of a specified chiral compound. In some embodiments, chirally pure compositions comprise at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% of a specified chiral compound. In some embodiments, a chirally pure composition comprises a single enantiomer of a compound. In some embodiments, the particular stereochemical configuration is the (S) enantiomer. In some embodiments, the particular stereochemical configuration is the (R) enantiomer.
  • a composition described herein has an enantiomeric excess of an indicated enantiomer.
  • the chirally pure composition comprises a single enantiomer of a compound of Formula I in an enantiomeric excess of about 90% or greater. In some embodiments, the composition comprises a single enantiomer of a compound of Formula I in an enantiomeric excess of about 95% or greater. In some embodiments, the composition comprises a single enantiomer of a compound of Formula I in an enantiomeric excess of about 99% or greater. In some embodiments, the single enantiomer is the (S) enantiomer. In some embodiments, the single enantiomer is the (R) enantiomer.
  • a moiety is selected from the group consisting of:
  • a moiety is selected from the group consisting of:
  • a moiety is selected from the group consisting of:
  • a moiety is: wherein each R A is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two R A , together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl.
  • a moiety is: wherein each R A i ⁇ s as described in classes and subclasses here, both singly and in combination, and carbon atom a is chirally pure (e.g., is a single (S) or (R) enantiomer).
  • a moiety is: wherein R 1 is as described in classes and subclasses here, both singly and in combination.
  • a moiety is: wherein R 1 is as described in classes and subclasses here, both singly and in combination, and carbon atom a is chirally pure (e.g., is a single (S) or (R) enantiomer).
  • carbon atom a is in the (S) stereochemical configuration. In some embodiments, carbon atom a is in the (R) stereochemical configuration.
  • B is selected from the group consisting of a bond, optionally substituted -Ci-Ce aliphatic, optionally substituted -C3-C7 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • B is selected from the group consisting of a bond, optionally substituted -Ci-Ce aliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 hctcroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • B is a bond.
  • B is optionally substituted Ci-Ce aliphatic.
  • B is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • B is 5- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 1 is selected from the group consisting of hydrogen, halogen, CN, O(R), -N(R) 2 , -OC(O)(R), C(O)O(R), -C(O)N(R) 2 , -S(R), S(O)R, S(O) 2 R, - cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 1 is hydrogen, CN, O(R), -N(R)2, -OC(O)(R), C(O)O(R), -C(0)N(R)2, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 1 is optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 1 is wherein R 1a is optionally substituted -Ci-Ce aliphatic, C3-C7 cycloaliphatic, or 4- to 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 1 is optionally substituted Ce-Cio aryl.
  • R 1 is C(0)N(R)2.
  • X 1 is N or CR X ;
  • X 2 is C or N
  • X 3 is N or CR X ;
  • Ring ⁇ is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R x is independently selected from the group consisting of hydrogen or optionally substituted Ci-Ce aliphatic;
  • A is -L'-A 1 -*, where * represents a point of attachment to B;
  • a 1 is selected from the group consisting of -optionally substituted Ci-Ce aliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 hctcroatoms selected from N, O, and S, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
  • B is selected from the group consisting of a bond, optionally substituted -Ci-Cd aliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
  • R 1 is selected from the group consisting of hydrogen, -CN, -O(R), -N(R)2, -OC(O)(R), -C(O)O(R), -C(O)N(R)i, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
  • X 1 is N or CR X ;
  • X 2 is N
  • X 3 is CR X ;
  • Ring ⁇ is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R x is hydrogen;
  • A is -L'-A 1 -*, where * represents a point of attachment to B;
  • L 1 is a bond
  • a 1 is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
  • R 1 is selected from the group consisting of hydrogen, halogen, -CN, -O(R), -N(R)2, - OC(O)(R), -C(O)O(R), -C(O)N(R)2, optionally substituted Ci-Ce aliphatic, optionally comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cw aryl, and optionally substituted 5- to 10-mcmbcrcd hctcroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
  • X 1 is N or CH
  • X 2 is N
  • X 3 is CH
  • Ring Y is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • A is -L'-A 1 -*, where * represents a point of attachment to B;
  • L 1 is a bond
  • a 1 is 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R A ;
  • R 1 is selected from the group consisting of hydrogen, -C(O)O(R), -C(0)N(R)2, optionally substituted C1-C6 aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R A i is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two R A , together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
  • X 1 is N or CH
  • X 2 is N
  • X 3 is CH
  • Ring Y is optionally substituted 5-membered heteroaryl comprising 1 to 4 heteroatoms selected A is -iJ-A 1 -*, where * represents a point of attachment to B;
  • L 1 is a bond
  • a 1 is 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R A ;
  • R 1 is selected from the group consisting of hydrogen, -C(O)O(R), -C(0)N(R)2, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R A is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two R A , together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
  • X 1 is N or CH
  • X 2 is N
  • X 3 is CH
  • Ring ⁇ is optionally substituted 5-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • A is -L'-A 1 -*, where * represents a point of attachment to B;
  • L 1 is a bond
  • a 1 is 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R A ;
  • R 1 is 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with R 1a ; each R ‘ is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two R A , together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl;
  • Ria is hydrogen, Ci-Ce aliphatic, or optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
  • X 1 is N or CH
  • X 2 is N
  • X 3 is N or CH
  • X 4 is O, S, N, NH, or CH, as valency permits;
  • X 5 is O, S, N, NH, or CH, as valency permits;
  • X 6 is O, S, N, NH, or CH, as valency permits;
  • A is -iJ-A 1 -*, where * represents a point of attachment to B;
  • L 1 is a bond
  • a 1 is 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R A ;
  • R 1 is 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with R 1a ; each R A is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two R A , together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl;
  • Ria is hydrogen, Ci-Ce aliphatic, or optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
  • X 1 is N or CH
  • X 2 is N
  • X 3 is CH; X 5 is N;
  • X 6 is N
  • A is -L'-A 1 -*, where * represents a point of attachment to B;
  • L 1 is a bond
  • a 1 is 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R A ;
  • R 1 is 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with R 1a ; each R “ is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two R A , together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl;
  • Ria is hydrogen, Ci-Ce aliphatic, or optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
  • the present disclosure provides a compound represented by Formula II- 1 : or a pharmaceutically acceptable salt thereof, wherein X 1 , R A , and R 1 are as described in classes and subclasses here, both singly and in combination.
  • Formula II-2 or a pharmaceutically acceptable salt thereof, wherein carbon atom a is a chirally pure carbon atom.
  • the present disclosure provides a compound represented by Formula III-2:
  • the present disclosure provides a compound represented by
  • the present disclosure provides a compound represented by Formula III-4: or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound represented by
  • the present disclosure provides a compound (e.g., a compound represented by any one of Formula I to III-5) that is selected from Table 1:
  • the present disclosure provides a compound (e.g., a compound represented by any one of Formula I to III- 5) that is selected from Table 2:
  • the present disclosure provides a compound (e.g., a compound represented by any one of Formula I to III-5) that is selected from Table 3:
  • an APMAP inhibitor described herein can be conjugated to a moiety useful for engaging another protein (e.g., the APMAP inhibitor is configured onto one end of a heterobifunctional compound, and the other end is a moiety that binds to a target of interest).
  • an APMAP inhibitor described herein is configured onto a heterobifunctional compound that further comprises a moiety that causes degradation of APMAP.
  • an APMAP inhibitor described herein be conjugated, either directly or through a linker moiety, to a moiety that binds to an E3 ligase (e.g., CRBN, VHL, IAP, MDM2, DDB1, DCAF15, or 0TRCP).
  • E3 ligase e.g., CRBN, VHL, IAP, MDM2, DDB1, DCAF15, or 0TRCP.
  • such a compound causes degradation of APMAP in a biological sample.
  • E3 ligase binding moieties and linkers useful to configure to APMAP inhibitors described herein are described in WO2016/149668, W02017/011590, WO2017/030814A, WO2019/060693, WO2019/060742, WO2017/197036,
  • provided compounds are provided and/or utilized in a salt form (c.g., a pharmaceutically acceptable salt form).
  • a salt form c.g., a pharmaceutically acceptable salt form.
  • Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a composition described herein is formulated for administration to a patient in need of such composition.
  • a composition described herein is formulated for oral administration to a patient.
  • Compounds and compositions, according to method of the present disclosure are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.
  • compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or via an implanted reservoir.
  • the compositions are administered orally, intraperitoneally, or intravenously.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such aass,, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight [0162]
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include, but are not limited to, 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, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include
  • compositions described herein may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax, and polyethylene glycols.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions described herein may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Dosage forms for topical or transdermal administration of a compound disclosed herein The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, car drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the present disclosure provides, among other things, methods of treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of an APMAP inhibitor.
  • the present disclosure provides, among other things, methods of treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound (e.g., a compound of any one of Formula I-III-5) or composition (e.g., a pharmaceutical composition) described herein.
  • a compound e.g., a compound of any one of Formula I-III-5
  • composition e.g., a pharmaceutical composition
  • a APMAP inhibitor useful for treatment of diseases, disorders, and conditions described herein is one having less than 5.00 pM IC50 in an assay as described in Example 8. In some embodiments, a APMAP inhibitor useful for treatment of diseases, disorders, and conditions described herein is one having less than 0.50 pM IC50 in an assay as described in Example 8. In some embodiments, a APMAP inhibitor useful for treatment of diseases, disorders, and conditions described herein is one having less than 0.050 pM IC50 in an assay as described in Example 8.
  • the disease, disorder, or condition responsive to APMAP 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 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, 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, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblasto
  • the cancer is a leukemia.
  • the cancer is acute leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, myelogenous leukemia, leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, polycythemia vera, multiple myeloma, or erythroleukemia.
  • the cancer is a cancer or related myeloproliferative disorder selected from histiocytosis, essential thrombocythemia, myelofibrosis, heavy chain disease, and other malignancies and hypcrprol iterative 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 ttuummoorr,, 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,
  • 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 Cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion meso
  • the cancer an antibody-dependent cellular- phagocytosis (ADCP)-resistant cancer.
  • the cancer comprises U266 cells.
  • the cancer is a metastatic cancer. In some embodiments, the cancer is a relapsed and/or refractory cancer.
  • the cancer is ovarian cancer, uterine cancer, gestational trophoblastic disease, endometrial ccaanncceerr,, cervical ccaanncceerr,, embryonal carcinoma, choriocarcinoma, prostate cancer (including hormone insensitive and castrate resistant prostate cancers), testicular ttuummoorrss (including ggeerrmm cell testicular ccaanncceerr / 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, meningi
  • the disease, disorder, or condition responsive to APMAP inhibition is an infectious disease, disorder, or condition.
  • the infectious disease, disorder, 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, disorder, or condition responsive to APMAP inhibition is a neurodegenerative disease, disorder, or condition.
  • an APMAP inhibitor described herein is capable of crossing the blood-brain barrier, such that an APMAP inhibitor described herein can be administered to the brain of a subject. In some embodiments, an APMAP inhibitor is administered to the subject’s brain.
  • Brain-penetrant compounds described herein arc particularly useful for treating neurological or neurodegenerative diseases, disorders, and conditions.
  • the neurodegenerative disease, disorder, or condition is multiple sclerosis; Huntington’s disease; or Parkinson’s disease.
  • the neurodegenerative disease, disorder, 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’s disease.
  • the disease of frontal neuronal degeneration is frontotemporal dementia.
  • the disease, disorder, or condition responsive to APMAP inhibition is selected from those listed in Table 4.
  • the disease, disorder, or condition is septicemia. In some embodiments, the disease, disorder, or condition is obesity.
  • the subject is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a pediatric human. In some embodiments, the subject is a geriatric human.
  • the present disclosure provides a compound (e.g., a compound of any one of Formula I to III-5) for use in medicine.
  • the present disclosure provides a compound (e.g., a compound of any one of Formula I to III-5) in the manufacture of a medicament.
  • the medicament is for treating a disease, disorder, or condition described herein.
  • the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to the subject a compound described herein (e.g., a compound of any one of Formula I to III-5) and one or more additional therapeutic agents.
  • a compound described herein e.g., a compound of any one of Formula I to III-5
  • the present disclosure provides a regimen of treating a disease, disorder, or condition that comprises combination therapy.
  • a compound described herein is used in combination with an additional therapeutic agent that binds to a target selected from amyloid beta (A[3) (e.g., unmodified Ap or modified Ap, e.g., pyroglutamate-modified AP), BCMA, CCR4, CD19, CD20, CD22, CD24, CD30, CD33, CD38, CD47, CD52, CD79b, ,
  • A[3 amyloid beta
  • A[3 e.g., unmodified Ap or modified Ap, e.g., pyroglutamate-modified AP
  • CEACAM5 CEACAM6, Claudin 6, Claudin 18.2, CTLA-4, DLL3, EGER, FGFR2, GD2,
  • RANKE SLAMF7, SMAGP, TF, TREM2, TROP2, VEGF, VEGFR, VEGFR2, or epidermal growth factor receptor with exon 20 insertion mutations, to treat a disease, disorder, or condition, such as cancer or a neurodegenerative disease, disorder, or condition.
  • a disease, disorder, or condition such as cancer or a neurodegenerative disease, disorder, or condition.
  • combination therapies are described in more detail below.
  • the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein and co-administering (e.g., 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.
  • one or more other therapeutic agents may be part of a single dosage form, mixed together with a first compound in a single composition. If administered as a multiple dosage regime, 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 present 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
  • the second therapeutic agent prepared as a second pharmaceutical composition, where the first pharmaceutical composition and the second pharmaceutical composition arc administered simultaneously, sequentially, or separately.
  • the amount and frequency of administration of the second therapeutic agent can use standard dosages and standard administration frequencies used for the particular therapeutic agent. See, e.g., Physicians’ Desk Reference, 70th Ed., PDR Network, 2015; incorporated herein by reference.
  • CTLA-4 DLL3, EGFR, FGFR2, GD2, GPRC5D, GUCY2C, HER2, LAG3, Mesothelin, MET,
  • 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 EGER, 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 Ap (e.g., unmodified Ap or modified Ap, e.g., pyroglutamate-modified AP).
  • the target is BCMA.
  • the target is CCR4.
  • the target is CD19.
  • the target is CD20.
  • the target is CD22.
  • the target is CD24.
  • the target is CD30.
  • the target is CD33.
  • the target is CD38.
  • the target is CD47.
  • the target is CD52.
  • the target is CD79b.
  • the target is Nectin-4. In some embodiments, the target is PDGFRa. In some embodiments, the target is PD-1. In some embodiments, the target is PD-L1. In some embodiments, the target is PSMA. In some embodiments, the target is RANKL. In some embodiments, the target is SLAMF7. In some embodiments, the target is SMAGP. In some embodiments, the target is TF. In some embodiments, the target is VEGF. In some embodiments, the target is VEGFR. In some embodiments, the target is VEGFR2. In some embodiments, the target is epidermal growth factor receptor with exon 20 insertion mutations.
  • the additional therapeutic agent is an antibody.
  • the additional therapeutic agent is Alemtuzumab, Amivantamab (e.g., Amivantamab-vmjw), Avelumab, Bemarituzumab, Bevacizumab, Cetuximab, Cosibelimab, Daratumumab, Denosumab, Dinutiximab, Elotuzumab, Elranatamab (e.g., Elranatamab-bcmm), Isatuximab (e.g., Isatuximab-irfc), Magrolizumab, Margetuximab (e.g., Margetuximab-cmkb), Mogamulizumab (e.g., Mogamulizumab-kpkc), Naxitamab (e.g., Naxitamab-gqgk), Necitumumab, Obinutuzumab, Amivantamab (e.
  • Ramucirumab Rituximab, Tafasitamab (e.g., Tafasitamab-cxix), Talquetamab (e.g., Talquetamab-tgvs), Teclistamab (e.g., Teclistamab-cqyv), Trastuzumab, TTI-622, Evorpacept, a SIRPaFc fusion protein, or Zolbetuximab.
  • Tafasitamab e.g., Tafasitamab-cxix
  • Talquetamab e.g., Talquetamab-tgvs
  • Teclistamab e.g., Teclistamab-cqyv
  • Trastuzumab TTI-622
  • Evorpacept a SIRPaFc fusion protein
  • Zolbetuximab Zalbetuximab.
  • the additional therapeutic agent is ABBV-916 (under development by Abbvie), Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK-6640 (under development by OncoTherapy Science (formerly Immunas Pharma)), Lecanemab (e.g., Lecanemab-irmb), MEDI-1814 (under development by Medimmune (AstraZeneca)), NS- 101 (under development by Neuracle Science), PMN-310 (underdevelopment by ProMIS Neurosciences), PRX-012 (underdevelopment by Prothena), Remtemetug, Sabirnetug, SHR-1707 (under development by Atridia), or Trontinemab.
  • 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 SIRPaFc 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 SIRPa linked to the Fc region of human IgG4.
  • the additional therapeutic agent is Alemtuzumab. In some additional therapeutic agent is Amivantamab-vmjw. Tn some embodiments, the additional therapeutic agent is Avclumab. In some embodiments, the additional therapeutic agent is Bcmarituzumab. In some embodiments, the additional therapeutic agent is Bevacizumab. In some embodiments, the additional therapeutic agent is Cetuximab. In some embodiments, the additional therapeutic agent is Cosibelimab. In some embodiments, the additional therapeutic agent is Daratumumab. In some embodiments, the additional therapeutic agent is Denosumab. In some embodiments, the additional therapeutic agent is Dinutiximab.
  • the additional therapeutic agent is Elotuzumab. In some embodiments, the additional therapeutic agent is Elranatamab. In some embodiments, the additional therapeutic agent is Elranatamab-bcmm. In some embodiments, the additional therapeutic agent is Isatuximab. In some embodiments, the additional therapeutic agent is Isatuximab-irfc. In some embodiments, the additional therapeutic agent is Magrolizumab. In some embodiments, the additional therapeutic agent is Margetuximab. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb. In some embodiments, the additional therapeutic agent is Mogamulizumab. In some embodiments, the additional therapeutic agent is Mogamulizumab-kpkc.
  • the additional therapeutic agent is Naxitamab. In some embodiments, the additional therapeutic agent is Naxitamab-gqgk. In some embodiments, the additional therapeutic agent is Necitumumab. In some embodiments, the additional therapeutic agent is Obinutuzumab. In some embodiments, the additional therapeutic agent is Ofatumumab. In some embodiments, the additional therapeutic agent is Olaratumab. In some embodiments, the additional therapeutic agent is Panitumumab. In some embodiments, the additional therapeutic agent is Pertuzumab. In some embodiments, the additional therapeutic agent is Ramucirumab. In some embodiments, the additional therapeutic agent is Rituximab. In some embodiments, the additional therapeutic agent is Tafasitamab.
  • the additional therapeutic agent is Talquetamab. In some embodiments, the additional therapeutic agent is Talquetamab-tgvs. In some embodiments, the additional therapeutic agent is Tafasitamab-cxix. In some embodiments, the additional therapeutic agent is Teclistamab. In some embodiments, the additional therapeutic agent is Teclistamab-cqyv. In some embodiments, the additional therapeutic agent is Trastuzumab. In some embodiments, the additional therapeutic agent is TTI-622. In some embodiments, the additional therapeutic agent is evorpacept. In some embodiments, the additional therapeutic agent is a SIRPaFc fusion proteins. [0211] In some embodiments, the additional therapeutic agent is ABBV-916.
  • the additional therapeutic agent is Aducanumab. In some embodiments, the additional therapeutic agent is Crenezumab. In some embodiments, the additional therapeutic agent is Donanemab. In some embodiments, the additional therapeutic agent is Ganterenumab. In some embodiments, the additional therapeutic agent is KHK-6640. In some embodiments, the additional therapeutic agent is Lecanemab. In some embodiments, the additional therapeutic agent is Lecanemab-irmb. In some embodiments, the additional therapeutic agent is MEDI-1814. In some embodiments, the additional therapeutic agent is NS- 101. In some embodiments, the additional therapeutic agent is PMN-310. In some embodiments, the additional therapeutic agent is PRX-012. In some embodiments, the additional therapeutic agent is Remternetug. In some embodiments, the additional therapeutic agent is Sabirnetug. In some embodiments, the additional therapeutic agent is SHR-1707. In some embodiments, the additional therapeutic agent is Trontinemab.
  • 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 some embodiments, the additional therapeutic agent is Enfortumab vedotin. In some embodiments, the additional therapeutic agent is Gemtuzumab ozogamicin. In some embodiments, the additional therapeutic agent is Ibritumomab tiuxetan. In some embodiments, the additional therapeutic agent is Inotuzumab ozogamicin. In some embodiments, the additional therapeutic agent is Loncastuximab tesirine. In some embodiments, the additional therapeutic agent is Moxetumomab pasudotox. In some embodiments, the additional therapeutic agent is Polatuzumab vedotin.
  • the additional therapeutic agent is Sacituzumab govitecan. In some embodiments, the additional therapeutic agent is Tisotumab vedotin. In some embodiments, the additional therapeutic agent is Trastuzumab deruxtecan. In some embodiments, the additional therapeutic agent is Trastuzumab emtansine.
  • the present disclosure provides a method of treating a subject an APMAP inhibitor described herein in combination with an anti-amyloid beta ( Ap) antibody.
  • an APMAP inhibitor is administered in combination with an anti-amyloid beta antibody, and thereby stimulates phagocytosis of Ap plaques.
  • an APMAP inhibitor is administered in combination with an anti-amyloid beta antibody, and thereby reduces the number or size of Ap plaques.
  • the neurological or neurodegenerative disease, disorder, or condition is Alzheimer’s Disease.
  • an anti-amyloid beta (AP) antibody is selected from ABBV- 916, Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK-6640, Lecanemab (e.g., Lecanemab-irmb), MEDI-1814, NS-101, PMN-310, PRX-012, Remternetug, Sabimetug, SHR- 1707, and Trontinemab.
  • an anti-amyloid beta (AP) antibody is ABBV- 916.
  • an anti-amyloid beta (AP) antibody is Aducanumab.
  • an anti-amyloid beta (AP) antibody is Crenezumab. In some embodiments, an antiamyloid beta (AP) antibody is Donanemab. In some embodiments, an anti-amyloid beta (AP) antibody is Ganterenumab. In some embodiments, an anti-amyloid beta (AP) antibody is KHK- 6640. In some embodiments, an anti-amyloid beta (AP) antibody is Lecanemab (e.g., Lecanemab- irmb). In some embodiments, an anti-amyloid beta (AP) antibody is MEDI-1814. In some embodiments, an anti-amyloid beta (AP) antibody is NS-101.
  • an antiamyloid beta (AP) antibody is PMN-310. In some embodiments, an anti-amyloid beta (AP) antibody is PRX-012. In some embodiments, an anti-amyloid beta (AP) antibody is Remternetug. In some embodiments, an anti-amyloid beta (AP) antibody is Sabirnetug. In some embodiments, an anti-amyloid beta (AP) antibody is SHR-1707. In some embodiments, an anti-amyloid beta (AP) antibody is Trontinemab.
  • Another aspect of the invention provides a method for treating a disease, disorder, or condition responsive to APMAP inhibition, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of (i) a compound describe herein (e.g., a compound of any one of Formula I to III-5) and (ii) CAR-T therapy, to treat the disease, disorder, or condition.
  • a compound describe herein e.g., a compound of any one of Formula I to III-5
  • CAR-T therapy is idecabtagene vicleucel or lisocabtagene maraleucel.
  • the CAR-T therapy is idecabtagene vicleucel
  • the disease, disorder, 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 therapy is lisocabtagene maraleucel
  • the disease, disorder, or condition is a large B-cell lymphoma, such as a relapsed or refractory large B-ccll 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.
  • DLBCL diffuse large B cell lymphoma
  • the methods may be further characterized according to the identity of the disease, disorder, or condition to be treated.
  • the disease, disorder, 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.
  • 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.
  • DLBCL diffuse large B-cell lymphom
  • 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 Sezary syndrome.
  • the disease, disorder, or condition is an autoimmune and/or inflammatory disorder. In some embodiments, the disease, disorder, 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, disorder, or condition to be treated.
  • additional therapeutic agent used e.g., the inhibitor of a protein
  • Exemplary combinations of additional therapeutic agent used (e.g., the inhibitor of a protein) and the disease, disorder, or condition to be treated are set forth in Table 4 below. Table 4
  • B-NHL B-Cell Non-Hodgkin Lymphoma
  • First line (IL) B-NHL in combination with first line chemotherapy and, in patients achieving a complete response or partial response as single-agent maintenance therapy.
  • Non-progressing including stable disease
  • low-grade B-NHL as a single agent after IL cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
  • CVP prednisone
  • Rituximab IL DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
  • B-cell lymphoma B-cell lymphoma
  • BL Burkitt lymphoma
  • BLL Burkitt-like lymphoma
  • B-AL mature B-cell acute leukemia
  • Tafasitamab e.g., Diffuse large B-cell lymphoma Tafasitamab-cxix
  • MM Multiple myeloma
  • VMP prednisone
  • MM in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for ASCT and in patients with RR-MM (second line (2L)).
  • MM in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for ASCT.
  • MM in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy.
  • Protein Target patients who have received at least one prior line of therapy including CD38
  • lenalidomide and a proteasome inhibitor.
  • MM as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (Pl) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.
  • Pl proteasome inhibitor
  • Isatuximab e.g., Isatuximab-irfc
  • pomalidomide and dexamethasone for the treatment of adult patients with MM who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor.
  • Elotuzumab In combination with lenalidomide and dexamethasone for the treatment of adult patients with RR-MM who have received one to three prior therapies.
  • SCCHN head and neck
  • Amivantamab e.g., Non-small cell lung cancer Amivantamab-vmjw
  • Adjuvant for the treatment of HER2 overexpressing breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, with docetaxel and carboplatin, or as a single agent following multi-modality
  • trastuzumab an thracy cline based therapy.
  • mBrCa in combination with paclitaxel for first-line treatment of HER2-overexpressing mBrCa or as a single agent for treatment of
  • HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in combination with cisplatin and capecitabine or 5- fluorouracil in combination with cisplatin and capecitabine or 5- fluorouracil.
  • trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not
  • Pertuzumab received prior anti-HER2 therapy or chemotherapy.
  • Margetuximab e.g. Breast cancer Margetuximab-cmkb
  • Ramucirumab (Cyramza) In combination with docetaxel, for treatment of metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have
  • Metastatic colorectal cancer (alone and in combination with standard of care and bevacizumab)
  • TTI-622 Multiple myeloma, alone and with standard of care including daratumumab, elotuzumab and Isatuximab-irfc Name of Additional
  • Metastatic colorectal cancer in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment.
  • VEGF Protein Target: VEGF Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan.
  • Epithelial ovarian, fallopian tube, or primary peritoneal cancer a) in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection; b) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens; or c) in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Avastin as a single agent, for platinumsensitive recurrent disease Name of Additional
  • HCC Hepatocellular Carcinoma
  • Denosumab Prevention of skeletal-related events in patients with bone metastases from solid tumors.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-2 interleukin-2
  • RA 13-cis-retinoic acid
  • Naxitamab e.g., Neuroblastoma Naxitamab-gqgk
  • GMCSF granulocyte-macrophage colony-stimulating factor
  • Aducanumab e.g., Aducanumab-avwa
  • Lecanemab e.g., Lecanemab-irmb In patients with mild cognitive impairment or mild dementia stage of disease
  • the present disclosure provides a method of treating a disease, disorder, or conditon responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of (i) a compound described herein (e.g., a compound of any one of Formula I to III-5) and (ii) an additional therapeutic agent, wherein: a) the additional therapeutic agent is Rituximab, and the disease, disorder, or condition is:
  • B- NHL B-Cell Non-Hodgkin Lymphoma
  • First line (IL) B-NHL in patients achieving a complete response or partial response as single-agent maintenance therapy, and wherein the Rituximab is administered in combination with a first line chemotherapy;
  • Non-progressing including stable disease, low-grade, B-NHL as a single agent after IL cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy;
  • IL DLBCL where the Rituximab is administered in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracy cline-based chemotherapy regimen;
  • the additional therapeutic agent is Tafasitamab-cxix, and the disease, disorder, or condition is:
  • the additional therapeutic agent is Alemtuzumab, and the disease, disorder, or condition is Chronic lymphocytic leukemia;
  • the additional therapeutic agent is Mogamulizumab-kpkc, and the disease, disorder, or condition is:
  • MM Multiple myeloma
  • VMP prednisone
  • RR-Multiple myeloma is an adult patient who has received one to three prior therapies, wherein the Elotuzumab is administered in combination with lenalidomide and dexamethasone; or
  • Cetuximab is administered in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy;
  • Cetuximab is administered as a single-agent in a patient who has failed oxaliplatin- and irinotecan-based chemotherapy or who is intolerant to irinotecan;
  • the additional therapeutic agent is Panitumumab
  • the disease, disorder, or condition is:
  • the additional therapeutic agent is Necitumumab, and the disease, disorder, or condition is:
  • HER2 overexpressing breast cancer wherein the Trastuzumab is administered as pail of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, with docetaxel and carboplatin, or as a single agent following multi-modality anthracy cline based therapy;
  • HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive); or • HER2-positive early breast cancer at high risk of recurrence, wherein the Pertuzumab is administered in combination with trastuzumab and chemotherapy; q) wherein the additional therapeutic agent is Margetuximab-cmkb, and the disease, disorder, or condition is:
  • metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease, wherein the Margetuximab- cmkb is administered in combination with chemotherapy; r) wherein the additional therapeutic agent is Zolbetuximab, and the disease, disorder, or condition is:
  • EGER or ALK genomic tumor aberrations should have disease progression on FDA approved therapy for these aberrations prior to receiving CYRAMZA;
  • Magrolimab is administered alone and with standard of care, including rituximab, or Obinutuzumab; or
  • Magrolimab is administered alone and with standard of care including daratumumab, elotuzumab and Isatuximab-irfc; y) wherein the additional therapeutic agent is TTI-622, and the disease, disorder, or condition is:
  • TTI-622 is administered alone and with standard of care including daratumumab, elotuzumab and Isatuximab-irfc;
  • TTI-622 is administered alone and with standard of care, including rituximab, or Obinutuzumab or lenalidomide or Tafasitamab- cxix;
  • Acute myeloid leukemia wherein the TTI-622 is administered alone or with standard of care and/or venetoclax; z) wherein the additional therapeutic agent is Bevacizumab, and the disease, disorder, or condition is:
  • Bevacizumab is administered in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab product-containing regimen;
  • Bevacizumab is administered in combination with carboplatin and paclitaxel for first- line treatment;
  • Bevacizumab is administered in combination with paclitaxel and cisplatin, or paclitaxel and topotecan;
  • Bevacizumab is administered: a) in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection; b) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum- resistant recurrent disease who received no more than 2 prior chemotherapy regimens; or c) in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Avastin as a single agent, for platinum- sensitive recurrent disease; or
  • Hepatocellular Carcinoma wherein the Bevacizumab is administered in combination with atezolizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy; aa) wherein the additional therapeutic agent is Denosumab, and the disease, disorder, or condition is:
  • Dinutiximab is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA); ac) wherein the additional therapeutic agent is Naxitamab-gqgk, and the disease, disorder, or condition is:
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-2 interleukin-2
  • RA 13-cis-retinoic acid
  • Neuroblastoma or • relapsed or refractory high-risk neuroblastoma in the bone or bone marrow in pediatric patients 1 year of age and older and adult patients who have demonstrated a partial response, minor response, or stable disease to prior therapy, wherein the Naxitamab-gqgk is administered in combination with granulocyte-macrophage colony-stimulating factor (GMCSF); ad) wherein the additional therapeutic is Aducanumab, and the disease, disorder, or condition is:
  • the additional therapeutic agent is a combination of two, three, or four therapeutic agents or treatments. In some embodiments, the additional therapeutic agent is a combination of two therapeutic agents or treatments. In some embodiments, the additional therapeutic agent is a combination of three therapeutic agents or treatments. In some embodiments, the additional therapeutic agent is a combination of four therapeutic agents or treatments. In some embodiments, the treatment is radiation therapy.
  • the additional therapeutic agent is Rituximab in combination with CHOP. In some embodiments, the additional therapeutic agent is Rituximab in combination with CVP. In some embodiments, the additional therapeutic agent is Rituximab in combination with fludarabine and cyclophosphamide. In some embodiments, the additional therapeutic agent is Rituximab in combination with BTKi. In some embodiments, the additional therapeutic agent is Rituximab in combination with venetoclax.
  • the additional therapeutic agent is Rituximab in combination with CAR-T. In some embodiments, the additional therapeutic agent is Rituximab in combination with venetoclax. In some embodiments, the additional therapeutic agent is Rituximab in combination with Ibrutinib. In some embodiments, the additional therapeutic agent is Rituximab in combination with acalabrutinib. In some embodiments, the additional therapeutic agent is Rituximab in combination with zanubrutinib.
  • the additional therapeutic t i Rit i b i bi ti ith ti b ti ib I b di t th dditi l therapeutic agent is Rituximab in combination with orelabrutinib. In some embodiments, the additional therapeutic agent is Rituximab in combination with idclalisib. In some embodiments, the additional therapeutic agent is Rituximab in combination with autologous stem cell transplantation (ASCT). In some embodiments, the additional therapeutic agent is Rituximab in combination with Copanlisib. In some embodiments, the additional therapeutic agent is Rituximab in combination with Tazemetostat.
  • ASCT autologous stem cell transplantation
  • the additional therapeutic agent is Rituximab in combination with Axicabtagene ciloleucel. In some embodiments, the additional therapeutic agent is Rituximab in combination with Tisagenlecleucel. In some embodiments, the additional therapeutic agent is Rituximab in combination with Mosunetuzumab-axgb. In some embodiments, the additional therapeutic agent is Rituximab in combination with Lisocabtagene maraleucel. In some embodiments, the additional therapeutic agent is Rituximab in combination with Polatuzumab vedotin-piiq.
  • the additional therapeutic agent is Obinutuzumab in combination with chlorambucil. In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with acalabrutinib. In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with Venetoclax. In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with ibrutinib. In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with bendamustine.
  • the additional therapeutic agent is Tafasitamab-cxix in combination with Lenalidomide.
  • the additional therapeutic agent is Daratumumab in combination with bortezomib, melphalan and prednisone (VMP). In some embodiments, the additional therapeutic agent is Daratumumab in combination with lenalidomide and dexamethasone. In some embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib, thalidomide, and dexamethasone. In some embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib and dexamethasone. In some embodiments, the additional therapeutic agent is Daratumumab in combination with pomalidomide and dexamethasone.
  • the additional therapeutic agent is Daratumumab in combination with carl'ilzomib and dexamethasone. In some 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 some embodiments, the additional therapeutic agent is Daratumumab in combination with bendamustine, dexamethasone, and either carfilzomib or bortezomib. In some embodiments, the additional therapeutic agent is Daratumumab in combination with Idecabtagene autoleucel. In some embodiments, the additional therapeutic agent is Daratumumab in combination with Ciltacabtagene autoleucel. In some embodiments, the additional therapeutic agent is Daratumumab in combination with Teclistamab-cqyv.
  • the additional therapeutic agent is Isatuximab-irfc in combination with carfilzomib and dexamethasone. In some embodiments, 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. In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with Idecabtagene autoleucel. In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with Ciltacabtagene autoleucel. In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with Teclistamab-cqyv.
  • the additional therapeutic agent is Elotuzumab in combination with lenalidomide and dexamethasone. In some 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 some embodiments, the additional therapeutic agent is Elotuzumab in combination with Idecabtagene autoleucel. In some embodiments, the additional therapeutic agent is Elotuzumab in combination with Ciltacabtagene autoleucel. In some embodiments, the additional therapeutic agent is Elotuzumab in combination with Teclistamab-cqyv.
  • the additional therapeutic agent is Cetuximab in combination with radiation therapy. In some embodiments, the additional therapeutic agent is Cetuximab in therapeutic agent is Cetuximab in combination with FOLFIRI. In some embodiments, the additional therapeutic agent is Cetuximab in combination with irinotecan.
  • the additional therapeutic agent is Cetuximab in combination with Regorafenib. In some embodiments, the additional therapeutic agent is Cetuximab in combination with trifluridine and tipiracil. In some embodiments, the additional therapeutic agent is Cetuximab in combination with trifluridine, tipiracil, and bevacizumab. In some embodiments, the additional therapeutic agent is Cetuximab in combination with a Her2 inhibitor. In some embodiments, the additional therapeutic agent is Cetuximab in combination with a BrafV600E inhibitor.
  • the additional therapeutic agent is Panitumumab in combination with FOLFOX.
  • the additional therapeutic agent is Panitumumab in combination with Regorafenib. In some embodiments, the additional therapeutic agent is Panitumumab in combination with trifluridine and tipiracil. In some embodiments, the additional therapeutic agent is Panitumumab in combination with trifluridine, tipiracil, and bevacizumab. In some embodiments, the additional therapeutic agent is Panitumumab in combination with a Her2 inhibitor. In some embodiments, the additional therapeutic agent is Panitumumab in combination with a BrafV 600E inhibitor.
  • the additional therapeutic agent is Necitumumab in combination with gemcitabine and cisplatin.
  • the additional therapeutic agent is Amivantamab-vmjw in combination with Nivo. In some embodiments, the additional therapeutic agent is Amivantamab- vmjw in combination with Pembro. In some embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Atezo. In some embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Docetaxel. In some embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Gemcitabine.
  • the additional therapeutic agent is Trastuzumab in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with docetaxel and carboplatin. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with with cisplatin and capecitabine. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with 5-fluorouracil.
  • the additional therapeutic agent is Trastuzumab in combination with Fam-trastuzumab deruxtecan-nxki. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with Sacituzumab govitecan. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with systemic chemotherapy. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with a biomarker guided Rx. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with a Her2 inhibitor. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with a BrafV 600E inhibitor.
  • the additional therapeutic agent is Pertuzumab in combination with trastuzumab and docetaxel. In some embodiments, the additional therapeutic agent is Pertuzumab in combination with trastuzumab and chemotherapy.
  • the additional therapeutic agent is Margetuximab-cmkb in combination with chemotherapy. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with capecitabine. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with capecitabine. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with eribulin. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with gemcitabine. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with vinorelbine.
  • the additional therapeutic agent is Margetuximab-cmkb in combination with lapatinib. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with tucatinib. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with neratinib.
  • the additional therapeutic agent is Zolbetuximab in combination with mFOLFOXb.
  • the additional therapeutic agent is Zolbetuximab in combination with Regorafenib and trifluridine. In some embodiments, the additional therapeutic agent is Zolbetuximab in combination with Regorafenib and tipiracil. In some embodiments, the additional trifluridine. In some embodiments, the additional therapeutic agent is Zolbetuximab in combination with Rcgorafcnib, Bcvacizumab and tipiracil.
  • the additional therapeutic agent is Ramucirumab in combination with paclitaxel. In some embodiments, the additional therapeutic agent is Ramucirumab in combination with erlotinib. In some embodiments, the additional therapeutic agent is Ramucirumab in combination with docetaxel. In some embodiments, 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 doxorubicin.
  • the additional therapeutic agent is Avelumab. In some embodiments, the additional therapeutic agent is Magrolizumab. In some embodiments, the additional therapeutic agent is TTI-622. In some embodiments, the additional therapeutic agent is Bevacizumab. In some embodiments, 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-gcjgk in combination with granulocyte-macrophage colony- stimulating factor (GMCSF).
  • GMCSF granulocyte-macrophage colony- stimulating factor
  • the additional therapeutic agent is a leukotriene inhibitor, nonsteroidal anti-inflammatory drug (NSAID), steroid, tyrosine kinase inhibitor, receptor kinase inhibitor, modulator of nuclear receptor family of transcription factor, HSP90 inhibitor, adenosine receptor (A2A) agonist, disease modifying antirheumatic drugs (DMARDS), phosphodiesterase (PDF) inhibitor, neutrophil elastase inhibitor, modulator of Axl kinase, an anti-cancer agent, antiallergic agent, anti-nausea agent (or anti-emetic), pain reliever, cytoprotective agent, or a combination thereof.
  • NSAID nonsteroidal anti-inflammatory drug
  • steroid steroid
  • tyrosine kinase inhibitor inhibitor
  • receptor kinase inhibitor modulator of nuclear receptor family of transcription factor
  • HSP90 inhibitor adenosine receptor (A2A) agonist
  • DARDS disease modifying antirheumatic drugs
  • 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 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.
  • 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, fdgotinib, 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 EGER 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, fcxaraminc, hypocholamidc, 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, CNF 1010, or combinations thereof.
  • the additional therapeutic agent is an adenosine receptor 2A (A2A) agonist.
  • A2A adenosine receptor 2A
  • Examples of 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).
  • DMARDS disease modifying antirheumatic drugs
  • 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.
  • PDE phosphodiesterase
  • 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), [0260]
  • the additional therapeutic agent is an anti-cancer agent or chcmo-thcrapcutic agent.
  • anti-cancer agents considered for use in combination therapies of the invention include but are not limited to 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 pre-
  • the additional therapeutic agent is selected from anastrozole
  • 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 axe 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, BYE?
  • the additional therapeutic agent is selected based on the disease, disorder, 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
  • 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®, EV ACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).
  • doxorubicin hydrochloride Adriamycin®
  • carboplatin PARAPLATIN®
  • CYTOXAN® cyclophosphamide
  • PLATINOL-AQ® cisplatin
  • DOXIL® DOX-SL®
  • EV ACET® EV ACET®
  • 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 (A VASTIN®), 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 A VASTIN®
  • irinotecan hydrochloride CAMPTOSTAR®
  • capecitabine XELODA®
  • cetuximab ERBITUX®
  • the additional therapeutic agent is selected from methotrexate, methotrexate EPF (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 EPF 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
  • the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®) and topotccan hydrochloride (HYC AMTIN®).
  • the additional therapeutic agent is selected from methotrexate, methotrexate EPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), bleomycin (BLENOXANE®), cetuximab (ERBITUX®), cisplatin (PLATINOL®, PLATINOL-AQ®) and docetaxel (TAXOTERE®).
  • EPF e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®
  • fluorouracil ADRUCIL®, EFUDEX®, FLUOROPLEX®
  • BLENOXANE® cetuximab
  • cisplatin PATINOL®, PLATINOL-AQ®
  • docetaxel TXOTERE®
  • 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®).
  • antiallergic agents may be administered to minimize the risk of an allergic reaction.
  • Suitable antiallergic 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 lorazepam (ATIVAN®, dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof.
  • medication to alleviate the pain experienced during the treatment period is prescribed to make the patient more comfortable.
  • analgesics such as hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OP ANA®), 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®
  • OP ANA® oxymorphone hydrochloride
  • 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) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disease, disorder, or condition.
  • the compound described herein (e.g., a compound of Formula I) and the additional therapeutic agent(s) arc administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disease, disorder, or condition.
  • the compound described herein (e.g., a compound of Formula I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
  • the compound described herein 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.
  • kits comprising a therapeutically effective amount of a compound described herein (e.g., a compound of Formula 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.
  • Step-1 Synthesis of tert-butyl 6-(l-methyl-lH-pyrazol-3-yl)-2,3-dihydro-4ZM,4-oxazine-4- carboxylate
  • Step-2 Synthesis of tert-butyl 2-( 1 -methyl- 1/7- pyrazol-3-yl) mor pholine-4-carboxy late
  • Step-1 Synthesis of 4- (tert-butyl) 2-(l,3-dioxoisoindolin-2-yl) morpholine-2,4-dicarboxylate
  • Step-2 Synthesis of tert-butyl 2-(pyridin-2-yl) morpholine-4-carboxylate and tert-butyl 2- (pyridin-4-yl) morpholine-4-carboxylate
  • Step-1 Synthesis of tert-butyl 3-carbamothioylpyrrolidine-l-carboxylate
  • Step-1 Synthesis of tert-butyl (2-(4-methylthiazol-2-yl)ethyl)carbamate
  • Step-4 Synthesis of tert-butyl 2-(4-(cyclohex-l-en-l-yl)thiazol-2-yl)morpholine-4- carboxylate s
  • the resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (5.00 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-1 Synthesis of tert-butyl 6-(4-(2-hydroxyethyl)phenyl)-2,3-dihydro-4H-l,4-oxazine-4- carboxylate
  • Step-2 Synthesis of tert-butyl 2-(4-(2-hydroxyethyl)phenyl)morpholine-4-carboxylate
  • Step-3 Synthesis of tert-butyl 2-(4-(2-oxoethyl)phenyl) morpholine-4-carboxylate
  • Step-1 Synthesis of tert-butyl (2S,6/Z)-2-carbamoyl-6-methylmorpholine-4-carboxylate
  • Step-2 Synthesis of tert-butyl(2S,6/?)-2-carbamothioyl-6-methylmorpholine-4-carboxylate
  • Step-3 Synthesis of (2S,6i?)-2-(4-(tert-butyl)thiazol-2-yl)-6-methylmorpholine hydrobromide (Int-9) [0304]
  • the mixture of tert-butyl (2S,67?)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (400 mg, 1.54 mmol, 1.00 cquiv) and 1-bromopinacolonc (550 mg, 3.07 mmol, 2.00 cquiv) in EtOH (4.00 mL) was stirred for 2h at 80°C.
  • the mixture was allowed to cool down to room temperature.
  • the mixture was basified to pH 8 with NHg/MeOH.
  • the resulting mixture was concentrated under reduced pressure.
  • Step-6 Synthesis of 3-(4-benzylmorpholin-2-yl)benzonitrile 9
  • 4-benzyl-2-(3-bromophenyl)morpholine 200 mg, 0.602 mmol, 1.00 equiv
  • dicthynylzinc 69.5 mg, 0.602 mmol, 1.00 equiv
  • Pd(PPh3)4 69.6 mg, 0.0600 mmol, 0.100 equiv
  • Step-2 Synthesis of 2-(4-tert-butyI-l,3-thiazol-2-yl)-l-[(2-hydroxyethyl)amino]propan-2-ol
  • Step-3 Synthesis of tert-butyl V-
  • Step-4 Synthesis of tert-butyl 2-(4-tert-butyl-l,3-thiazol-2-yl)-2-methylmorpholine-4- carboxylate
  • Step-2 Synthesis of tert-butyl (R)-6-carbamothioyl-2,2-dimethylmorpholine-4-carboxylate
  • Step-3 Synthesis of (7?)-6-(4-(tert-butyl)thiazol-2-yl)-2,2-dimethylmorpholine (Int-12) [0319]
  • the mixture of tert-butyl (7?)-6-carbamothioyl-2,2-dimethylmorpholine-4-carboxylate (480 mg, 1.75 mmol, 1.00 equiv) and 1-bromopinacolonc (470 mg, 2.62 mmol, 1.50 equiv) in ethanol (5.00 mL) was stirred at 80°C for 2h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure.
  • Step-1 Synthesis of tert-butyl l-carbamoyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate
  • Step-2 Synthesis of tert-butyl l-carbamothioyl-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate
  • tert-butyl l-carbamothioyl-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate 250 mg, 1.03 mmol, l.OOcquiv
  • Lawcsson Reagent 626 mg, 1.54 mmol, 1.50 equiv
  • Step-3 Synthesis of l-(4-tert-butyl-l,3-thiazol-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (Int-13)
  • Step-1 Synthesis of l-(4-(tert-butyl)thiazol-2-yl)-2-chloroethan-l-one [0323]
  • 2-bromo-4-tert-butyl-l ,3-thiazole (2.00 g, 9.09 mmol, 1.00 equiv) in Et2 ⁇ ) (20.0 mL) was added dropwisc n-butyllithium solution (2.5 M in THE, 7.3 mL, 18.1 mmol) at -78°C under N2 atmosphere.
  • the reaction mixture was stirred at - 78°C for 30 mins.
  • Step-2 Synthesis of l-(4-(tert-butyl)thiazol-2-yl)-2-chloroethan-l-ol
  • Step-4 Synthesis of tert-butyl (2-(4-(tert-butyl)thiazoL2-yl)-2-hydroxyethyl)((R)-l- hydroxypropan-2-yl)carbamat
  • Step-5 Synthesis of tert-butyl (2R,5R)-2-(4-(tert-butyl)thiazol-2-yl)-5-methylmorpholine-4- carboxylate
  • Example 1 Synthesis of Compounds 3 and 4: (7?)-2-(4-methylthiazol-2-yl)-4-(tetrazolo[l,5- />]pyridazin-6-yl)morpholine, and (S)-2-(4-methylthiazol-2-yl)-4-(tetrazolo[l,5-6]pyridazin- 6-yl)morpholine
  • Step-1 Synthesis of tert-butyl 2-carbamoylmorpholine-4-carboxylate [0331] A solution of 4-(tert-butoxycarbonyl)morpholine -2-carboxylic acid (5.00 g, 21.6 mmol, 1.00 cquiv), NH4CI (2.31 g, 43.2 mmol, 2.00 cquiv), DIEA (8.38 g, 64.8 mmol, 3.00 cquiv) and HATH (9.87 g, 25.9 mmol, 1.20 equiv) in DCM (50 mL) was stirred for 14h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum.
  • 4-(tert-butoxycarbonyl)morpholine -2-carboxylic acid 5.00 g, 21.6 mmol, 1.00 cquiv
  • NH4CI (2.31 g, 43.2 mmol, 2.00 cquiv)
  • DIEA
  • Step-2 Synthesis of tert-butyl 2-carbamothioylmorpholine-4-carboxylate

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Abstract

The present disclosure provides, among other things, compounds, and compositions useful as inhibitors of adipocyte plasma membrane associated protein (APMAP). The presently provided compounds and compositions are useful in the treatment of diseases, disorders, and conditions associated with APMAP. In some embodiments, the present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof, wherein R1, A, B, X1, X2, X3, and Y are as described in classes and subclasses here, both singly and in combination.

Description

HETERO ARYL MODULATORS OF APMAP AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No. 63/566,162, filed March 15, 2024, which is herein incorporated by reference in its entirety.
BACKGROUND
[0001] Phagocytes are immune cells that play a critical role in both the early and late stages of immune responses. Their main role is to circulate and migrate through tissues to ingest and destroy microbes, abnormal cells, and cellular debris. Enhancing uptake by macrophages has been posited to engage the immunomodulatory potential of the myeloid compartment and more broadly stimulate a productive adaptive immune response.
[0002] Adipocyte plasma membrane associated protein (APMAP) is a paraoxonase-like enzyme that resides in the endoplasmic reticulum. See, for example, Albrektsen, et al. Biochem J. (2001) vol. 359, 393-402. APMAP has been identified as a cancer-intrinsic anti-phagocytic factor. See, for example, Mosser etal. Hum. Mol. Genet. (2015) vol. 24, 371-82 and Kamber et al. Nature (2021) vol. 597, 549-554.
SUMMARY
[0003] There remains a need for new therapies for the treatment of diseases and disorders associated with APMAP inhibition. For example, as reported in PCT Application Publication No. WO 2022/076446, agents that are inhibitors of APMAP can be used to treat particular diseases, disorders, and conditions, such as cancer. The present disclosure provides, among other things, new compounds and compositions that are useful as APMAP inhibitors and for treatment of diseases, disorders, and conditions responsive to APMAP inhibition.
[0004] In some embodiments, the present disclosure provides a compound represented by
Formula I: or a pharmaceutically acceptable salt thereof, wherein R1, A, B, X1, X2, X3, and Ring Y are as described in classes and subclasses here, both singly and in combination.
[0005] In some embodiments, the present disclosure provides a compound represented by
Formula II- 1 :
II- 1 or a pharmaceutically acceptable salt thereof, wherein X1, RA, and R1 are as described in classes and subclasses here, both singly and in combination.
[0006] In some embodiments, the present disclosure provides a compound represented by
Formula II-2: or a pharmaceutically acceptable salt thereof, wherein X1 and R1 arc as described in classes and subclasses herein, both singly and in combination, and the carbon atom a is a chirally pure carbon atom.
[0007] In some embodiments, the present disclosure provides a compound represented by
Formula 11-3:
II-3 or a pharmaceutically acceptable salt thereof, wherein X1 and R1 are as described in classes and subclasses herein, both singly and in combination.
[0008] In some embodiments, the present disclosure provides a compound represented by
Formula II-4: or a pharmaceutically acceptable salt thereof wherein X1 and R1 are as described in classes and subclasses herein, both singly and in combination.
[0009] In some embodiments, the present disclosure provides a compound represented by
Formula III- 1 :
III-l or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, X6, RA, and R1a are as described in classes and subclasses here, both singly and in combination.
[0010] In some embodiments, the present disclosure provides a compound represented by Formula III-2:
III-2 or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, X6, RA, and R1a as described in classes and subclasses here, both singly and in combination, and carbon atom a is a chirally pure carbon atom.
[0011] In some embodiments, the present disclosure provides a compound represented by
Formula III-3:
III-3 or a pharmaceutically acceptable salt thereof, wherein X1 and R1a are as described in classes and subclasses herein, both singly and in combination, and carbon atom a is a chirally pure carbon atom.
[0012] In some embodiments, the present disclosure provides a compound represented by
Formula III-4:
III-4 or a pharmaceutically acceptable salt thereof, wherein X1 and R1a are as described in classes and subclasses herein, both singly and in combination.
[0013] In some embodiments, the present disclosure provides a compound represented by
Formula III-5:
III-5 or a pharmaceutically acceptable salt thereof wherein X1 and R la are as described in classes and subclasses herein, both singly and in combination.
[0014] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound as described herein, e.g., a compound of any of Formula I-III-5.
[0015] In some embodiments, the present disclosure provides a method for treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any of Formula I-III-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutical [0016] In some embodiments, the present disclosure provides a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any of Formula I-III-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof.
[0017] In some embodiments, the present dislcosure provides a method of inhibiting the activity of APMAP in a subject to treat a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any of Formula I-III-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof.
[0018] In some embodiments, the present disclosure provides a method for treating an autoimmune and/or inflammatory disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any of Formula I-III-5), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Fig. 1 is a bar chart showing the extent of rituximab-induced antibody-dependent cellular phagocytosis (ADCP) of Ramos lymphoma cells by J774A.1 mouse macrophages in a dose-response assay in the presence or absence of Compound 4 at the indicated concentrations. [0020] Fig. 2 is a bar chart showing the extent of cetuximab-induced ADCP of MDA-MB-231 breast cancer cells by J774A.1 mouse macrophages in the presence or absence of Compound 4 at the indicated concentration.
[0021] Fig. 3 is a bar chart showing the extent of TTI-622-induced ADCP of A375 melanoma cells by J774A.1 mouse macrophages in the presence or absence of Compound 4 at the indicated concentration.
[0022] Fig. 4 is a bar chart showing the extent of cetuximab-induced ADCP of A375 melanoma cells by J774A.1 mouse macrophages in the presence or absence of Compound 4 at the indicated concentration. [0023] Fig. 5 is a bar chart showing the extent of rituximab-induced ADCP of Ramos lymphoma cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
[0024] Fig. 6 is a bar chart showing the extent of cetuximab-induced ADCP of FaDu head and neck squamous cell carcinoma (HNSCC) cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
[0025] Fig. 7 is a bar chart showing the extent of trastuzumab-induced ADCP of SKOV-3 ovarian cancer cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
[0026] Fig. 8 is a bar chart showing the extent of trastuzumab-induced ADCP of BT-474 breast cancer cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
[0027] Fig. 9 is a bar chart showing the extent of avelumab-induced ADCP of RKO colon carcinoma cells by primary human macrophages isolated from three individual donors in the presence or absence of Compound 4 at the indicated concentration.
[0028] Figs. 10A-10D are bar charts showing the trastuzumab-induced cytokine/chemokine concentrations of TNFa (Fig. 10A), IL-6 (Fig. 10B), IL- 10 (Fig. 10C), and IFNy (Fig. 10D) observed in coculture during ADCP of SK-BR-3 breast cancer cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
[0029] Figs. 11A-11C are bar charts showing the avelumab-induced cytokine/chemokine concentrations of TNFa (Fig. 11A), IL-10 (Fig. 1 IB), and MIPla (Fig. 11C) observed in coculture during ADCP of RKO colon carcinoma cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration.
[0030] Figs. 12A-12D are bar charts showing the rituximab-induced cytokine/chemokine concentrations of IL-10 (Fig. 12A), IP-10 (Fig. 12B), MCP-1 (Fig. 12C), and MIP-la (Fig. 12D) observed in coculture during ADCP of Ramos lymphoma cells by primary human macrophages in the presence or absence of Compound 4 at the indicated concentration, in the presence of B6H12 at the indicated concentration, or using modified APMAP-knockout (APMAP KO) Ramos lymphoma cells. [0031] Fig. 13 is a bar chart showing the extent of tumor cell depletion following ADCP of Ramos lymphoma cells by J774A.1 mouse macrophages in the presence or absence of each of rituximab and Compound 4 at the indicated concentration.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0032] The present disclosure provides, among other things, compounds, and compositions useful as modulators of adipocyte plasma membrane associated protein (APMAP). In some embodiments, the provided compounds and compositions are useful as inhibitors of APMAP. The presently provided compounds and compositions are useful in the treatment of diseases, disorders, and conditions associated with APMAP, including, for example, cancer, and inflammatory diseases.
[0033] In some embodiments, the present disclosure provides a compound represented by
Formula I:
I or a pharmaceutically acceptable salt thereof, wherein R1, A, B, X1, X2, X3, and Ring Y are as described in classes and subclasses here, both singly and in combination.
Compounds and Definitions
[0034] Compounds of this disclosure include those described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated, For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of Elements, CAS version,
Handbook of Chemistry and Physics, 75' Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and
March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0035] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (c.g., enantiomeric or diastcrcomcric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, Tables 1-3 show one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.
[0036] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure.
[0037] A or An ; The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.
[0038] About or approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familial" within the context, will appreciate the relevant degree of variance encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "approximately" or "about" may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.
[0039] Administering: As used herein, the term "administering" or "administration" typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime- and-boost protocol. A prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine). In the case of an immunogenic composition, a prime-and-boost protocol can result in an increased immune response in a patient.
[0040] Agent; As used herein, the term “agent,” is a compound, molecule, or entity of any chemical class including, for example, a small molecule, polypeptide, nucleic acid, saccharide, lipid, metal, or a combination or complex thereof. Example agents include compounds and compositions described herein, such as a compound or composition comprising a compound of any one of Formula I to III-5.
[0041] Agonist: As used herein, the term “agonist” generally refers to an agent whose presence or level correlates with elevated level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an agonist is one whose presence or level correlates with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known agonist, e.g., a positive control). In some embodiments, an agonist may be a direct agonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an agonist may be an indirect agonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity).
[0042] Aliphatic: The term “aliphatic” refers to 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 or more than one points of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., Ci-e). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., CM). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but arc not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups and hybrids thereof. A preferred aliphatic group is Ci-e alkyl.
[0043] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, CM, CI- 3, or C1-2). Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2- ethyl-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
[0044] Alkylene: The term “alkylene” is refers to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group, hi some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-mcmbcrcd ring. The substituents can be on the same or different atoms. The suffix “-ene” or “-enyl” when appended to certain groups herein are intended to refer to a bifunctional moiety of said group. For example, “-ene” or “-enyl”, when appended to “cyclopropyl” becomes “cyclopropylene” or
“cyclopropylenyl” and is intended to refer to a bifunctional cyclopropyl group, e.g., [0045] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
[0046] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-1, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
[0047] Antagonist-. As will be understood by those skilled in the art, the term “antagonist,” generally refers to an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an antagonist is one whose presence or level correlates with a target level or activity that is comparable to or less than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known antagonist, e.g., a positive control). In some embodiments, an antagonist may be a direct antagonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an antagonist may be an indirect antagonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity. [0048] APMAP Inhibitor: The term “APMAP inhibitor,” as used herein, refers to an agent that is an inhibitor, as that term is defined herein, of Adipocyte plasma membrane associated protein. Inhibitory activity of APMAP inhibitors described herein can be reported by their half- maximal inhibitor concentration (IC50), which indicates the amount of agent needed to inhibit biological processes by half. Example APMAP inhibitors include compounds and compositions described herein, such as a compound or a composition comprising a compound of any one of Formula I - HI-5.
[0049] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., Ce-Cu), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include
[0050] Bicyclic: The term “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. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” 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. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, 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. Unless otherwise specified, 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:
N
H
O
HN
NH N
Exemplary bridged bicyclics include:
NH
NH
HN
NH NH
HN HN O' N H
N s 0
[0051] Biological sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
[0052] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.
[0053] Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality (ies)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
[0054] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc.
[0055] Cycloaliphatic. As used herein, the term “cycloaliphatic” refers to a monocyclic C3-8 hydrocarbon or a bicyclic Ce-io hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.
[0056] Cycloalkyl-. As used herein, the term “cycloalkyl” refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohcptyl.
[0057] Dosage form or unit dosage form: Those skilled in the ail will appreciate that the term
“dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).
[0058] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).
[0059] Effective Amount: 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. [0060] Excipient: As used herein, the term “excipient” refers to a non -therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
[0061] Halogen: The term “halogen” or “halo” means F, Cl, Br, or I.
[0062] Heteroaliphatic". The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwise specified, heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2- CH2-O-CH2-CH2-O-CH3, and the like.
[0063] Heteroaryl: The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 147t-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l ,2-a]pyrimidinyl, imidazo[l ,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. The terms “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 the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4//-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
[0064] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
[0065] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 6- to 10-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-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. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxo lyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.
[0066] Inhibitor: As used herein, the term “inhibitor” refers to an entity (e.g., an agent) whose presence correlates with decreased level or activity of a target. In some embodiments, an inhibitor may act directly (in which case it exerts its influence directly upon its target, for example by binding to the target); in some embodiments, an inhibitor may act indirectly (in which case it exerts its influence by interacting with and/or otherwise altering a regulator of the target, so that level and/or activity of the target is reduced). Inhibitory activity can be measured, for example, reported by half-maximal inhibitor concentration (ICso), which indicates the amount of agent needed to inhibit biological processes by half. Example inhibitors include compounds and compositions described herein, such as a compound or a composition comprising a compound of any of Formula I to III-5.
[0067] Modulator-. The term “modulator,” as used herein, refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can cause an increase or decrease in the magnitude of a certain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator. For example, a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist. For example, a modulator can be an inhibitor of a particular target, as those terms are defined herein. Example modulators include compounds and compositions described herein, such as a compound or a composition comprising a compound of any of Formula I to III-5.
[0068] Oral: The phrases “oral administration” and “administered orally” as used herein have [0069] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
[0070] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
[0071] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: 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; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
[0072] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically 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.
[0073] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., 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. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). 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. Other pharmaceutically acceptable 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, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[0074] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977, 66(1), 1-19; P. Gould, International J. of Pharmaceutics 1986, 33, 201-217; Anderson el al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference. [0075] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci 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.
[0076] Substituted or optionally substituted: As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “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. “Substituted” applies to one or more
-rR1 hydrogens that arc cither explicit or implicit from the structure (c.g., refers to at least
NH
R1 R1 NH
'NH N
R1
; and refers to at least 9 R1 R1 , or
NH
R1 ). Unless otherwise indicated, 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. The term “stable,” as used herein, 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 provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
[0077] Suitable monovalent substituents on a substitutable carbon atom of an “optionally s bstit ted” gro p are independentl halogen; (CH ) R°; (CH ) OR°; 0(CH ) R° O
(CIM straight or branched alkylene)O-N(R°)2; or -(CM straight or branched alkylene)C(O)O
N(RO)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci
6 aliphatic, -CH2Ph, -0(CH2)o iPh, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
[0078] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)O 2R*, alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CIM aliphatic, - CH2Ph, -0(CH2)O iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent [0079] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: wherein each independent occurrence of R* is selected from hydrogen, Ci e aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently CM aliphatic, -CH2PI1, -0(CH2)o iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0081] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R', taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently CIM aliphatic, -CH2PI1, -0(CH2)o~iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0083] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and/or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer.
[0084] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc?). In some embodiments, a small molecule is not a lipid.
[0085] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.
[0086] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and/or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and/or structural isomers), isotopic forms, etc.
[0087] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more stereoisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.
[0088] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.
[0089] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g., 2H or 3H for H; nC, 13C or 14C for 12C; 13N or 15N for 14N; 17O or 18O for 16O; 36C1 for 35C1 or 37C1; 18F for 19F; 131 II ffoorr 127I; etc.). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.
[0090] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
[0091] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and/or utilized in accordance with the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.
[0092] Those skilled in the art will further appreciate that, in small molecule structures, the symbol >zvvv , as used herein, refers to a point of attachment between two atoms. Additionally, or alternatively, the symbol ■/vvu refers to a point of attachment ring in a spirocyclic manner.
[0093] Treat: As used herein, the terms “treat, ” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
APMAP Modulators
[0094] The present disclosure provides, among other things compounds and compositions useful as APMAP modulators, and uses thereof in the treatment of certain diseases, disorders, and conditions, as described herein. In some embodiments, present disclosure provides, among other things, compounds, and compositions useful as APMAP inhibitors, and uses thereof in the treatment of certain diseases, disorders, and conditions, as described herein.
[0095] In some embodiments, the present disclosure provides a compound represented by
Formula I:
Formula I, or a pharmaceutically acceptable salt thereof, wherein:
X1 is CRX or N;
X2 is C or N; X3 is CRX or N;
Ring ¥ is optionally substituted 4- to 6-mcmbcrcd hctcroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; each Rx is independently selected from the group consisting of hydrogen, halogen, -CN, -OR, optionally substituted Ci-Ce aliphatic, and optionally substituted C3-C7 cycloaliphatic,
A is -L'-A1-*, where * represents a point of attachment to B;
L1 is a bond, -O-, -S-, -N(R)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or optionally substituted Ci-Ce aliphatic;
A1 is selected from the group consisting of -optionally substituted Ci-Ce aliphatic, optionally substituted -C3-C12 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cw aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
B is selected from the group consisting of a bond, optionally substituted -Ci-Ce aliphatic, optionally substituted -C3-C7 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
R1 is selected from the group consisting of hydrogen, halogen, -CN, -O(R), -N(R)2, - OC(O)(R), -C(O)O(R), -C(O)N(R)2, -S(R), -S(O)R, -S(O)2R, -N(R)C(O)R, =NC(O)R, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
[0096] In some embodiments, a compound of formula I is non-racemic. Reference to a “non- racemic” compound is intended to refer to a compound where (R) and (S) enantiomers are not present in an equal amount.
[0097] In some embodiments, the present disclosure provides a compound represented by
N N
[0098] As used herein, reference to a compound that is a racemate refers to a homogeneous single phase of enantiomers of the indicated compound. See, e.g., Alan. G. Mitchell, J. Pharm. Pharmaceut. Set., 1(1):8-12, 1998. It is understood that a compound that is a racemate may have different physical or biological properties relative to a compound that is a single enantiomer of the indicated compound.
[0099] In some embodiments, the present disclosure encompasses an insight that particular enantiomers, or molecules having a particular configuration at a particular carbon atom, are particularly active as inhibitors of APMAP, whereas the other enantiomer is less active. Reference to a compound of Formula I not being a racemate means that the compound is not an unresolved mixture of R/S enantiomers. Accordingly, in some such embodiments, the racemate is intended reported scope. For example, when a compound that is referred to as not being a racemate means that the following compound is excluded: s
N N N
O.
, but the specific enantiomers are intended to be included:
[0100] As described generally herein, X1 is N or CRX. In some embodiments, X1 is N. In some embodiments, X1 is CRX. In some embodiments, X1 is CH.
[0101] As described generally herein, X2 is N or C. In some embodiments, X2 is N. In some embodiments, X2 is C.
[0102] As described generally herein, X3 is N or CRX. In some embodiments, X3 is N. In some embodiments, X3 is CRX. In some embodiments, X3 is CH.
[0103] In some embodiments, X1 is N, X2 is N, and X3 is N. In some embodiments, X1 is CRX, X2 is N, and X3 is N. In some embodiments, X1 is N, X2 is C, and X3 is N. In some embodiments, X1 is N, X2 is N, and X3 is CRX. In some embodiments, X1 is CRX, X2 is C, and X3 is N. In some embodiments, X1 is CRX, X2 is N, and X3 is CRX. In some embodiments, X1 is N, X2 is C, and X3 is CRX. In some embodiments, X1 is CRX, X2 is C, and X3 is CRX.
[0104] As described generally herein, Ring Y is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
[0105] In some embodiments, Ring Y is an optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Ring Y is 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with -(CH2)IMR°. In some embodiments, Ring Y is 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with R°, where R° is optionally substituted Ci-Ce aliphatic. In some embodiments, Ring Y is unsubstituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Ring Y is an optionally substituted 5-membered heteroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S. In some embodiments, Ring Y is: wherein
X4 is O, S, N, NRX, or CRX, as valency permits;
X5 is O, S, N, NRX, or CRX, as valency permits; and
X6 is O, S, N, NRX, or CRX, as valency permits.
[0106] As described generally herein, X4 is O, S, N, N(RX), or C(RX), as valency permits. A selection of a value for X4 is made from the perspective of a person having ordinary skill in the art understanding which options are available that provide a stable compound. In some embodiments, X4 is O. In some embodiments, X4 is S. In some embodiments, X4 is N. In some embodiments, X4 is N(RX). In some embodiments, X4 is N(H). In some embodiments, X4 is N(CI-C6 aliphatic). In some embodiments, X4 is N(CHs). In some embodiments, X4 is C(RX). In some embodiments, X4 is C(H). In some embodiments, X4is QCHa). In some embodiments, X4 is N or C(RX).
[0107] As described generally herein, X5 is O, S, N, N(RX), or C(RX ), as valency permits. A selection of a value for X5 is made from the perspective of a person having ordinary skill in the art understanding which options arc available that provide a stable compound. In some embodiments, X5 is O. In some embodiments, X5 is S. In some embodiments, X5 is N. In some embodiments, X5 is N(RX). In some embodiments, X5 is N(H). In some embodiments, X5 is N(Ci-Ce aliphatic). In some embodiments, X5 is N(CH3). In some embodiments, X5 is C(RX). In some embodiments, X5 is C(H). In some embodiments, X5 is ClCHa). In some embodiments, X5 is N or C(RX).
[0108] As described generally herein, X6 is O, S, N, N(RX), or C(RX ), as valency permits. A selection of a value for X6 is made from the perspective of a person having ordinary skill in the art understanding which options are available that provide a stable compound. In some embodiments, X6 is O. In some embodiments, X6 is S. In some embodiments, X6 is N. In some embodiments, X6 is N(RX). In some embodiments, X6 is N(H). In some embodiments, X6 is N(CI-C6 aliphatic). In some embodiments, X6 is N(CHj). In some embodiments, X6 is C(RX). In some embodiments, [0109] In some embodiments, (i) X1 is N, X2 is N, X3 is CRX, X4 is N, X5 is N, and X6 is N; or (ii) X1 is CRX, X2 is N, X3 is CRX, X4 is N, X5 is N, and X6 is N; or (iii) X1 is N, X2 is C, X3 is CRX, X4 is NRX, X5 is N, and X6 is N; or (iv) X1 is N, X2 is C, X3 is CRX, X4 is N, X5 is NRX, and X6 is N; or (v) X1 is N, X2 is C, X3 is CRX, X4 is N, X5 is N, and X6 is NRX; or (vi) X1 is N, X2 is C, X3 is CRX, X4 is N, X5 is CRX, and X6 is NRX; or (vii) X1 is N, X2 is C, X3 is CRX, X4 is NRX, X5 is CRX, and X6 is N; or (viii) X1 is N, X2 is C, X3 is CRX, X4 is NRX, X5 is N, and X6 is CRX; or (ix) X1 is N, X2 is C, X3 is CRX, X4 is CRX, X5 is N, and X6 is NRX; or (x) X1 is N, X2 is C, X3 is CRX, X4 is N, X5 is O, and X6 is N; or (xi) X1 is N, X2 is C, X3 is CRX, X4 is N, X5 is S, and X6 is N; or (xii) X1 is N, X2 is N, X3 is CRX, X4 is CRX, X5 is CRX, and X6 is N; or (xiii) X1 is N, X2 is N, X3 is CRX, X4 is CRX, X5 is N, and X6 is N; or (xiv) X1 is N, X2 is N, X3 is CRX, X4 is N, X5 is CRX, and X6 is N; or (xv) X1 is CRX, X2 is N, X3 is CRX, X4 is N, X5 is CRX, and X6 is N. In some embodiments, (i) X1 is N, X2 is N, X3 is CRX, X4 is N, X5 is N, and X6 is N; or (ii) X1 is CRX, X2 is N, X3 is CRX, X4 is N, X5 is N, and X6 is N. In some embodiments, X1 is N, X2 is N, X3 is CRX, X4 is N, X5 is N, and X6 is N. In some embodiments, X1 is CRX, X2 is N, X3 is CRX, X4 is N, X5 is N, and X6 is N.
[0110] As described generally herein, Rx is selected from the group consisting of hydrogen, halogen, -CN, -OR, optionally substituted C1-C6 aliphatic, and optionally substituted C3-C7 cycloaliphatic. In some embodiments, Rx is hydrogen or optionally substituted Ci-Ce aliphatic. In some embodiments, Rx is hydrogen. In some embodiments, Rx is optionally substituted Ci-Ce aliphatic. In some embodiments, Rx is methyl.
[0111] In some embodiments, a moiety
X3
Y
2 is selected from the group consisting of:
[0112] In some embodiments, a moiety is
[0113] In some embodiments, a moiety is
[0114] In some embodiments, a moiety is
[0115] As described generally herein, moiety A is -iJ-A1-*, where * represents a point of attachment to moiety B [0116] As described generally herein, L1 is a bond, -O-, -S-, -N(R)-, -OC(O)-, C(O)O-, - C(O)N(R)-, -N(R)C(O)-, S(O)-, S(O)2-, or optionally substituted Ci-Ce aliphatic. In some embodiments, L1 is a bond, -O-, or -N(R)-.
[0117] As described generally herein, A1 is selected from the group consisting of -optionally substituted Ci-Ce aliphatic, optionally substituted -C3-C12 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A1 is optionally substituted Ci- Ce aliphatic, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A1 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
[0118] In some embodiments, L1 is a bond, and A1 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
In some embodiments, L1 is -O- or -N(R)- and A1 is Ci-Ce aliphatic.
[0119] In some embodiments, when L1 is a bond and A1 is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, moiety B is connected to moiety A at a chiral carbon atom on moiety A. In some embodiments, the connection between moiety B and moiety A is chirally pure (e.g., is non-racemic). In some embodiments, the connection between moiety B and moiety A is in a single stereochemical configuration (e.g., is non-racemic, or has an absolute configuration of (R) or (S)). As used here, reference to a “chirally pure” carbon atom refers to a carbon atom that is chiral, non-racemic, and has an absolute stereochemical configuration that is either is in (R) or (S) stereochemical configuration. In some embodiments, the particular stereochemical configuration is the (S) enantiomer. In some embodiments, the particular stereochemical configuration is the (R) enantiomer. In some embodiments, the connection between moiety B and moiety A is in the (S) a chirally pure carbon atom on moiety A refers to a chirally pure connection between moiety A and R1. That is, in some embodiments, when B is a bond, then a bond between moiety A and R1 is either in the (S) or (R) stereochemical configuration. In some embodiments, when B is a bond, then a bond between moiety A and R1 is in the (S) stereochemical configuration. In some embodiments, when B is a bond, then a bond between moiety A and R1 is in the R stereochemical configuration. As used herein, reference to a “chirally pure” composition refers to a composition comprising greater than 50% and typically comprises at least about 60%, 70%, 80%, 90%, or even more of a compound that is in a particular stereochemical configuration. In some embodiments, chirally pure compositions comprise at least from about 90% to about 99% of a specified chiral compound. In some embodiments, chirally pure compositions comprise at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% of a specified chiral compound. In some embodiments, a chirally pure composition comprises a single enantiomer of a compound. In some embodiments, the particular stereochemical configuration is the (S) enantiomer. In some embodiments, the particular stereochemical configuration is the (R) enantiomer.
[0120] In some embodiments, a composition described herein has an enantiomeric excess of an indicated enantiomer. The term “enantiomeric excess” indicates the excess of an enantiomer in a mixture of enantiomers, and is calculated according to the following formula: ee=[|m 1 -m 2\/(m 1 +m 2)]xl00% ee: enantiomeric excess mi : fraction of enantiomer 1 m2: fraction of enantiomer 2.
[0121] In some embodiments, the chirally pure composition comprises a single enantiomer of a compound of Formula I in an enantiomeric excess of about 90% or greater. In some embodiments, the composition comprises a single enantiomer of a compound of Formula I in an enantiomeric excess of about 95% or greater. In some embodiments, the composition comprises a single enantiomer of a compound of Formula I in an enantiomeric excess of about 99% or greater. In some embodiments, the single enantiomer is the (S) enantiomer. In some embodiments, the single enantiomer is the (R) enantiomer.
[0122] In some embodiments, a moiety is selected from the group consisting of:
[0123] In some embodiments, a moiety is selected from the group consisting of:
[0124] In some embodiments, a moiety is selected from the group consisting of:
[0125] In some embodiments, a moiety is: wherein each RA is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl. [0126] In some embodiments, a moiety is: wherein each RA i ■ s as described in classes and subclasses here, both singly and in combination, and carbon atom a is chirally pure (e.g., is a single (S) or (R) enantiomer).
In some embodiments, a moiety is: wherein R1 is as described in classes and subclasses here, both singly and in combination.
[0127] In some embodiments, a moiety is: wherein R1 is as described in classes and subclasses here, both singly and in combination, and carbon atom a is chirally pure (e.g., is a single (S) or (R) enantiomer).
[0128] In some embodiments, carbon atom a is in the (S) stereochemical configuration. In some embodiments, carbon atom a is in the (R) stereochemical configuration.
[0129] As described generally herein, B is selected from the group consisting of a bond, optionally substituted -Ci-Ce aliphatic, optionally substituted -C3-C7 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is selected from the group consisting of a bond, optionally substituted -Ci-Ce aliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 hctcroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is a bond. In some embodiments, B is optionally substituted Ci-Ce aliphatic. In some embodiments, B is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is 5- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
[0130] As described generally herein, R1 is selected from the group consisting of hydrogen, halogen, CN, O(R), -N(R)2, -OC(O)(R), C(O)O(R), -C(O)N(R)2, -S(R), S(O)R, S(O)2R, - cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R1 is selected from halogen, CN, O(R), -N(R)2, -OC(O)(R), C(O)O(R), -C(0)N(R)2, -S(R), S(O)R, S(O)2R, -N(R)C(O)R, =NC(O)R, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R1 is hydrogen, CN, O(R), -N(R)2, -OC(O)(R), C(O)O(R), -C(0)N(R)2, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
[0131] In some embodiments, R1 is optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, wherein R1 is wherein R1a is optionally substituted -Ci-Ce aliphatic, C3-C7 cycloaliphatic, or 4- to 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
In some embodiments, R1 is optionally substituted Ce-Cio aryl.
In some embodiments, R1 is C(0)N(R)2.
In some embodiments of Formula I:
X1 is N or CRX;
X2 is C or N;
X3 is N or CRX;
Ring ¥ is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each Rxis independently selected from the group consisting of hydrogen or optionally substituted Ci-Ce aliphatic;
A is -L'-A1-*, where * represents a point of attachment to B; A1 is selected from the group consisting of -optionally substituted Ci-Ce aliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 hctcroatoms selected from N, O, and S, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
B is selected from the group consisting of a bond, optionally substituted -Ci-Cd aliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
R1 is selected from the group consisting of hydrogen, -CN, -O(R), -N(R)2, -OC(O)(R), -C(O)O(R), -C(O)N(R)i, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
[0132] In some embodiments of Formula I:
X1 is N or CRX;
X2 is N;
X3 is CRX;
Ring ¥ is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each Rx is hydrogen;
A is -L'-A1-*, where * represents a point of attachment to B;
L1 is a bond;
A1 is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
B is a bond;
R1 is selected from the group consisting of hydrogen, halogen, -CN, -O(R), -N(R)2, - OC(O)(R), -C(O)O(R), -C(O)N(R)2, optionally substituted Ci-Ce aliphatic, optionally comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cw aryl, and optionally substituted 5- to 10-mcmbcrcd hctcroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
[0133] In some embodiments of Formula I:
X1 is N or CH;
X2 is N;
X3 is CH;
Ring Y is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;
A is -L'-A1-*, where * represents a point of attachment to B;
L1 is a bond;
A1 is 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 RA;
B is a bond;
R1 is selected from the group consisting of hydrogen, -C(O)O(R), -C(0)N(R)2, optionally substituted C1-C6 aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each RA i is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
[0134] In some embodiments of Formula I:
X1 is N or CH;
X2 is N;
X3 is CH;
Ring Y is optionally substituted 5-membered heteroaryl comprising 1 to 4 heteroatoms selected A is -iJ-A1-*, where * represents a point of attachment to B;
L1 is a bond;
A1 is 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 RA;
B is a bond;
R1 is selected from the group consisting of hydrogen, -C(O)O(R), -C(0)N(R)2, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each RA is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
[0135] In some embodiments of Formula I:
X1 is N or CH;
X2 is N;
X3 is CH;
Ring ¥ is optionally substituted 5-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;
A is -L'-A1-*, where * represents a point of attachment to B;
L1 is a bond;
A1 is 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 RA;
B is a bond;
R1 is 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with R1a ; each R ‘ is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl;
Ria is hydrogen, Ci-Ce aliphatic, or optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
[0136] In some embodiments of Formula I:
X1 is N or CH;
X2 is N;
X3 is N or CH;
X4 is O, S, N, NH, or CH, as valency permits;
X5 is O, S, N, NH, or CH, as valency permits;
X6 is O, S, N, NH, or CH, as valency permits;
A is -iJ-A1-*, where * represents a point of attachment to B;
L1 is a bond;
A1 is 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 RA;
B is a bond;
R1 is 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with R1a ; each RA is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl;
Ria is hydrogen, Ci-Ce aliphatic, or optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
[0137] In some embodiments of Formula I:
X1 is N or CH;
X2 is N;
X3 is CH; X5 is N;
X6 is N;
A is -L'-A1-*, where * represents a point of attachment to B;
L1 is a bond;
A1 is 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 RA;
B is a bond;
R1 is 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with R1a ; each R “ is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl;
Ria is hydrogen, Ci-Ce aliphatic, or optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
[0138] In some embodiments, the present disclosure provides a compound represented by Formula II- 1 : or a pharmaceutically acceptable salt thereof, wherein X1, RA, and R1 are as described in classes and subclasses here, both singly and in combination.
[0139] In some embodiments, the present disclosure provides a compound represented by
Formula II-2: or a pharmaceutically acceptable salt thereof, wherein carbon atom a is a chirally pure carbon atom.
[0140] In some embodiments, the present disclosure provides a compound represented by
Formula II-3:
II-3 or a pharmaceutically acceptable salt thereof.
[0141] In some embodiments, the present disclosure provides a compound represented by
Formula II-4: or a pharmaceutically acceptable salt thereof.
[0142] In some embodiments, the present disclosure provides a compound represented by
Formula III- 1 :
III-l or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, X6, RA, and R la are as described in classes and subclasses here, both singly and in combination.
[0143] In some embodiments, the present disclosure provides a compound represented by Formula III-2:
III-2 or a pharmaceutically acceptable salt thereof, wherein carbon atom a is a chirally pure carbon atom.
[0144] In some embodiments, the present disclosure provides a compound represented by
Formula III-3:
III-3 or a pharmaceutically acceptable salt thereof, wherein carbon atom a is a chirally pure carbon atom and X1 is as described in classes and subclasses here, both singly and in combination.
[0145] In some embodiments, the present disclosure provides a compound represented by Formula III-4: or a pharmaceutically acceptable salt thereof.
[0146] In some embodiments, the present disclosure provides a compound represented by
Formula III- 5:
III-5 h ti ll t bl lt th f [0147] In some embodiments, the present disclosure provides a compound (e.g., a compound represented by any one of Formula I to III-5) that is selected from Table 1:
Table 1 [0148] In some embodiments, the present disclosure provides a compound (e.g., a compound represented by any one of Formula I to III- 5) that is selected from Table 2:
Table 2
Cpd
or a pharmaceutically acceptable salt thereof.
[0149] In some embodiments, the present disclosure provides a compound (e.g., a compound represented by any one of Formula I to III-5) that is selected from Table 3:
Table 3
O.
or a pharmaceutically acceptable salt thereof.
[0150] In some embodiments, an APMAP inhibitor described herein can be conjugated to a moiety useful for engaging another protein (e.g., the APMAP inhibitor is configured onto one end of a heterobifunctional compound, and the other end is a moiety that binds to a target of interest). In some embodiments, an APMAP inhibitor described herein is configured onto a heterobifunctional compound that further comprises a moiety that causes degradation of APMAP. In some embodiments, an APMAP inhibitor described herein be conjugated, either directly or through a linker moiety, to a moiety that binds to an E3 ligase (e.g., CRBN, VHL, IAP, MDM2, DDB1, DCAF15, or 0TRCP). In some embodiments, such a compound causes degradation of APMAP in a biological sample. Examples of suitable E3 ligase binding moieties and linkers useful to configure to APMAP inhibitors described herein are described in WO2016/149668, W02017/011590, WO2017/030814A, WO2019/060693, WO2019/060742, WO2017/197036,
WO2017/197046, and in L. Hu, et al., Mol Biomed., 2022 Dec 20;3(l):46. [0151] In some embodiments, provided compounds are provided and/or utilized in a salt form (c.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.
Uses, Formulation, and Administration
Pharmaceutically Acceptable Compositions
[0152] According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient. [0153] Compounds and compositions, according to method of the present disclosure, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.
[0154] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.
[0155] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [0156] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glyccridcs. Fatty acids, such as oleic acid and its glyceride derivatives arc useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
[0157] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [0158] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[0159] In some embodiments, provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.
[0160] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such aass,, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and/or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[0161] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain pail of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight [0162] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[0163] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, 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, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[0164] Alternatively, pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.
[0165] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[0166] Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[0167] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
[0168] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.
[0169] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
[0170] Pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[0171] Dosage forms for topical or transdermal administration of a compound disclosed herein The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, car drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Methods of Treating Diseases, Disorders, and Conditions
[0172] As described herein, the present disclosure provides, among other things, methods of treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of an APMAP inhibitor. In some embodiments, the present disclosure provides, among other things, methods of treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound (e.g., a compound of any one of Formula I-III-5) or composition (e.g., a pharmaceutical composition) described herein. As illustrated, for example, in Example 8, compounds and compositions exhibit APMAP inhibition as demonstrated in reported biological assays. In some embodiments, a APMAP inhibitor useful for treatment of diseases, disorders, and conditions described herein is one having less than 5.00 pM IC50 in an assay as described in Example 8. In some embodiments, a APMAP inhibitor useful for treatment of diseases, disorders, and conditions described herein is one having less than 0.50 pM IC50 in an assay as described in Example 8. In some embodiments, a APMAP inhibitor useful for treatment of diseases, disorders, and conditions described herein is one having less than 0.050 pM IC50 in an assay as described in Example 8.
[0173] In some embodiments, the disease, disorder, or condition is responsive to APMAP inhibition is an infectious disease, disorder, or condition, a neurological or neurodegenerative disease, disorder, or condition, or cancer.
[0174] In some embodiments, the disease, disorder, or condition responsive to APMAP 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.
[0175] In some embodiments, 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.
[0176] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a sarcoma or carcinoma.
[0177] In some embodiments, the cancer is prostate cancer, breast cancer, lung cancer, liver cancer, bladder cancer, urinary tract cancer, or eye cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is eye cancer.
[0178] In some embodiments, 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 Sezary syndrome.
[0179] In some embodiments, 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, 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, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin’s disease, Wilms’ tumor and teratocarcinomas.
[0180] In some embodiments, 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, hepatocellular carcinoma, pancreatic cancer, bladder carcinoma, renal cell carcinoma, kidney cancer, Wilms’ tumor, thyroid cancer, parathyroid tumor, synovioma, soft tissue sarcoma (e.g., rhabdomyosarcoma (RMS)), Kaposi sarcoma, synovial sarcoma, osteosarcoma, Ewing’s sarcoma, malignant rhabdoid tumor, leiomyosarcoma, liposarcoma, lymphangioendothelio- sarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, I'i bro sarcoma, chondrosarcoma, or endotheliosarcoma.
[0181] In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is lymphoma, leukemia, or myeloma.
[0182] In some embodiments, the cancer is a lymphoma. In some embodiments, the cancer is Burkitt’s lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, nonHodgkin’s lymphoma, lymphoid malignancies of T-cell or B-cell origin, peripheral T-cell lymphoma, adult T-cell leukemia-lymphoma, or Waldenstrom’s macroglobulinemia.
[0183] In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is acute leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, myelogenous leukemia, leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, polycythemia vera, multiple myeloma, or erythroleukemia.
[0184] In some embodiments, the cancer is a myelodysplastic and/or myeloproliferative syndrome. In some embodiments, the cancer is a myelodysplastic syndrome. In some embodiments, the cancer is a myeloproliferative syndrome.
[0185] In some embodiments, the cancer is a cancer or related myeloproliferative disorder selected from histiocytosis, essential thrombocythemia, myelofibrosis, heavy chain disease, and other malignancies and hypcrprol iterative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus.
[0186] In some embodiments, 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.
[0187] In some embodiments, 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.
[0188] In some embodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing’s ttuummoorr,, 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, medulloblastoma, and hemangioblastoma. In some embodiments, 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 Cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.
[0189] In some embodiments, the cancer an antibody-dependent cellular- phagocytosis (ADCP)-resistant cancer. In some embodiments, the cancer comprises U266 cells.
[0190] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a relapsed and/or refractory cancer.
[0191] In some embodiments, the cancer is ovarian cancer, uterine cancer, gestational trophoblastic disease, endometrial ccaanncceerr,, cervical ccaanncceerr,, embryonal carcinoma, choriocarcinoma, prostate cancer (including hormone insensitive and castrate resistant prostate cancers), testicular ttuummoorrss (including ggeerrmm cell testicular ccaanncceerr / 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), 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, hepatocellular- carcinoma, pancreatic cancer, bladder carcinoma, renal cell carcinoma, kidney cancer, Wilms’ tumor, thyroid cancer, parathyroid tumor, synovioma, soft tissue sarcoma (e.g., rhabdomyosarcoma (RMS)), Kaposi sarcoma, synovial sarcoma, osteosarcoma, Ewing’s sarcoma, malignant rhabdoid tumor, leiomyosarcoma, liposarcoma, lymphangioendothelio-sarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, fibrosarcoma, chondrosarcoma, or cndothcliosarcoma.
[0192] In some embodiments, the disease, disorder, or condition responsive to APMAP inhibition is an infectious disease, disorder, or condition.
[0193] In some embodiments, the infectious disease, disorder, 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.
[0194] In some embodiments, the disease, disorder, or condition responsive to APMAP inhibition is a neurodegenerative disease, disorder, or condition.
[0195] In some embodiments, an APMAP inhibitor described herein is capable of crossing the blood-brain barrier, such that an APMAP inhibitor described herein can be administered to the brain of a subject. In some embodiments, an APMAP inhibitor is administered to the subject’s brain. Brain-penetrant compounds described herein arc particularly useful for treating neurological or neurodegenerative diseases, disorders, and conditions.
[0196] In some embodiments, the neurodegenerative disease, disorder, or condition is multiple sclerosis; Huntington’s disease; or Parkinson’s disease. In some embodiments, the neurodegenerative disease, disorder, or condition is a disease involving amyloid beta deposit formation or a disease of frontal neuronal degeneration. In some embodiments, the disease involving amyloid beta deposit formation is Alzheimer’s disease. In some embodiments, the disease of frontal neuronal degeneration is frontotemporal dementia.
[0197] In some embodiments, the disease, disorder, or condition responsive to APMAP inhibition is selected from those listed in Table 4.
[0198] In some embodiments, the disease, disorder, or condition is septicemia. In some embodiments, the disease, disorder, or condition is obesity.
[0199] In some embodiments, the subject is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a pediatric human. In some embodiments, the subject is a geriatric human.
[0200] In some embodiments, the present disclosure provides a compound (e.g., a compound of any one of Formula I to III-5) for use in medicine. [0201] In some embodiments, the present disclosure provides a compound (e.g., a compound of any one of Formula I to III-5) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease, disorder, or condition described herein.
Combination Therapies
[0202] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to the subject a compound described herein (e.g., a compound of any one of Formula I to III-5) and one or more additional therapeutic agents. In some embodiments, the present disclosure provides a regimen of treating a disease, disorder, or condition that comprises combination therapy. In some embodiments, a compound described herein is used in combination with an additional therapeutic agent that binds to a target selected from amyloid beta (A[3) (e.g., unmodified Ap or modified Ap, e.g., pyroglutamate-modified AP), BCMA, CCR4, CD19, CD20, CD22, CD24, CD30, CD33, CD38, CD47, CD52, CD79b, ,
CEACAM5, CEACAM6, Claudin 6, Claudin 18.2, CTLA-4, DLL3, EGER, FGFR2, GD2,
GPRC5D, GUCY2C, HER2, LAG3, Mesothelin, MET, Nectin-4, PDGFRa, PD-1, PD-L1, PSMA,
RANKE, SLAMF7, SMAGP, TF, TREM2, TROP2, VEGF, VEGFR, VEGFR2, or epidermal growth factor receptor with exon 20 insertion mutations, to treat a disease, disorder, or condition, such as cancer or a neurodegenerative disease, disorder, or condition. Such combination therapies are described in more detail below.
[0203] Accordingly, in some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein and co-administering (e.g., simultaneously, or sequentially) an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents.
[0204] 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. If administered as a multiple dosage regime, one or more other therapeutic agent and first compound may be administered simultaneously, sequentially or within a period of time from one another.
[0205] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[0206] When administered concurrently, the compounds of the present 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. In some embodiments, 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 arc administered simultaneously, sequentially, or separately. In some embodiments, the amount and frequency of administration of the second therapeutic agent can use standard dosages and standard administration frequencies used for the particular therapeutic agent. See, e.g., Physicians’ Desk Reference, 70th Ed., PDR Network, 2015; incorporated herein by reference.
[0207] In some embodiments, the present disclosure provides a method for treating a disease, disorder, or condition responsive to APMAP inhibition, 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 any one of Formula I to III-5) and (ii) an additional therapeutic agent, to treat the disease, disorder, or condition.
[0208] In some embodiments, the present disclosure provides a method for treating a disease, disorder, or condition responsive to APMAP inhibition, 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 any one of Formula I to III-5) and (ii) an additional modified Ap, e.g., pyroglutamate-modified AP), BCM A, CCR4, CD 19, CD20, CD22, CD24, CD30, CD33, CD38, CD47, CD52, CD79b, CEACAM5, CEACAM6, Claudin 6, Claudin 18.2,
CTLA-4, DLL3, EGFR, FGFR2, GD2, GPRC5D, GUCY2C, HER2, LAG3, Mesothelin, MET,
Nectin-4, PDGFRa, PD-1, PD-L1, PSMA, RANKL, SLAMF7, SMAGP, TF, TREM2, TR0P2,
VEGF, VEGFR, VEGFR2, or epidermal growth factor receptor with exon 20 insertion mutations, to treat the disease, disorder, or condition. In some embodiments, the target is CCR4, CD19, CD20, CD22, CD30, CD33, CD38, CD47, CD52, or CD79b. In some embodiments, the target is Claudin 18.2 or CTLA-4. In some embodiments, the target is EGER, FGFR2, or epidermal growth factor receptor with exon 20 insertion mutations. In some embodiments, the target is GD2, HER2, LAG3, MET, Nectin-4, PDGFRa, or PD-L1. In some embodiments, the target is RANKL, SLAMF7, TF, or TROP2. In some embodiments, the target is VEGF or VEGFR. In some embodiments, the target is Ap (e.g., unmodified Ap or modified Ap, e.g., pyroglutamate-modified AP). In some embodiments, the target is BCMA. In some embodiments, the target is CCR4. In some embodiments, the target is CD19. In some embodiments, the target is CD20. In some embodiments, the target is CD22. In some embodiments, the target is CD24. In some embodiments, the target is CD30. In some embodiments, the target is CD33. In some embodiments, the target is CD38. In some embodiments, the target is CD47. In some embodiments, the target is CD52. In some embodiments, the target is CD79b. In some embodiments, the target is CEACAM5. In some embodiments, the target is CEACAM6. In some embodiments, the target is Claudin 6. In some embodiments, the target is Claudin 18.2. In some embodiments, the target is CTLA-4. In some embodiments, the target is DLL3. In some embodiments, the target is EGFR. In some embodiments, the target is FGFR2. In some embodiments, the target is GD2. In some embodiments, the target is GPRC5D. In some embodiments, the target is GUCY2C. In some embodiments, the target is HER2. In some embodiments, the target is LAG3. In some embodiments, the target is Mesothelin. In some embodiments, the target is MET. In some embodiments, the target is Nectin-4. In some embodiments, the target is PDGFRa. In some embodiments, the target is PD-1. In some embodiments, the target is PD-L1. In some embodiments, the target is PSMA. In some embodiments, the target is RANKL. In some embodiments, the target is SLAMF7. In some embodiments, the target is SMAGP. In some embodiments, the target is TF. In some embodiments, the target is VEGF. In some embodiments, the target is VEGFR. In some embodiments, the target is VEGFR2. In some embodiments, the target is epidermal growth factor receptor with exon 20 insertion mutations.
In some embodiments, the additional therapeutic agent is an inhibitor. In some embodiments, the additional therapeutic agent is an agonist.
[0209] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is Alemtuzumab, Amivantamab (e.g., Amivantamab-vmjw), Avelumab, Bemarituzumab, Bevacizumab, Cetuximab, Cosibelimab, Daratumumab, Denosumab, Dinutiximab, Elotuzumab, Elranatamab (e.g., Elranatamab-bcmm), Isatuximab (e.g., Isatuximab-irfc), Magrolizumab, Margetuximab (e.g., Margetuximab-cmkb), Mogamulizumab (e.g., Mogamulizumab-kpkc), Naxitamab (e.g., Naxitamab-gqgk), Necitumumab, Obinutuzumab, Ofatumumab, Olaratumab, Panitumumab, Pertuzumab,
Ramucirumab, Rituximab, Tafasitamab (e.g., Tafasitamab-cxix), Talquetamab (e.g., Talquetamab-tgvs), Teclistamab (e.g., Teclistamab-cqyv), Trastuzumab, TTI-622, Evorpacept, a SIRPaFc fusion protein, or Zolbetuximab. In some embodiments, the additional therapeutic agent is ABBV-916 (under development by Abbvie), Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK-6640 (under development by OncoTherapy Science (formerly Immunas Pharma)), Lecanemab (e.g., Lecanemab-irmb), MEDI-1814 (under development by Medimmune (AstraZeneca)), NS- 101 (under development by Neuracle Science), PMN-310 (underdevelopment by ProMIS Neurosciences), PRX-012 (underdevelopment by Prothena), Remtemetug, Sabirnetug, SHR-1707 (under development by Atridia), or Trontinemab. In some embodiments, the additional therapeutic agent is an antibody-drug-conjugate. In some embodiments, 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. In some embodiments, the additional therapeutic agent is a SIRPaFc fusion protein (such as described in U.S. Patent No. 10,906,954, which is herein incorporated by reference in its entirety). In some embodiments, the additional agent is a fusion of a CD47-binding domain of human SIRPa linked to the Fc region of human IgG4.
[0210] In some embodiments, the additional therapeutic agent is Alemtuzumab. In some additional therapeutic agent is Amivantamab-vmjw. Tn some embodiments, the additional therapeutic agent is Avclumab. In some embodiments, the additional therapeutic agent is Bcmarituzumab. In some embodiments, the additional therapeutic agent is Bevacizumab. In some embodiments, the additional therapeutic agent is Cetuximab. In some embodiments, the additional therapeutic agent is Cosibelimab. In some embodiments, the additional therapeutic agent is Daratumumab. In some embodiments, the additional therapeutic agent is Denosumab. In some embodiments, the additional therapeutic agent is Dinutiximab. In some embodiments, the additional therapeutic agent is Elotuzumab. In some embodiments, the additional therapeutic agent is Elranatamab. In some embodiments, the additional therapeutic agent is Elranatamab-bcmm. In some embodiments, the additional therapeutic agent is Isatuximab. In some embodiments, the additional therapeutic agent is Isatuximab-irfc. In some embodiments, the additional therapeutic agent is Magrolizumab. In some embodiments, the additional therapeutic agent is Margetuximab. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb. In some embodiments, the additional therapeutic agent is Mogamulizumab. In some embodiments, the additional therapeutic agent is Mogamulizumab-kpkc. In some embodiments, the additional therapeutic agent is Naxitamab. In some embodiments, the additional therapeutic agent is Naxitamab-gqgk. In some embodiments, the additional therapeutic agent is Necitumumab. In some embodiments, the additional therapeutic agent is Obinutuzumab. In some embodiments, the additional therapeutic agent is Ofatumumab. In some embodiments, the additional therapeutic agent is Olaratumab. In some embodiments, the additional therapeutic agent is Panitumumab. In some embodiments, the additional therapeutic agent is Pertuzumab. In some embodiments, the additional therapeutic agent is Ramucirumab. In some embodiments, the additional therapeutic agent is Rituximab. In some embodiments, the additional therapeutic agent is Tafasitamab. In some embodiments, the additional therapeutic agent is Talquetamab. In some embodiments, the additional therapeutic agent is Talquetamab-tgvs. In some embodiments, the additional therapeutic agent is Tafasitamab-cxix. In some embodiments, the additional therapeutic agent is Teclistamab. In some embodiments, the additional therapeutic agent is Teclistamab-cqyv. In some embodiments, the additional therapeutic agent is Trastuzumab. In some embodiments, the additional therapeutic agent is TTI-622. In some embodiments, the additional therapeutic agent is evorpacept. In some embodiments, the additional therapeutic agent is a SIRPaFc fusion proteins. [0211] In some embodiments, the additional therapeutic agent is ABBV-916. In some embodiments, the additional therapeutic agent is Aducanumab. In some embodiments, the additional therapeutic agent is Crenezumab. In some embodiments, the additional therapeutic agent is Donanemab. In some embodiments, the additional therapeutic agent is Ganterenumab. In some embodiments, the additional therapeutic agent is KHK-6640. In some embodiments, the additional therapeutic agent is Lecanemab. In some embodiments, the additional therapeutic agent is Lecanemab-irmb. In some embodiments, the additional therapeutic agent is MEDI-1814. In some embodiments, the additional therapeutic agent is NS- 101. In some embodiments, the additional therapeutic agent is PMN-310. In some embodiments, the additional therapeutic agent is PRX-012. In some embodiments, the additional therapeutic agent is Remternetug. In some embodiments, the additional therapeutic agent is Sabirnetug. In some embodiments, the additional therapeutic agent is SHR-1707. In some embodiments, the additional therapeutic agent is Trontinemab.
[0212] In some embodiments, the additional therapeutic agent is an antibody-drug-conjugate. In some embodiments, 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.
[0213] In some embodiments, the additional therapeutic agent is Brentuximab vedotin. In some embodiments, the additional therapeutic agent is Enfortumab vedotin. In some embodiments, the additional therapeutic agent is Gemtuzumab ozogamicin. In some embodiments, the additional therapeutic agent is Ibritumomab tiuxetan. In some embodiments, the additional therapeutic agent is Inotuzumab ozogamicin. In some embodiments, the additional therapeutic agent is Loncastuximab tesirine. In some embodiments, the additional therapeutic agent is Moxetumomab pasudotox. In some embodiments, the additional therapeutic agent is Polatuzumab vedotin. In some embodiments, the additional therapeutic agent is Sacituzumab govitecan. In some embodiments, the additional therapeutic agent is Tisotumab vedotin. In some embodiments, the additional therapeutic agent is Trastuzumab deruxtecan. In some embodiments, the additional therapeutic agent is Trastuzumab emtansine.
[0214] In some embodiments, the present disclosure provides a method of treating a subject an APMAP inhibitor described herein in combination with an anti-amyloid beta ( Ap) antibody. In some embodiments, an APMAP inhibitor is administered in combination with an anti-amyloid beta antibody, and thereby stimulates phagocytosis of Ap plaques. In some embodiments, an APMAP inhibitor is administered in combination with an anti-amyloid beta antibody, and thereby reduces the number or size of Ap plaques. In some embodiments, the neurological or neurodegenerative disease, disorder, or condition is Alzheimer’s Disease.
[0215] In some embodiments, an anti-amyloid beta (AP) antibody is selected from ABBV- 916, Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK-6640, Lecanemab (e.g., Lecanemab-irmb), MEDI-1814, NS-101, PMN-310, PRX-012, Remternetug, Sabimetug, SHR- 1707, and Trontinemab. In some embodiments, an anti-amyloid beta (AP) antibody is ABBV- 916. In some embodiments, an anti-amyloid beta (AP) antibody is Aducanumab. In some embodiments, an anti-amyloid beta (AP) antibody is Crenezumab. In some embodiments, an antiamyloid beta (AP) antibody is Donanemab. In some embodiments, an anti-amyloid beta (AP) antibody is Ganterenumab. In some embodiments, an anti-amyloid beta (AP) antibody is KHK- 6640. In some embodiments, an anti-amyloid beta (AP) antibody is Lecanemab (e.g., Lecanemab- irmb). In some embodiments, an anti-amyloid beta (AP) antibody is MEDI-1814. In some embodiments, an anti-amyloid beta (AP) antibody is NS-101. In some embodiments, an antiamyloid beta (AP) antibody is PMN-310. In some embodiments, an anti-amyloid beta (AP) antibody is PRX-012. In some embodiments, an anti-amyloid beta (AP) antibody is Remternetug. In some embodiments, an anti-amyloid beta (AP) antibody is Sabirnetug. In some embodiments, an anti-amyloid beta (AP) antibody is SHR-1707. In some embodiments, an anti-amyloid beta (AP) antibody is Trontinemab.
[0216] Another aspect of the invention provides a method for treating a disease, disorder, or condition responsive to APMAP inhibition, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of (i) a compound describe herein (e.g., a compound of any one of Formula I to III-5) and (ii) CAR-T therapy, to treat the disease, disorder, or condition. In some embodiments, the CAR-T therapy is idecabtagene vicleucel or lisocabtagene maraleucel. In some embodiments, the CAR-T therapy is idecabtagene vicleucel, and the disease, disorder, 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 therapy is lisocabtagene maraleucel, and the disease, disorder, or condition is a large B-cell lymphoma, such as a relapsed or refractory large B-ccll 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.
[0217] The methods may be further characterized according to the identity of the disease, disorder, or condition to be treated. Lor example, in some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, 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. In some embodiments, 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 Sezary syndrome.
[0218] In some embodiments, the disease, disorder, or condition is an autoimmune and/or inflammatory disorder. In some embodiments, the disease, disorder, or condition is rheumatoid arthritis.
[0219] In some embodiments, 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, disorder, or condition to be treated. Exemplary combinations of additional therapeutic agent used (e.g., the inhibitor of a protein) and the disease, disorder, or condition to be treated are set forth in Table 4 below. Table 4
Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
B-Cell Non-Hodgkin Lymphoma.
Relapsed or refractory, low grade or follicular, B-Cell Non-Hodgkin Lymphoma (B-NHL) as a single agent.
First line (IL) B-NHL in combination with first line chemotherapy and, in patients achieving a complete response or partial response as single-agent maintenance therapy.
Diffuse large B-cell lymphoma
Non-progressing (including stable disease), low-grade, B-NHL as a single agent after IL cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
Rituximab IL DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
(Protein Target: IL advanced stage, CD20-positive, diffuse large CD20) B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy.
Chronic Lymphocytic Leukemia
Adult patients with Chronic Lymphocytic Leukemia
Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC).
Rheumatoid Arthritis.
Rheumatoid Arthritis in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies.
Chronic lymphocytic leukemia
Ofatumumab
Chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
(Protein Target: CD20)
Chronic lymphocytic leukemia
In combination with chlorambucil, for the treatment of patients with previously untreated CLL (sp. if del(17p)/TP53 mutation)
Obinutuzumab Follicular lymphoma
In combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma
(Protein Target: who relapsed after, or are refractory to, a rituximab-containing CD20) regimen.
In combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma.
Ibritumomab Follicular lymphoma tiuxetan
Relapsed or refractory follicular lymphoma.
(Protein Target: CD20)
Tafasitamab , e.g., Diffuse large B-cell lymphoma Tafasitamab-cxix
Relapsed or refractory DLBCL in combination with lenalidomide (pts not candidate for high dose chemo-autologous stem cell transplant (ASCT))
(Protein Target: CD 19)
Alemtuzumab Chronic lymphocytic leukemia
(Protein Target: CD52) Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
Mogamulizumab, Mycosis fungoides e-g.,
Mogamulizumab- Sezary syndrome kpkc
Relapsed or refractory mycosis fungoides or Sezary syndrome
(Protein Target: CCR4)
Multiple myeloma
Multiple myeloma (MM) in combination with bortezomib, melphalan and prednisone (VMP) in newly diagnosed patients who arc ineligible for ASCT.
MM in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for ASCT and in patients with RR-MM (second line (2L)).
MM in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for ASCT.
Daratumumab
MM in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy.
MM in combination with pomalidomide and dexamethasone in
(Protein Target: patients who have received at least one prior line of therapy including CD38) lenalidomide and a proteasome inhibitor.
MM in combination with carfilzomib and dexamethasone in patients with RR-MM who have received one to three prior lines of therapy.
MM as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (Pl) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.
Light chain (AL) amyloidosis
Light chain (AL) amyloidosis in combination with bortezomib, cyclophosphamide and dexamethasone in newly diagnosed patients. Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
Multiple myeloma
Isatuximab, e.g., Isatuximab-irfc In combination with pomalidomide and dexamethasone, for the treatment of adult patients with MM who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor.
(Protein Target: In combination with carfilzomib and dexamethasone, for the treatment CD38) of adult patients with RR-MM who have received 1 to 3 prior lines of therapy.
Multiple myeloma
Elotuzumab In combination with lenalidomide and dexamethasone for the treatment of adult patients with RR-MM who have received one to three prior therapies.
(Protein Target:
Combination with pomalidomide and dexamethasone for the treatment SLAMF7) of adult patients with RR-MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
Head and Neck Cancer
Squamous cell carcinoma
Locally or regionally advanced squamous cell carcinoma of head and neck (SCCHN) in combination with radiation therapy.
Recurrent locoregional disease or metastatic SCCHN in combination
Cetuximab with platinum-based therapy with fluorouracil.
Recurrent or metastatic SCCHN progressing after platinum-based therapy.
(Protein Target: EGER) Colorectal cancer
K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test.
In combination with FOLFIRI for first-line treatment.
In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy. Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
As a single-agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.
Colorectal cancer
Panitumumab
RAS WT metastatic CRC
In combination with FOLFOX for first-line treatment.
(Protein Target:
As monotherapy following disease progression after prior treatment EGFR) with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy.
Necitumumab Non-small cell lung cancer
In combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous NSCLC.
(Protein Target: EGFR)
Amivantamab, e.g., Non-small cell lung cancer Amivantamab-vmjw
Adult patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed
(Protein Target: on or after platinum-based chemotherapy. EGFR Ex20 & MET) Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
Breast cancer
Adjuvant for the treatment of HER2 overexpressing breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, with docetaxel and carboplatin, or as a single agent following multi-modality
Trastuzumab an thracy cline based therapy.
In mBrCa, in combination with paclitaxel for first-line treatment of HER2-overexpressing mBrCa or as a single agent for treatment of
(Protein Target: HER2-overexpressing BrCa in patients who have received one or Hcr2) more chemotherapy regimens for metastatic disease.
Gastric or gastroesophageal junction adenocarcinoma
HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in combination with cisplatin and capecitabine or 5- fluorouracil.
Breast cancer
In combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not
Pertuzumab received prior anti-HER2 therapy or chemotherapy.
The neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater
(Protein Target: than 2 cm in diameter or node positive). Her2)
The adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence, in combination with trastuzumab and chemotherapy.
Margetuximab, e.g, Breast cancer Margetuximab-cmkb
In combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for
(Protein Target: metastatic disease. Her2)
Zolbetuximab Gastro-esophageal junction adenocarcinoma Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
(Protein Target: Previously untreated, locally advanced unresectable or metastatic
Claudin 18.2) HER2 -/Claudin 18.2+ gastric or gastro-esophageal junction adenocarcinoma.
Metastatic gastric or gastro-esophageal junction adenocarcinoma
As a single agent or in combination with paclitaxel, for treatment of advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
Non-small cell lung cancer
In combination with erlotinib, for first-line treatment of metastatic NSCLC with EGFR ex 19 deletions or ex21 (L858R) mutations.
Ramucirumab (Cyramza) In combination with docetaxel, for treatment of metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have
(Protein Target: disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. VEGFR2)
Colorectal cancer
In combination with FOLFIRI, for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
Hepatocellular carcinoma
As a single agent, for the treatment of HCC in patients who have an alpha fetoprotein of >400 ng/mL and have been treated with sorafenib.
Bemarituzumab Gastric cancer
FGFR2 OE Gastric cancerlL with FOLFOX6 or chemo + nivolumab.
(Protein Target: FGFR2)
Olaratumab Soft tissue sarcoma in combination with doxorubicin therapy for patients who do not have a curative option with surgery or radiation. Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
(Protein Target: PDGFRa)
Cosibelimab Cutaneous squamous cell carcinoma (cSCC).
(Protein Target: PD- Ll)
Avelumab Urothelial cancer, Renal cancer
(Protein Target: PD- Ll)
Triple negative breast cancer (alone and in combination with standard of care)
Metastatic colorectal cancer, (alone and in combination with standard of care and bevacizumab)
Urothelial cancer (alone and in combination with standard of care)
Magrolimab
Head and neck squamous cell carcinoma alone and in combination with standard of care and /or cetuximab
Low and high Myelodysplastic syndrome with azacytidine
(Protein Target: CD47)
Acute myeloid leukemia alone and with standard of care and or venetoclax
Diffuse large B cell lymphoma, alone and with standard of care, including rituximab, or Obinutuzumab
Multiple myeloma, alone and with standard of care including daratumumab, elotuzumab and Isatuximab-irfc
TTI-622 Multiple myeloma, alone and with standard of care including daratumumab, elotuzumab and Isatuximab-irfc Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
(Protein Target: Diffuse large B cell lymphoma, alone and with standard of care, CD47) including rituximab, or Obinutuzumab or lenalidomide or Taf asitamab -cxix
Ovarian cancer aloen an in combination with Pegylated liposomal doxorubicin
Low and high Myelodysplastic syndrome with azacytidine
Acute myeloid leukemia alone and with standard of care and or venetoclax
Metastatic colorectal cancer, in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment.
Metastatic colorectal cancer, in combination with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second- line treatment in patients who have progressed on a first- line bevacizumab product-containing regimen.
Unresectable, locally advanced, recurrent, or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment.
Bevacizumab
Recurrent glioblastoma in adults
Metastatic renal cell carcinoma in combination with interferon alfa.
(Protein Target: VEGF) Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan.
Epithelial ovarian, fallopian tube, or primary peritoneal cancer: a) in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection; b) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens; or c) in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Avastin as a single agent, for platinumsensitive recurrent disease Name of Additional
Disease, Disorder, or Condition for Treatment Therapeutic Agent
Hepatocellular Carcinoma (HCC) in combination with atezolizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy
Denosumab Prevention of skeletal-related events in patients with bone metastases from solid tumors.
Treatment of adults and skeletally mature adolescents with giant cell
(Protein Target: tumor of bone that is unresectable or where surgical resection is likely RANKL) to result in severe morbidity.
Neuroblastoma
Dinutiximab
In combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma
(Protein Target: who achieve at least a partial response to prior first-line multiagent, GD2) multimodality therapy.
Naxitamab, e.g., Neuroblastoma Naxitamab-gqgk
In combination with granulocyte-macrophage colony-stimulating factor (GMCSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk
(Protein Target: neuroblastoma in the bone or bone marrow who have demonstrated a GD2) partial response, minor response, or stable disease to prior therapy.
Alzheimer’s disease
Aducanumab, e.g., Aducanumab-avwa
In patients with mild cognitive impairment or mild dementia stage of disease
(Protein Target: AB)
Alzheimer’ s disease
Lecanemab e.g., Lecanemab-irmb In patients with mild cognitive impairment or mild dementia stage of disease
(Protein Target: AB)
[0220] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or conditon responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of (i) a compound described herein (e.g., a compound of any one of Formula I to III-5) and (ii) an additional therapeutic agent, wherein: a) the additional therapeutic agent is Rituximab, and the disease, disorder, or condition is:
• B-Cell Non-Hodgkin Lymphoma;
• Relapsed or refractory, low grade or follicular, B-Cell Non-Hodgkin Lymphoma (B- NHL) as a single agent;
• First line (IL) B-NHL in patients achieving a complete response or partial response as single-agent maintenance therapy, and wherein the Rituximab is administered in combination with a first line chemotherapy;
• Diffuse large B-cell lymphoma;
• Non-progressing (including stable disease), low-grade, B-NHL as a single agent after IL cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy;
IL DLBCL, where the Rituximab is administered in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracy cline-based chemotherapy regimen;
• IL advanced stage, CD20-positive, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL), wherein the Rituximab is administered in combination with chemotherapy;
• Chronic Lymphocytic Leukemia;
• Chronic Lymphocytic Leukemia; or
• Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC); b) the additional therapeutic agent is Ofatumumab, and the disease, disorder, or condition is:
• Chronic lymphocytic leukemia; or
• Chronic lymphocytic leukemia refractory to fludarabine and alcmtuzumab; c) the additional therapeutic agent is Obinutuzumab, and the disease, disorder, or condition is:
• Chronic lymphocytic leukemia;
• previously untreated CLL (sp. if del(17p)/TP53 mutation), wherein the Obinutuzumab is administered in combination with chlorambucil; • follicular lymphoma, wherein the Obinutuzumab is administered in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients who relapsed after, or are refractory to, a rituximab-containing regimen; or
• previously untreated stage II bulky, III or IV follicular lymphoma, wherein the Obinutuzumab is administered in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission; d) the additional therapeutic agent is Ibritumomab tiuxetan, and the disease, disorder, or condition is:
• Follicular lymphoma; or
• Relapsed or refractory follicular lymphoma; e) the additional therapeutic agent is Tafasitamab-cxix, and the disease, disorder, or condition is:
• Diffuse large B-cell lymphoma; or
• Relapsed or refractory DLBCL, wherein the Tafasitamab-cxix is administered in combination with lenalidomide; f) the additional therapeutic agent is Alemtuzumab, and the disease, disorder, or condition is Chronic lymphocytic leukemia; g) the additional therapeutic agent is Mogamulizumab-kpkc, and the disease, disorder, or condition is:
• Mycosis fungoides;
• Sezary syndrome; or
• Relapsed or refractory mycosis fungoides or Sezary syndrome; h) the additional therapeutic agent is Daratumumab, and the disease, disorder, or condition is:
• Multiple myeloma;
• Multiple myeloma (MM), wherein the Daratumumab is administered in combination with bortezomib, melphalan and prednisone (VMP) in newly diagnosed patients who are ineligible for ASCT ;
• Multiple myeloma, wherein the Daratumumab is administered in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for ASCT and in patients with RR-MM (second line (2L)); • Multiple myeloma, wherein the Daratumumab is administered in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for ASCT;
• Multiple myeloma, wherein the Daratumumab is administered in combination with bortezomib and dexamethasone in a patient who has received at least one prior therapy;
• Multiple myeloma, wherein the Daratumumab is administered in combination with pomalidomide and dexamethasone in a patient who has received at least one prior line of therapy including lenalidomide and a proteasome inhibitor;
• Multiple myeloma, wherein the Daratumumab is administered in combination with carfilzomib and dexamethasone in a patient with RR-MM who has received one to three prior lines of therapy;
• Multiple myeloma, wherein the patient has received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who is doublerefractory to a PI and an immunomodulatory agent;
• Light chain amyloidosis; or
• Light chain amyloidosis, wherein the Daratumumab is administered in combination with bortezomib, cyclophosphamide and dexamethasone in a patient newly diagnosed with Light chain amyloidosis; i) the additional therapeutic agent is Isatuximab-irfc, and the disease, disorder, or condition is:
• Multiple myeloma;
• Multiple myeloma for the treatment of adult patients, wherein the Isatuximab-irfc is administered in combination with pomalidomide and dexamethasone, wherein patient has received at least 2 prior therapies including lenalidomide and a proteasome inhibitor; or
• RR-Multiple myeloma in an adult patient who has received 1 to 3 prior lines of therapy, wherein the Isatuximab-irfc is administered in combination with carfilzomib and dexamethasone; j) the additional therapeutic agent is Elotuzumab, and the disease, disorder, or condition is:
• Multiple myeloma; • RR-Multiple myeloma is an adult patient who has received one to three prior therapies, wherein the Elotuzumab is administered in combination with lenalidomide and dexamethasone; or
• RR-Multiple myeloma in a patient who has received at least two prior therapies including lenalidomide and a proteasome inhibitor, wherein the Elotuzumab is administered in combination with pomalidomide and dexamethasone; k) the additional therapeutic agent is Cetuximab, and the disease, disorder, or condition is:
• Head and Neck Cancer;
• Squamous cell carcinoma;
• Locally or regionally advanced squamous cell carcinoma of head and neck (SCCHN), wherein the Cetuximab is administered in combination with radiation therapy;
• Recurrent locoregional disease or metastatic SCCHN, wherein the Cetuximab is administered in combination with platinum-based therapy with fluorouracil;
• Recurrent or metastatic SCCHN progressing after platinum-based therapy;
• Colorectal cancer;
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test;
• Cancer, wherein the Cetuximab is administered in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or
• Cancer, wherein the Cetuximab is administered as a single-agent in a patient who has failed oxaliplatin- and irinotecan-based chemotherapy or who is intolerant to irinotecan;
1) the additional therapeutic agent is Panitumumab, and the disease, disorder, or condition is:
• Colorectal cancer;
• RAS WT metastatic CRC;
• Cancer characterized by disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy; m) the additional therapeutic agent is Necitumumab, and the disease, disorder, or condition is:
• Non-small cell lung cancer; or
• Metastatic squamous NSCLC, wherein the Necitumumab is administered in combination with gemcitabine and cisplatin for first line treatment of patients; n) wherein the additional therapeutic agent is Amivantamab-vmjw, and the disease, disorder, or condition is:
• Non-small cell lung cancer; or
• Locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, where the disease has progressed on or after platinum-based chemotherapy; o) wherein the additional therapeutic agent is Trastuzumab, and the disease, disorder, or condition is:
• Breast cancer;
• HER2 overexpressing breast cancer, wherein the Trastuzumab is administered as pail of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, with docetaxel and carboplatin, or as a single agent following multi-modality anthracy cline based therapy;
• mBrCa, wherein the Trastuzumab is administered in combination with paclitaxel for first line treatment of HER2-overexpressing mBrCa or as a single agent for treatment of HER2-overexpressing BrCa in patients who have received one or more chemotherapy regimens for metastatic disease;
• Gastric or gastroesophageal junction adenocarcinoma; or
• HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, wherein the Trastuzumab is administered in combination with cisplatin and capecitabine or 5 -fluorouracil; p) wherein the additional therapeutic agent is Pertuzumab, and the disease, disorder, or condition is:
• Breast cancer;
• HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy, wherein the Pertuzumab is administered in combination with trastuzumab and docetaxel;
• HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive); or • HER2-positive early breast cancer at high risk of recurrence, wherein the Pertuzumab is administered in combination with trastuzumab and chemotherapy; q) wherein the additional therapeutic agent is Margetuximab-cmkb, and the disease, disorder, or condition is:
• Breast cancer; or
• metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease, wherein the Margetuximab- cmkb is administered in combination with chemotherapy; r) wherein the additional therapeutic agent is Zolbetuximab, and the disease, disorder, or condition is:
• Gastro-esophageal junction adenocarcinoma; or
• Previously untreated, locally advanced unresectable or metastatic HER2-/Claudin 18.2+ gastric or gastro-esophageal junction adenocarcinoma; s) wherein the additional therapeutic agent is Ramucirumab, and the disease, disorder, or condition is:
• Metastatic gastric or gastro-esophageal junction adenocarcinoma;
• Advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy, wherein the Ramucirumab is administered as a single agent or in combination with paclitaxel;
• Non-small cell lung cancer;
• first-line treatment of metastatic NSCLC with EGER exl9 deletions or ex21 (L858R) mutations, wherein the Ramucirumab is administered in combination with erlotinib;
• metastatic NSCLC with disease progression on or after platinum-based chemotherapy, wherein the Ramucirumab is administered in combination with docetaxel;
• EGER or ALK genomic tumor aberrations should have disease progression on FDA approved therapy for these aberrations prior to receiving CYRAMZA;
• Colorectal cancer; • Metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine, wherein the Ramucirumab is administered in combination with FOLFIRI;
• Hepatocellular carcinoma; or
• HCC in patients who have an alpha fetoprotein of >400 ng/mL and have been treated with sorafenib; t) wherein the additional therapeutic agent is Bemarituzumab, and the disease, disorder, or condition is:
• Gastric cancer; or
• FGFR2 OE Gastric cancer IL with FOLFOX6 or chemotherapy + nivolumab; or u) wherein the additional therapeutic agent is Olaratumab, and the disease, disorder, or condition is soft tissue sarcoma, wherein the is Olaratumab is administered in combination with doxombicin therapy for patients who do not have a curative option with surgery or radiation; v) wherein the additional therapeutic agent is Cosibelimab, and the disease, disorder, or condition is Cutaneous squamous cell carcinoma (cSCC); w) wherein the additional therapeutic agent is Avelumab, and the disease, disorder, or condition is:
• Urothelial cancer; or
• Renal cancer; x) wherein the additional therapeutic agent is Magrolimab, and the disease, disorder, or condition is:
• Triple negative breast cancer, wherein the Magrolimab is administered alone and in combination with standard of care;
• Metastatic colorectal cancer, wherein the Magrolimab is administered alone and in combination with standard of care and bevacizumab;
• Urothelial cancer, wherein the Magrolimab is administered alone and in combination with standard of care;
• Head and neck squamous cell carcinoma, wherein the Magrolimab is administered alone and in combination with standard of care and/or cetuximab;
• Low and high Myelodysplastic syndrome with azacytidine; • Acute myeloid leukemia, wherein the Magrolimab is administered alone and with standard of care and or venetoclax;
• Diffuse large B cell lymphoma, wherein the Magrolimab is administered alone and with standard of care, including rituximab, or Obinutuzumab; or
• Multiple myeloma, wherein the Magrolimab is administered alone and with standard of care including daratumumab, elotuzumab and Isatuximab-irfc; y) wherein the additional therapeutic agent is TTI-622, and the disease, disorder, or condition is:
• Multiple myeloma, wherein the TTI-622 is administered alone and with standard of care including daratumumab, elotuzumab and Isatuximab-irfc;
• Diffuse large B cell lymphoma, wherein the TTI-622 is administered alone and with standard of care, including rituximab, or Obinutuzumab or lenalidomide or Tafasitamab- cxix;
• Ovarian cancer, wherein the TTI-622 is administered alone an in combination with Pegylated liposomal doxorubicin;
• Low and high Myelodysplastic syndrome, wherein the TTI-622 is administered with azacytidine; or
• Acute myeloid leukemia, wherein the TTI-622 is administered alone or with standard of care and/or venetoclax; z) wherein the additional therapeutic agent is Bevacizumab, and the disease, disorder, or condition is:
• Metastatic colorectal cancer, wherein the Bevacizumab is administered in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment;
• Metastatic colorectal cancer, wherein the Bevacizumab is administered in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab product-containing regimen;
• Unresectable, locally advanced, recurrent, or metastatic non-squamous non-small cell lung cancer, wherein the Bevacizumab is administered in combination with carboplatin and paclitaxel for first- line treatment;
• Recurrent glioblastoma in adults; • Metastatic renal cell carcinoma, wherein the Bevacizumab is administered in combination with interferon alfa;
• Persistent, recurrent, or metastatic cervical cancer, wherein the Bevacizumab is administered in combination with paclitaxel and cisplatin, or paclitaxel and topotecan;
• Epithelial ovarian, fallopian tube, or primary peritoneal cancer, wherein the Bevacizumab is administered: a) in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection; b) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum- resistant recurrent disease who received no more than 2 prior chemotherapy regimens; or c) in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Avastin as a single agent, for platinum- sensitive recurrent disease; or
• Hepatocellular Carcinoma (HCC), wherein the Bevacizumab is administered in combination with atezolizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy; aa) wherein the additional therapeutic agent is Denosumab, and the disease, disorder, or condition is:
• bone metastases from solid tumors for prevention of skeletal-related events in patients; or
• giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity; ab) wherein the additional therapeutic agent is Dinutiximab, and the disease, disorder, or condition is:
• Neuroblastoma; or
• high-risk neuroblastoma in pediatric patients who achieve at least a partial response to prior first-line multiagent, multimodality therapy, wherein the Dinutiximab is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA); ac) wherein the additional therapeutic agent is Naxitamab-gqgk, and the disease, disorder, or condition is:
• Neuroblastoma; or • relapsed or refractory high-risk neuroblastoma in the bone or bone marrow in pediatric patients 1 year of age and older and adult patients who have demonstrated a partial response, minor response, or stable disease to prior therapy, wherein the Naxitamab-gqgk is administered in combination with granulocyte-macrophage colony-stimulating factor (GMCSF); ad) wherein the additional therapeutic is Aducanumab, and the disease, disorder, or condition is:
• Alzheimer’s disease; or
• mild cognitive impairment or mild dementia stage of disease; or ae) wherein the additional therapeutic is Lecanemab, and the disease, disorder, or condition is:
• Alzheimer’s disease; or
• mild cognitive impairment or mild dementia stage of disease.
[0221] In some embodiments, the additional therapeutic agent is a combination of two, three, or four therapeutic agents or treatments. In some embodiments, the additional therapeutic agent is a combination of two therapeutic agents or treatments. In some embodiments, the additional therapeutic agent is a combination of three therapeutic agents or treatments. In some embodiments, the additional therapeutic agent is a combination of four therapeutic agents or treatments. In some embodiments, the treatment is radiation therapy.
[0222] In some embodiments, the additional therapeutic agent is Rituximab in combination with CHOP. In some embodiments, the additional therapeutic agent is Rituximab in combination with CVP. In some embodiments, the additional therapeutic agent is Rituximab in combination with fludarabine and cyclophosphamide. In some embodiments, the additional therapeutic agent is Rituximab in combination with BTKi. In some embodiments, the additional therapeutic agent is Rituximab in combination with venetoclax.
[0223] In some embodiments, the additional therapeutic agent is Rituximab in combination with CAR-T. In some embodiments, the additional therapeutic agent is Rituximab in combination with venetoclax. In some embodiments, the additional therapeutic agent is Rituximab in combination with Ibrutinib. In some embodiments, the additional therapeutic agent is Rituximab in combination with acalabrutinib. In some embodiments, the additional therapeutic agent is Rituximab in combination with zanubrutinib. In some embodiments, the additional therapeutic t i Rit i b i bi ti ith ti b ti ib I b di t th dditi l therapeutic agent is Rituximab in combination with orelabrutinib. In some embodiments, the additional therapeutic agent is Rituximab in combination with idclalisib. In some embodiments, the additional therapeutic agent is Rituximab in combination with autologous stem cell transplantation (ASCT). In some embodiments, the additional therapeutic agent is Rituximab in combination with Copanlisib. In some embodiments, the additional therapeutic agent is Rituximab in combination with Tazemetostat. In some embodiments, the additional therapeutic agent is Rituximab in combination with Axicabtagene ciloleucel. In some embodiments, the additional therapeutic agent is Rituximab in combination with Tisagenlecleucel. In some embodiments, the additional therapeutic agent is Rituximab in combination with Mosunetuzumab-axgb. In some embodiments, the additional therapeutic agent is Rituximab in combination with Lisocabtagene maraleucel. In some embodiments, the additional therapeutic agent is Rituximab in combination with Polatuzumab vedotin-piiq.
[0224] In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with chlorambucil. In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with acalabrutinib. In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with Venetoclax. In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with ibrutinib. In some embodiments, the additional therapeutic agent is Obinutuzumab in combination with bendamustine.
[0225] In some embodiments, the additional therapeutic agent is Tafasitamab-cxix in combination with Lenalidomide.
[0226] In some embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib, melphalan and prednisone (VMP). In some embodiments, the additional therapeutic agent is Daratumumab in combination with lenalidomide and dexamethasone. In some embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib, thalidomide, and dexamethasone. In some embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib and dexamethasone. In some embodiments, the additional therapeutic agent is Daratumumab in combination with pomalidomide and dexamethasone. In some embodiments, the additional therapeutic agent is Daratumumab in combination with carl'ilzomib and dexamethasone. In some embodiments, the additional therapeutic agent is Daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone.
[0227] In some embodiments, the additional therapeutic agent is Daratumumab in combination with Elotuzumab, lenalidomide, dexamethasone, and Bortezomib. In some embodiments, the additional therapeutic agent is Daratumumab in combination with bendamustine, dexamethasone, and either carfilzomib or bortezomib. In some embodiments, the additional therapeutic agent is Daratumumab in combination with Idecabtagene autoleucel. In some embodiments, the additional therapeutic agent is Daratumumab in combination with Ciltacabtagene autoleucel. In some embodiments, the additional therapeutic agent is Daratumumab in combination with Teclistamab-cqyv.
[0228] In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with carfilzomib and dexamethasone. In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with pomalidomide and dexamethasone.
[0229] In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with bendamustine, dexamethasone, and either carfilzomib or bortezomib. In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with Idecabtagene autoleucel. In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with Ciltacabtagene autoleucel. In some embodiments, the additional therapeutic agent is Isatuximab-irfc in combination with Teclistamab-cqyv.
[0230] In some embodiments, the additional therapeutic agent is Elotuzumab in combination with lenalidomide and dexamethasone. In some embodiments, the additional therapeutic agent is Elotuzumab in combination with pomalidomide and dexamethasone.
[0231] In some embodiments, the additional therapeutic agent is Elotuzumab in combination with bendamustine, dexamethasone, and either carfilzomib or bortezomib. In some embodiments, the additional therapeutic agent is Elotuzumab in combination with Idecabtagene autoleucel. In some embodiments, the additional therapeutic agent is Elotuzumab in combination with Ciltacabtagene autoleucel. In some embodiments, the additional therapeutic agent is Elotuzumab in combination with Teclistamab-cqyv.
[0232] In some embodiments, the additional therapeutic agent is Cetuximab in combination with radiation therapy. In some embodiments, the additional therapeutic agent is Cetuximab in therapeutic agent is Cetuximab in combination with FOLFIRI. In some embodiments, the additional therapeutic agent is Cetuximab in combination with irinotecan.
[0233] In some embodiments, the additional therapeutic agent is Cetuximab in combination with Regorafenib. In some embodiments, the additional therapeutic agent is Cetuximab in combination with trifluridine and tipiracil. In some embodiments, the additional therapeutic agent is Cetuximab in combination with trifluridine, tipiracil, and bevacizumab. In some embodiments, the additional therapeutic agent is Cetuximab in combination with a Her2 inhibitor. In some embodiments, the additional therapeutic agent is Cetuximab in combination with a BrafV600E inhibitor.
[0234] In some embodiments, the additional therapeutic agent is Panitumumab in combination with FOLFOX.
[0235] In some embodiments, the additional therapeutic agent is Panitumumab in combination with Regorafenib. In some embodiments, the additional therapeutic agent is Panitumumab in combination with trifluridine and tipiracil. In some embodiments, the additional therapeutic agent is Panitumumab in combination with trifluridine, tipiracil, and bevacizumab. In some embodiments, the additional therapeutic agent is Panitumumab in combination with a Her2 inhibitor. In some embodiments, the additional therapeutic agent is Panitumumab in combination with a BrafV 600E inhibitor.
[0236] In some embodiments, the additional therapeutic agent is Necitumumab in combination with gemcitabine and cisplatin.
[0237] In some embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Nivo. In some embodiments, the additional therapeutic agent is Amivantamab- vmjw in combination with Pembro. In some embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Atezo. In some embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Docetaxel. In some embodiments, the additional therapeutic agent is Amivantamab-vmjw in combination with Gemcitabine.
[0238] In some embodiments, the additional therapeutic agent is Trastuzumab in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with docetaxel and carboplatin. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with with cisplatin and capecitabine. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with 5-fluorouracil.
[0239] In some embodiments, the additional therapeutic agent is Trastuzumab in combination with Fam-trastuzumab deruxtecan-nxki. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with Sacituzumab govitecan. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with systemic chemotherapy. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with a biomarker guided Rx. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with a Her2 inhibitor. In some embodiments, the additional therapeutic agent is Trastuzumab in combination with a BrafV 600E inhibitor.
[0240] In some embodiments, the additional therapeutic agent is Pertuzumab in combination with trastuzumab and docetaxel. In some embodiments, the additional therapeutic agent is Pertuzumab in combination with trastuzumab and chemotherapy.
[0241] In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with chemotherapy. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with capecitabine. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with capecitabine. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with eribulin. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with gemcitabine. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with vinorelbine.
[0242] In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with lapatinib. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with tucatinib. In some embodiments, the additional therapeutic agent is Margetuximab-cmkb in combination with neratinib.
[0243] In some embodiments, the additional therapeutic agent is Zolbetuximab in combination with mFOLFOXb.
[0244] In some embodiments, the additional therapeutic agent is Zolbetuximab in combination with Regorafenib and trifluridine. In some embodiments, the additional therapeutic agent is Zolbetuximab in combination with Regorafenib and tipiracil. In some embodiments, the additional trifluridine. In some embodiments, the additional therapeutic agent is Zolbetuximab in combination with Rcgorafcnib, Bcvacizumab and tipiracil.
[0245] In some embodiments, the additional therapeutic agent is Ramucirumab in combination with paclitaxel. In some embodiments, the additional therapeutic agent is Ramucirumab in combination with erlotinib. In some embodiments, the additional therapeutic agent is Ramucirumab in combination with docetaxel. In some embodiments, the additional therapeutic agent is Ramucirumab in combination with FOLFIRI.
[0246] In some embodiments, the additional therapeutic agent is Ramucirumab in combination with Osimertinob.
[0247] In some embodiments, the additional therapeutic agent is Olaratumab in combination with doxorubicin.
[0248] In some embodiments, the additional therapeutic agent is Avelumab. In some embodiments, the additional therapeutic agent is Magrolizumab. In some embodiments, the additional therapeutic agent is TTI-622. In some embodiments, the additional therapeutic agent is Bevacizumab. In some embodiments, the additional therapeutic agent is Denosumab.
[0249] In some embodiments, 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).
[0250] In some embodiments, the additional therapeutic agent is Naxitamab-gcjgk in combination with granulocyte-macrophage colony- stimulating factor (GMCSF).
Further Exemplary Additional Therapeutic Agents
[0251] In some embodiments, the additional therapeutic agent is a leukotriene inhibitor, nonsteroidal anti-inflammatory drug (NSAID), steroid, tyrosine kinase inhibitor, receptor kinase inhibitor, modulator of nuclear receptor family of transcription factor, HSP90 inhibitor, adenosine receptor (A2A) agonist, disease modifying antirheumatic drugs (DMARDS), phosphodiesterase (PDF) inhibitor, neutrophil elastase inhibitor, modulator of Axl kinase, an anti-cancer agent, antiallergic agent, anti-nausea agent (or anti-emetic), pain reliever, cytoprotective agent, or a combination thereof. In some embodiments, the additional therapeutic agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof. [0252] In some embodiments, 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.
[0253] In some embodiments, the additional therapeutic agent is an NSAID. Examples of 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.
[0254] In some embodiments, the additional therapeutic agent is a steroid. Examples of 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.
[0255] In some embodiments, 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. In some embodiments, the tyrosine kinase inhibitor is ruxolitinib, tofacitinib, oclactinib, fdgotinib, 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.
In some embodiments, the additional therapeutic agent is a receptor kinase inhibitor, including among others, an inhibitor of EGER or HER2. Examples of 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.
[0256] In some embodiments, 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. In some embodiments, the inhibitor is pioglitazone, bexarotene, obeticholic acid, ursodeoxycholic acid, fcxaraminc, hypocholamidc, or combinations thereof.
In some embodiments, the additional therapeutic agent is an HSP90 inhibitor. Examples of 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, CNF 1010, or combinations thereof.
[0257] In some embodiments, the additional therapeutic agent is an adenosine receptor 2A (A2A) agonist. Examples of 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. In some embodiments, the adenosine receptor agonist is LNC-3050, LNC-3015, LNC-3047, LNC-3052, or combinations thereof.
In some embodiments, 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.
[0258] In some embodiments, 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.
In some embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor. Examples of neutrophil elastase inhibitors considered for use in combination therapies of the invention include but are not limited to sivelestat.
[0259] In some embodiments, the additional therapeutic agent is a modulator of Axl kinase. Examples of 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. In some embodiments, the modulator of Axl kinase is a monoclonal antibody targeting AXL (e.g., YW327.6S2) or an AXL decoy receptor (e.g., GL2I.T), [0260] In some embodiments, the additional therapeutic agent is an anti-cancer agent or chcmo-thcrapcutic agent. Examples of anti-cancer agents considered for use in combination therapies of the invention include but are not limited to 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 prednisolone, other alkylating agents such as mechlorethamine, chlorambucil, and ifosfamide, antimetabolites such as azathioprine or mercaptopurine, other microtubule inhibitors (vinca alkaloids like vincristine, vinblastine, vinorelbine, and vindesine, as well as taxanes), podophyllotoxins (etoposide, teniposide, etoposide phosphate, and epipodophyllotoxins), topoisomerase inhibitors, other cytotoxins such as actinomycin, daunorubicin, valrubicin, idarubicin, edrecolomab, epirubicin, bleomycin, plicamycin, mitomycin, as well as other anticancer antibodies (cetuximab, bevacizumab, ibritumomab, abagovomab, adecatumumab, afutuzumab, alacizumab, alemtuzumab, anatumomab, apolizumab, bavituximab, belimumab, bivatuzumab mertansine, blinatumomab, brentuximab vedotin, cantuzumab mertansine, catumazomab, cetuximab, citatuzumab bogatox, eixutumumab, clivatuzumab tetraxetan, conatumumab, dacetuzumab, daclizumab, detumomab, ecromeximab, edrecolomab, elotuzumab, epratuzumab, ertumaxomab, etaracizumab, farietuzumab, figitumumab, fresolimumab, galiximab, gembatumumab vedotin, gemtuzumab, ibritumomab tiuxetan, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lucatumumab, lumilisimab, mapatumumab, matuzumab, milatuzumab, mitumomab, nacolomab tafenatox, naptumomab estafenatox, necitumumab, nimotuzumab, ofatumumab, olaratumab, oportuzumab monatox, oregovomab, panitumumab, pemtumomab, pertuzumab, pintumomab, pritumumab, ramucirumab, rilotumumab, robatumumab, rituximab, sibrotuzumab, tacatuzumab tetraxetan, taplitumomab paptox, tenatumomab, ticilimumab, tigatuzumab, tositumomab or 1311-tositumomab, trastuzumab, tremelimumab, tuocotuzumab celmoleukin, veltuzumab, visilizumab, volocixumab, votumumab, zalutumumab, zanolimumab, IGN-101, MDX-010, ABX-EGR, EMD72000, ior-tl, MDX-220,
MRA, H-l l scFv, huJ591, TriGem, TriAb, R3, MT-201, G-250, ACA-125, Onyvax-105, CD:- 303, Therex, KW2871 , anti-HMI.24, Anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI mAh, Prostate Cancer antibody, H22xKi-r, ABX-Mai, Imutcran, Monopharm-C), and antibody-drug conjugates comprising any of the above agents (especially auristatins MMAE and MMAF, maytansinoids like DM-1, calicheamycins, or various cytotoxins).
[0261] In some embodiments, 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®), dacarbazinc (DTIC- Dome®), dactinomycin (actinomycin D, COSMEGAN®), daunorubicin hydrochloride (CERUBIDINE®), daunorubicin citrate liposome injection (DAUNOXOME®), dexamethasone, docetaxel (TAXOTERE®), doxorubicin hydrochloride (ADRIAMYCIN®, RUBEX®), etoposide (VEPESID®), fludarabine phosphate (FEUD ARA®), 5 -fluorouracil (ADRUCIL®, EFUDEX®), flutamide (EULEXIN®), tezacitibine, gemcitabine (difluorodeoxycitidine), hydroxyurea (HYDREA®), idarubicin (IDAMYCIN®), ifosfamide (IFEX®), irinotecan (CAMPTOSAR®), L- asparaginase (ELSPAR®), leucovorin calcium, melphalan (ALKERAN®), 6-mercaptopurine (PURINETHOL®), methotrexate (FOLEX®), mitoxantrone (NOVANTRONE®), gemtuzumab ozogamicin (MYLOTARGTM), paclitaxel (TAXOL®), nab-paclitaxel (ABRAXANE®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (GLIADEL®), tamoxifen citrate (NOLVADEX®), teniposide (VUMON®), 6-thioguanine, thiotepa, tirapazamine (TIRAZONE®), topotecan hydrochloride for injection (HYCAMPTIN®), vinblastine (VELBAN®), vincristine (ONCOVIN®), and vinorelbine (NAVELBINE®).
In some embodiments, 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. In a particular embodiment, the compounds of the present invention axe 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, BYE? 19 or CLR457, or a [0262] In some embodiments, the additional therapeutic agent is selected based on the disease, disorder, or condition that is being treated. For example, in the treatment of melanoma, 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®).
For the treatment of ovarian cancer, 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®, EV ACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).
[0263] For the treatment of thyroid cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®).
[0264] For the treatment of colon cancer, the additional therapeutic agent is selected from fluorouracil (e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®), bevacizumab (A VASTIN®), irinotecan hydrochloride (CAMPTOSTAR®), capecitabine (XELODA®), cetuximab (ERBITUX®), oxaliplatin (ELOXATIN®), leucovorin calcium (WELLCOVORIN®), regorafenib (STIVARGA®), panitumumab (VECTIBIX®), and ziv-aflibercept (ZALTRAP®). For the treatment of lung cancer, the additional therapeutic agent is selected from methotrexate, methotrexate EPF (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®).
[0265] For the treatment of pancreatic cancer, the other therapeutic agent may be selected from fluorouracil (ADRUCIL®), EFUDEX®, FLUOROPLEX®), erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®), and mitomycin or mitomycin C [0266] For the treatment of cervical cancer, the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®) and topotccan hydrochloride (HYC AMTIN®).
For the treatment of head and neck cancer, the additional therapeutic agent is selected from methotrexate, methotrexate EPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), bleomycin (BLENOXANE®), cetuximab (ERBITUX®), cisplatin (PLATINOL®, PLATINOL-AQ®) and docetaxel (TAXOTERE®).
[0267] For the treatment of leukemia, including chronic myelomonocytic leukemia (CMML), 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®).
[0268] In some instances, patients may experience allergic reactions to the compounds of the present invention and/or other anti-cancer agent(s) during or after administration. Therefore, antiallergic agents may be administered to minimize the risk of an allergic reaction. Suitable antiallergic 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®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate; e.g., DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL® and SOLU- MEDROL®); antihistamines, such as diphenhydramine (e.g., BENADRYL®), hydroxyzine, and cyproheptadine; and bronchodilators, such as the beta-adrenergic receptor agonists, albuterol (e.g., PROVENTIL®), and terbutaline (BRETHINE®).
[0269] In other instances, patients may experience nausea during and after administration of the compound of the present invention and/or other anti-cancer agent(s). Therefore, anti-emetics may be administered in preventing nausea (upper stomach) and vomiting. Suitable anti-emetics lorazepam (ATIVAN®, dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof.
[0270] In yet other instances, medication to alleviate the pain experienced during the treatment period is prescribed to make the patient more comfortable. Common over-the-counter analgesics, such TYLENOL®, are often used. 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 (OP ANA®), and fentanyl (e.g., DURAGESIC®) are also useful for moderate or severe pain.
Furthermore, cytoprotective agents (such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like) may be used as an adjunct therapy to protect normal cells from treatment toxicity and to limit organ toxicities. 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).
[0271] In yet another aspect, 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. In certain instances, a compound of the present invention may be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
[0272] The doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician. In some embodiments, the compound described herein (e.g., a compound of Formula I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disease, disorder, or condition. In other embodiments, the compound described herein (e.g., a compound of Formula I) and the additional therapeutic agent(s) arc administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disease, disorder, or condition. In some embodiments, the compound described herein (e.g., a compound of Formula I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
[0273] In some embodiments, the compound described herein (e.g., a compound of Formula 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), a pharmaceutically acceptable carrier, vehicle, or diluent, and optionally at least one additional therapeutic agent listed above. In some embodiments, the kit further comprises instructions, such as instructions for treating a disease described herein.
EXAMPLES
[0274] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
The following abbreviations are used herein:
MeCN Acetonitrile aq. aqueous _
DCM dichloromethane _
DMA N,N-Dimethylacetamide _
DMSO Dimethylsulfoxide _
DMF Dimethylformamide _ equiv Equivalent _
EtOAc or EA Ethyl acetate _
FA Formic acid _ h Hour or hours _
HPLC High pressure liquid chromatography
HESS Hank’s Balanced Salt solution buffer _
LCMS Liquid chromatography mass spectrometry
NMR Nuclear Magnetic Resonance _
PE Petroleum ether _
TEA Trifluoroacetic acid
Analytical Instrumentation and Purification
NMR Instrument Details: Bruker Avance III HD 300MHz or 400MHz.
LCMS Instrument Details: Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and
ELS detectors. Sofia model 400.
Synthesis of Intermediates
Synthesis of 6-chloro-| 1.2.3.4 |tetrazolo| 1.5-/? |py ridazine (Int-1)
[0275] A solution of NaNO2 (5.73 g, 83.0 mmol, 1.20 equiv) and 3-chloro-6- hydrazinylpyridazine (10.0 g, 69.1 mmol, 1 equiv) in AcOH (15.0 mL, 261 mmol, 3.78 equiv) and
H2O (85.0 mL) was stirred for 2h at 0°C. The precipitated solids were collected by filtration and washed with water (5x10.0 mL). This resulted in 6-chloro-[l,2,3,4]tetrazolo[l,5-&]pyridazine (6.30 g, 58.5%) as a yellow solid. XH NMR (400 MHz, DMSO-de) 8 8.91 (d, 7 = 9.6 Hz, 1H), 8.04 (d, 7= 9.5 Hz, 1H).
Synthesis of 2-( 1 -methyl- l//-pyrazol-3-yl (morpholine hydrochloride (Int-2) I
Step-1. Synthesis of tert-butyl 6-(l-methyl-lH-pyrazol-3-yl)-2,3-dihydro-4ZM,4-oxazine-4- carboxylate
[0276] A solution of tert-butyl 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro- oxazine-4-carboxylate (120 mg, 0.386 mmol, 1.00 equiv), 3-bromo-l-methylpyrazole (62.0 mg, 0.386 mmol, 1.00 equiv), K2CO3 (106 mg, 0.772 mmol, 2.00 equiv) and Pd(dppf)Ch (28.2 mg, 0.0390 mmol, 0.100 equiv) in dioxane (1.20 mL) and H2O (0.120 mL) was stirred for 3h at 60°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford tert-butyl 6-(l-methyl-177-pyrazol-3-yl)-2,3-dihydro-477-l,4-oxazine-4-carboxylate (50.0 mg, 48.8%) as a yellow oil. 'H NMR (300 MHz, DMSO-tZe) 8 7.63 (d, 7 = 2.2 Hz, 1H), 6.78 (d, J = 32.0 Hz, 1H), 6.22 (d, 7 = 2.3 Hz, 1H), 4.14 (d, 7 = 4.7 Hz, 2H), 3.81 (s, 3H), 3.63 (s, 2H), 1.47 (d, 7= 2.7 Hz, 9H).
Step-2. Synthesis of tert-butyl 2-( 1 -methyl- 1/7- pyrazol-3-yl) mor pholine-4-carboxy late
[0277] A solution of tert-butyl 6-(l-methyl-177-pyrazol-3-yl)-2,3-dihydro-477-l,4-oxazine-4- carboxylate (50.0 mg, 0.188 mmol, 1.00 equiv) and 10% Pd/C (5 mg, 0.0470 mmol, 0.250 equiv) in MeOH (3.00 mL) was stirred for 5h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x3 mL). The filtrate was concentrated under reduced pressure. This resulted in tert-butyl 2-( I -methyl- 17/-pyrazol-3-yl) h li 4 b l t (30 d ) ll il Step-3. Synthesis of 2-(l-methyl- l//-pyrazol-3-yl)morpholine hydrochloride (Int-2)
[0278] A solution of tert-butyl 2-(l-methyl-lH-pyrazol-3-yl)morpholine-4-carboxylate (30.0 mg, 0.112 mmol, 1.00 equiv) in HC1 in 1,4-dioxane (1.00 mL, 4M) was stirred for 2h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulted in 2-(l- methyl-lH-pyrazol-3-yl)morpholine hydrochloride (30 mg, crude) aass aa yellow oil. LCMS Calculated for: CsHnNsO: 167.11; Observed: 168.10 [M+H]+ .
Synthesis of 2-(pyridin-2-yl)morpholine (Int-3o) and 2-(pyridin-4-yl)morpholine (Int-3p
Step-1. Synthesis of 4- (tert-butyl) 2-(l,3-dioxoisoindolin-2-yl) morpholine-2,4-dicarboxylate
[0279] A solution of 4-(tert-butoxycarbonyl) morpholine-2-carboxylic acid (1.00 g, 4.32 mmol, 1.00 equiv), Whydroxyphthal imide (0.780 g, 4.75 mmol, 1.10 equiv) and EDCI (0.990 g, 5.19 mmol, 1.20 equiv) in DMF (10.0 mL) was stirred for 2h at room temperature. The reaction was quenched with Water at 0°C.The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous NaiSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford 4-tert-butyl 2-(l,3- dioxoisoindol-2-yl) morpholine-2,4-dicarboxylate (700 mg, 43.0%) as a white solid. LCMS Calculated for: C18H20N2O7: 376.13; Observed: 377.10 [M+H]+.
Step-2. Synthesis of tert-butyl 2-(pyridin-2-yl) morpholine-4-carboxylate and tert-butyl 2- (pyridin-4-yl) morpholine-4-carboxylate
[0280] A solution of 4-(tert-butyl) 2-(l,3-dioxoisoindolin-2-yl) morpho line-2, 4-dicarboxy late
(200 mg, 0.531 mmol, 1.00 equiv), pyridine (84.1 mg, 1.06 mmol, 2.00 equiv), TEA (606 mg,
5.31 mmol, 10.0 equiv) and 2,4,5,6-Tetrakis(diphenylamino)isophthalonitrile (5.00 mg, 0.00600 mmol, 0.0100 equiv) in MeCN (5.00 mL, 95.1 mmol, 179 equiv) was stirred for Ih at blue light under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl 2-(pyridin-2-yl) morpholine-4-carboxylate (50.0 mg, 17.8%) as a yellow oil and tertbutyl 2-(pyridin-4-yl)morpholine-4-carboxylate (100 mg, 20.34%) as a yellow solid.
Step-3. Synthesis of 2-(pyridin-2-yl)morpholine (Int-3o) and 2-(pyridin-4-yl)morpholine (Int-3p)
Int-3o lnt-3p
[0281] A solution of tert-butyl 2-(pyridin-2-yl) morpholine-4-carboxylate (50.0 mg, 0.189 mmol, 1.00 equiv) in HC1 in 1,4-dioxane (1.00 mL, 32.9 mmol, 174 equiv) was stirred for 2h at room temperature. The precipitated solids were collected by filtration and washed with H2O (3x2 mL). This resulted in 2-(pyridin-2-yl) morpholine (30.0 mg, 96.58%) as a white solid. Note: The Int-3p was obtained following the same protocol but starting from 2-(pyridin-4-yl) morpholine-4- carboxylate. lnt-3m
Step-1. Synthesis of 2-[benzyl(2-hydroxyethyl)amino]-l-(pyridin-3-yl)ethanone
[0282] To a solution of 2-bromo-l-(pyridin-3-yl)ethanone (5.50 g, 27.5 mmol, 1 equiv) in DMF (50 mL) was added 2-(benzylamino)ethanol (4.57 g, 30.2 mmol, 1.1 equiv) and K2CO3 (11.4 g, 82.5 mmol, 3.00 equiv). The mixture was stirred for Ih at 50°C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over anhydrous NaaSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc to afford 2-[benzyl(2- hydroxyethyl) amino]-l-(pyridin-3-yl)ethanone (2.60 g, 34.9%) as a yellow oil. 'H NMR (300 MHz, DMSO-de) 5 8.68 (d, 7 = 2.3 Hz, IH), 8.51 (dd, 7 = 4.8, 1.7 Hz, IH), 7.84 (dt, 7 = 7.9, 2.0 Hz, IH), 7.41 - 7.20 (m, 5H), 6.45 (s, IH), 4.15 - 4.06 (m, IH), 3.63 (dt, 7 = 11.2, 3.0 Hz, IH), 3.50 (d, 7 = 2.4 Hz, 2H), 2.74 (dd, 7 = 11.2, 1.4 Hz, IH), 2.68 - 2.59 (m, IH), 2.24 (td, 7 = 11.2,
4.3 Hz, 2H).
Step-2. Synthesis of 2-[benzyl(2-hydroxyethyl)amino]-l-(pyridin-3-yl)ethanol
[0283] To a solution of 2-[benzyl(2-hydroxyethyl)amino]-l-(pyridin-3-yl)ethanone (2.60 g, 9.62 mmol, 1 equiv) in MeOH (30 mL) was added NaBtk (0.550 g, 14.4 mmol, 1.50 equiv) at 0°C. The mixture was stirred at RT for Ih. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 2-[benzyl(2-hydroxyethyl)amino]-l-(pyridin-3-yl)ethanol (2.40 g, 91.6%) as a yellow oil. 'H NMR (300 MHz, DMSO-de) 8 8.49 (d, 7= 2.2 Hz, 1H), 8.44 (dd, 7 = 4.8, 1.7 Hz, 1H), 7.67 (dt, 7= 7.8, 2.0 Hz, 1H), 7.36 - 7.18 (m, 6H), 5.25 (d, 7= 3.6 Hz, 1H), 4.71 (td, 7 = 6.4, 2.9 Hz, 1H), 4.37 (t, 7 = 5.3 Hz, 1H), 3.69 (d, 7 = 2.2 Hz, 2H), 3.39 (qd, 7 = 6.0, 2.7 Hz, 2H), 2.75 - 2.54 (m, 4H).
Step-3. Synthesis of 4-benzyl-2-(pyridin-3-yl)morpholine
[0284] The mixture of 2-[bcnzyl(2-hydroxycthyl)amino]-l-(pyridin-3-yl)cthanol (2.00 g, 7.34 mmol, 1 equiv) in H2SO4 (70%, 20 mL) was stirred for 15h at 100°C. The mixture was allowed to cool down to room temperature. The mixture was basified to pH 10 with NaOH (10%). The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford 4-benzyl-2-(pyridin-3-yl)morpholine (600 mg, 32.1%) as a yellow oil. 'H NMR (300 MHz, Chloroform-rf) 5 8.64 - 8.57 (m, 1H), 8.57 - 8.51 (m, 1H), 7.70 (dt, 7= 7.9, 2.0 Hz, 1H), 7.40 - 7.23 (m, 6H), 4.65 (dd, J= 10.2, 2.5 Hz, 1H), 4.04 (ddd, 7= 11.4, 3.5, 1.6 Hz, 1H), 3.87 (td, 7= 11.4, 2.5 Hz, 1H), 3.58 (s, 2H), 2.94 (dt, 7= 11.5, 2.1 Hz, 1H), 2.79 (dq, 7 = 11.6, 2.1 Hz, 1H), 2.33 (td, 7= 11.4, 3.4 Hz, 1H), 2.14 (dd, 7 = 11.5, 10.2 Hz, 1H).
Step-4. Synthesis of 2-(pyridin-3-yl)morpholine (Int-3m)
[0285] To a solution of 4-benzyl-2-(pyridin-3-yl)morpholine (600 mg, 2.34 mmol, 1 equiv) in MeOH (10 mL) was added 10% Pd/C (180 mg, 1.69 mmol, 0.720 equiv) and HCOONH4 (744 mg, 11.8 mmol, 5.00 equiv). The resulting mixture was stirred for 5h at reflux. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 2- (pyridin-3-yl)morpholine (350 mg, 90.4%) as a yellow oil. 1H NMR (300 MHz, DMSO-t/e) 58.55 (d, J = 2.2 Hz, 1H), 8.49 (dd, J = 4.8, 1.7 Hz, 1H), 7.74 (dt, J = 7.9, 2.0 Hz, 1H), 7.37 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 4.63 (s, 2H), 4.49 (dd, J= 10.4, 2.6 Hz, 1H), 3.91 (dt, 7= 11.3, 2.0 Hz, 1H), 3.64 (ddd, 7 = 11.3, 9.5, 4.7 Hz, 1H), 3.01 (dd, 7 = 12.4, 2.6 Hz, 1H), 2.85 - 2.74 (m, 2H), 2.59 (dd, 7 = 12.3, 10.4 Hz, 1H).
Synthesis of 2-(6-methylpyridin-2-yl)morpholine (Int-4o) and 2-(2-methylpyridin-4- yl)morpholine (Int-4p)
Int-4o Int-4p
[0286] To a mixture of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (300 mg, 1.30 mmol, 1.00 equiv), AgNCL (2.20 g, 13.0 mmol, 10.0 equiv), (NH^iSiOs (888 mg, 3.89 mmol, 3.00 equiv), 2-methylpyridine (242 mg, 2.59 mmol, 2.00 equiv) in MeCN (2.00 mL) and H2O (1.00 mL) was added H2SO4 (636 mg, 6.48 mmol, 5.00 equiv). The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: xB ridge Prep Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: water (0.1% NH3H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 5%-50%B in 13min; Wave Length: 254nm/220nm; RTl(min): 9.01) to afford 2-(6-methylpyridin-2-yl)morpholine (13.0 mg, 6.00%) as an off-white solid and 2-(2-methylpyridin-4-yl)morpholine (20.0 mg, 8.65%) as an off- white solid. LCMS Calculated for: C10H14N2O: 178.11; Observed: 179.15 [M+H]+.
Synthesis of 4-methyl-2-(pyrrolidin-3-yl)thiazole (Int-5)
Step-1. Synthesis of tert-butyl 3-carbamothioylpyrrolidine-l-carboxylate
[0287] To a solution of tert-butyl 3-carbamoylpyrrolidine-l -carboxylate (3.00 g, 14.0 mmol, 1.00 equiv) in tetrahydrofuran (30.0 mL) was added Lawesson Reagent (5.66 g, 14.0 mmol, 1.00 equiv). The resulting mixture was stirred for 2h at room temperature. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl 3-carbamothioylpyrrolidine-l -carboxylate (3.00 g, 46.0%) as a yellow oil. LCMS Calculated for: C10H18N2O2S: 230.11 ; Observed: 175.20 [M+H-56]4".
Step-2. Synthesis of 4-methyl-2-(pyrrolidin-3-yl)thiazole (Int-5)
[0288] The mixture of tert-butyl 3-carbamothioylpyrrolidine-l -carboxylate (150 mg, 0.650 mmol, 1.00 equiv) and l-chloropropan-2-one (181 mg, 1.95 mmol, 3.00 equiv) in EtOH (2.00 mL) was stirred for 2h at 80°C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was basified to pH 8 with saturated NaHCOa (aq.). The resulting mixture was extracted with DCM/MeOH (10:1) (5 x 50 mL). The combined organic layers were dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-methyl-2-(pyrrolidin-3-yl)thiazole (50.0 mg, 46.0%) as a brown oil. LCMS Calculated for: CsHiaNaS: 168.07; Observed: 169.15 [M+H]+.
Synthesis of 2-(4-methylthiazol-2-yl)ethan-l-amine (Int-6)
Step-1. Synthesis of tert-butyl (2-(4-methylthiazol-2-yl)ethyl)carbamate
S
Boc N H
[0289] To a stirred solution of tert-butyl (3-amino-3-thioxopropyl)carbamate (500 mg, 2.45 mmol, 1.00 equiv) in EtOH (5.00 mL) was added (679 mg, 7.34 mmol, 3.00 equiv). The resulting mixture was stirred for 16h at 80"C. The reaction was allowed to cool down to room temperature.
The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl A'-|2-(4-mcthyl- l .3- thiazol-2-yl)ethyl] carbamate (300 mg, 50.6%) as a yellow oil. LCMS Calculated for: C10H11N7S: 242.11; Observed: 243.20 [M+H]+.
Step-2. Synthesis of 2-(4-methylthiazol-2-yl)ethan-l-amine (Int-6)
/T$
N NH2
[0290] To a stirred solution of tert-butyl N-[2-(4-methyl-l,3-thiazol-2-yl)ethyl]carbamate (300 mg, 1.238 mmol, 1 equiv) in HO in 1,4-dioxane (5.00 mL) was stirred for 2h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(4- methylthiazol-2-yl)ethan- 1 -amine (170 mg, 96.6%) as a yellow oil. LCMS Calculated for: C6HION2S: 142.06; Observed: 143.20 [M+H]+.
Synthesis of 2-(4-cyclohexylthiazol-2-yl)morpholine hydrochloride (Int-7)
Step-1. Synthesis of tert-butyl 2-(4-bromothiazoL2-yl)-2-hydroxymorpholine-4-carboxylate S
Br OH
N N'BOC o.
[0291] A solution of 2,4-dibromo-l,3-thiazole (5.79 g, 23.9 mmol, 1.20 equiv) in Et20 (50.0 mL) was treated with n-BuLi in THE (1 mol/L) (19.9 mL, 19.9 mmol, 1.00 equiv) for 30min at - 78°C under nitrogen atmosphere followed by the addition of tert-butyl 2-oxomorpholine-4- carboxylate (4.00 g, 19.9 mmol, 1.00 equiv) dropwise at -78°C. The resulting mixture was stirred for 2h at -78°C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (50.0 mL) at 0 C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (l x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl 2-(4- bromothiazol-2-yl)-2-hydroxymorpholine-4-carboxylate (3.20 g, 44.1%) as a yellow oil. LCMS Calculated for: CnHnBrlSECUS: 364.01; Observed: 363.15 [M-H]+.
Step-2. Synthesis of 2-(4-bromothiazoL2-yl)morpholine
[0292] To a stirred solution of tert-butyl 2-(4-bromothiazol-2-yl)-2-hydroxymorpholine-4- carboxylate (3.50 g, 9.58 mmol, 1.00 equiv) and EhSiH (5.57 g, 47.9 mmol, 5.00 equiv) in DCM (100 mL) was added TEA (54.6 g, 479 mmol, 50.0 equiv) at room temperature. The resulting mixture was stirred for 16h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(4-bromothiazol-2-yl)morpholine (5.00 g, 87.9%) as a yellow oil. LCMS Calculated for: CvHgBr^OS: 247.96; Observed: 249.00 [M+H]+.
Step-3. Synthesis of tert-butyl 2-(4-bromothiazol-2-yl)morpholine-4-carboxylate
S
Br
N'BOC
O.
[0293] To a stirred solution of 2-(4-bromo-l,3-thiazol-2-yl)morpholine (5.00 g, 20.1 mmol, 1.00 equiv) and DMAP (490 mg, 4.01 mmol, 0.200 equiv) in DCM (50.0 mL) were added TEA (6.09 g, 60.2 mmol, 3.00 equiv) and BOC2O (8.76 g, 40.1 mmol, 2.00 equiv) dropwise at 0°C. The water (50.0 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with water (l x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford tert-butyl 2-(4-bromo-l,3- thiazol-2-yl)morpholine-4-carboxylate (1.70 g, 24.3%) as a yellow oil. LCMS Calculated for: Ci2Hi7BrN2O3S: 348.01; Observed: 349.00 [M+H]+.
Step-4. Synthesis of tert-butyl 2-(4-(cyclohex-l-en-l-yl)thiazol-2-yl)morpholine-4- carboxylate s
N N-Boc
O.
[0294] To a stirred solution of tert-butyl 2-(4-bromothiazol-2-yl)morpholine-4-carboxylate (300 mg, 0.859 mmol, 1.00 equiv) and cyclohex- 1-en-l-ylboronic acid (162 mg, 1.29 mmol, 1.50 equiv) in dioxane (5.00 mL) and H2O (0.500 mL) were added Pd(dppf)C12.DCM (70.0 mg, 0.0860 mmol, 0.100 equiv) and K2CO3 (356 mg, 2.58 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (5.00 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford tert-butyl 2-(4-(cyclohex-l-en-l- yl)thiazol-2-yl)morpholine-4-carboxylate (250 mg, 83.0%) as a yellow oil. LCMS Calculated for: C18H26N2O3S: 350.17; Observed: 351.20 [M+H]+.
Step-5. Synthesis of tert-butyl 2-(4-cyclohexylthiazol-2-yl)morpholine-4-carboxylate
[0295] To a stirred solution of tert-butyl 2-(4-(cyclohex-l-en-l-yl)thiazol-2-yl)morpholine-4- carboxylate (250 mg, 0.713 mmol, 1.00 equiv) in MeOH (5.00 mL) was added 10% Pd/C (75.9 mg, 0.713 mmol, 1.00 equiv) at room temperature. To the above H2(g) was introduced in. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure to afford tcrt-butyl 2-(4-cyclohcxylthiazol-2-yl)morpholinc-4-carboxylatc (200 mg, 79.5%) as a yellow oil. LCMS Calculated for: C18H28N2O3S: 352.18; Observed: 353.25 [M+H]+.
Step-6. Synthesis of 2-(4-cyclohexylthiazol-2-yl)morpholine hydrochloride (Int-7)
/— x
N NHHCI
O.
[0296] To a stirred solution of tert-butyl 2-(4-cyclohexylthiazol-2-yl)morpholine-4- carboxylate (200 mg, 0.567 mmol, 1.00 equiv) in HC1 in 1,4-dioxane (4M, 2.00 mL) was stirred for Ih at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(4-cyclohexylthiazol-2-yl)morpholine hydrochloride (160 mg, 97.6%) as a yellow oil. LCMS Calculated for: C13H20N2OS: 252.13; Observed: 253.20 [M+H]+.
Synthesis of 2-(4-(prop-2-yn-l-yl)phenyl) morpholine hydrochloride (Int-8)
HCI/dioxane
N'BOC r.t, 2h NH
K2CO3,MeOH. 0.
O°C-r.t, 2h lnt-8 HCI
Step-1. Synthesis of tert-butyl 6-(4-(2-hydroxyethyl)phenyl)-2,3-dihydro-4H-l,4-oxazine-4- carboxylate
HO
N'BOC o.
[0297] A solution of tert-butyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro- 47/-l,4-oxazine-4-carboxylate (300 mg, 0.964 mmol, 1.00 equiv), 2-(4-bromophenyl) ethanol (213 mg, 1.06 mmol, 1.10 equiv), K2CO3 (266 mg, 1.93 mmol, 2.000 equiv) and Pd(dppf)Ch (70.5 mg, 0.0960 mmol, 0.100 equiv) in dioxane (3.00 mL) and H2O (0.300 mL) was stirred for 3h at 70°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl 6-(4-(2-hydroxyethyl)phenyl)-2,3-dihydro-4H-l,4-oxazine-4-carboxylate (200 mg, 67.9%) as a yellow oil. 'H NMR (300 MHz, DMSO-de) 6 7.37 (d, 7 = 7.7 Hz, 2H), 7.18 (d, 7 = 8.0 Hz, 2H), 4.63 (s, 1H), 4.18 (d, 7 = 4.1 Hz, 2H), 3.94 (s, 1H), 3.60 (dd, 7 = 17.7, 11.0 Hz, 4H), 2.70 (t, 7 = 7.1 Hz, 2H), 1.47 (d, 7= 2.9 Hz, 9H).
Step-2. Synthesis of tert-butyl 2-(4-(2-hydroxyethyl)phenyl)morpholine-4-carboxylate
[0298] A solution of tert-butyl 6-(4-(2-hydroxyethyl)phenyl)-2,3-dihydro-4H-l ,4-oxazine-4- carboxylate (200 mg, 0.655 mmol, 1.00 equiv) and Pd/C (100 mg, 0.940 mmol, 1.43 equiv) in MeOH (5.00 mL) was stirred for overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x3 mL). The filtrate was concentrated under reduced pressure. The result in tert-butyl 2-(4-(2-hydroxyethyl)phenyl) morpholine-4-carboxylate tert-butyl 2-(4-(2-hydroxyethyl)phenyl) morpholine-4-carboxylate(200 mg, crude) as a yellow oil.
Step-3. Synthesis of tert-butyl 2-(4-(2-oxoethyl)phenyl) morpholine-4-carboxylate
N'BOC o
[0299] To a stirred solution of tert-butyl 2-(4-(2-hydroxycthyl)phcnyl) morpholinc-4- carboxylate (200 mg, 0.651 mmol, 1.00 equiv) in DCM (2.00 mL) was added Dess-Martin (414 mg, 0.977 mmol, 1.50 equiv) in portions at 0°C. The resulting mixture was stirred for additional 3h at room temperature. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl 2-(4-(2-oxoethyl)phenyl) morpholine-4-carboxylate (70.0 mg, 35.2%) as a yellow oil. LCMS Calculated for: C17H23NO4: 305.16; Observed: 306.15 [M+H]+
[0300] To a stirred solution of tert-butyl 2-(4-(2-oxoethyl)phenyl) morpholine-4-carboxylate (70.0 mg, 0.229 mmol, 1.00 equiv) and K2CO3 (63.4 mg, 0.458 mmol, 2.00 equiv) in MeOH (1.00 mL) were added seyferth-gilbert homologation (48.4 mg, 0.252 mmol, 1.10 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for additional Ih at room temperature. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x20 mL), dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford tert-butyl 2-(4-(prop-2-yn-l-yl)phenyl) morpholine-4-carboxylate (35.0 mg, 50.7%) as a colorless oil.
Step-5. Synthesis of 2-(4-(prop-2-yn-l-yl)phenyl) morpholine hydrochloride (Int-8)
NH o. HCI
[0301] A solution of tert-butyl 2-[4-(prop-2-yn-l-yl)phenyl]morpholine-4-carboxylate (35.0 mg, 0.116 mmol, 1.00 equiv) in HO in 1,4-dioxane (1.00 mL) was stirred for 2h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. LCMS Calculated for: C13H15NO: 201.12; Observed: 202.10 [M+H]+.
Synthesis of (2S,6/?)-2-(4-(tert-butyl)thiazol-2-yl)-6-methylmorpholine hydrobromide (Int-
9)
Step-1. Synthesis of tert-butyl (2S,6/Z)-2-carbamoyl-6-methylmorpholine-4-carboxylate
[0302] To a stirred mixture of (2S,6R)-4-(tert-butoxycarbonyl)-6-methylmorpholine-2- carboxylic acid (500 mg, 2.04 mmol, 1.00 equiv) and EtgN (619 mg, 6.12 mmol, 3.00 equiv) in THF (5.00 mL) was added 2,2-dimethylpropanoyl chloride (295 mg, 2.45 mmol, 1.20 equiv) dropwise at 0°C. The resulting mixture was stirred for Ih at 0°C. NH3.H2O (2.50 mL, 64.2 mmol, 31.5 equiv) was added. The resulting mixture was stirred for Ih at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl (25,6R)-2- carbamoyl-6-methylmorpholine-4-carboxylate (600 mg, crude) as a yellow oil. LCMS Calculated for: C11H20N2O4: 244.14; Observed: 189.20 [M+H-56]+.
Step-2. Synthesis of tert-butyl(2S,6/?)-2-carbamothioyl-6-methylmorpholine-4-carboxylate
[0303] To the mixture of tert-butyl (2S,6R)-2-carbamoyl-6-methylmorpholine-4-carboxylate (600 mg, 2.46 mmol, 1.00 equiv) in THF (10.0 mL) was added Lawesson Reagent (993 mg, 2.46 mmol, 1.00 equiv). The mixture was stirred for 15h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2:1) to afford tert-butyl (2S,6R)-2-carbamothioyl-6- methylmorpholine-4-carboxylate (400 mg, 62.5%) as a brown oil. LCMS Calculated for: C11H20N2O3S: 260.12; Observed: 205.10 [M+H-56]+.
Step-3. Synthesis of (2S,6i?)-2-(4-(tert-butyl)thiazol-2-yl)-6-methylmorpholine hydrobromide (Int-9) [0304] The mixture of tert-butyl (2S,67?)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (400 mg, 1.54 mmol, 1.00 cquiv) and 1-bromopinacolonc (550 mg, 3.07 mmol, 2.00 cquiv) in EtOH (4.00 mL) was stirred for 2h at 80°C. The mixture was allowed to cool down to room temperature. The mixture was basified to pH 8 with NHg/MeOH. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford (25,67?)-2-(4-(tert-butyl)thiazol-2-yl)- 6-methylmorpholine hydrobromide (140 mg, 37.9%) as a yellow oil. 1H NMR (300 MHz, DMSO- d6) 87.21 (s, 1H), 4.94 (t, J= 4.1 Hz, 1H), 3.87 (Id, 7= 6.6, 3.2 Hz, 1H), 3.03 (d, 7= 4.2 Hz, 2H), 2.82 (dd, 7 = 12.5, 3.2 Hz, 1H), 2.44 (dd, 7 = 12.5, 6.9 Hz, 1H), 1.28 (s, 9H), 1.14 (d, 7 = 6.4 Hz, 3H).
Synthesis of 3-(morpholin-2-yl)benzonitrile (Int-10)
Step-1. Synthesis of 2-(3-bromophenyl) oxirane
[0305] A solution of trimethyl(oxo)-lambda6-sulfanylium iodide (11.9 g, 54.0 mmol, 1.00 equiv) in DMSO (100 mL) was treated with t-BuOK (6.67 g, 59.5 mmol, 1.10 equiv) for 30 min at room temperature under nitrogen atmosphere followed by the addition of 3-bromobenzaldehyde (10.0 g, 54.0 mmol, 1.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x3 00 mL), dried over anhydrous Na3SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(3-bromophenyl)oxirane (9.00 g, 83.7%) as a colorless oil.
Step-2. Synthesis of 2-(benzylamino)-l-(3-bromophenyl)ethan-l-ol
[0306] To a stirred solution of 2-(3-bromophenyl)oxirane (9.00 g, 45.2 mmol, 1.00 equiv) in benzylamine (90.0 mL). The resulting mixture was stirred for 2h at 70°C. The reaction was allowed to cool down to room temperature. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-(benzylamino)-l-(3-bromophenyl)ethan-l-ol (3.90 g, 28.2%) as a light-yellow oil. LCMS Calculated for: Ci5Hi6BrNO: 305.04; Observed: 306.15 [M+H]+. Step-3. Synthesis of A-benzyl-2V-(2-(3-bromophenyl)-2-hydroxyethyl)-2-chloroacetamide
[0307] To a stirred solution of 2-(benzylamino)-l-(3-bromophenyl)ethan-l-ol (3.90 g, 12.7 mmol, 1.00 equiv) and TEA (3.87 g, 38.2 mmol, 3.00 equiv) in DCM (40.0 mL) was added chloroacetyl chloride (2.01 g, 17.8 mmol, 1.40 equiv) dropwise at 0°C. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with water (1 x 100 mL), dried over anhydrous NaaSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-benzyl-N-(2-(3-bromophenyl)-2- hydroxyethyl)-2-chloroacetamide (3.20 g, 65.7%) as a light-yellow oil. LCMS Calculated for: CuHuBrClNCh: 381.01; Observed: 382.00 [M+H]+.
Step-4. Synthesis of 4-benzyl-6-(3-bromophenyl)morpholin-3-one
[0308] To a stirred solu y ( ( ophenyl)-2-hydroxyethyl)-2- 16.7 mmol, 2.00 equiv) in portions at 0°C. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was diluted with brine (50.0 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (l x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-benzyl-6-(3-bromophenyl)morpholin-3-one (2.00 g, 69.1%) as a light-yellow oil. LCMS Calculated for: CnHieBrNCL: 345.04; Observed: 346.10 [M+H]+.
Step-5. Synthesis of 4-benzyl-2-(3-bromophenyl)morpholine
[0309] To a stirred solution of 4-benzyl-6-(3-bromophenyl)morpholin-3-one (2.00 g, 5.78 mmol, 1.00 equiv) in THE (20.0 mL) was added BH3.THF (993 mg, 11.6 mmol, 2.00 equiv) at 0°C. The resulting mixture was stirred for 2h at room temperature. The reaction was quenched by the addition of MeOH (10 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. To the above mixture was added NaOH (IM) (10.0 mL). The resulting mixture was stirred for additional 30 min at 100°C. The reaction was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 4-benzyl-2-(3-bromophenyl)morpholine (1.20 g, 62.5%) as a colorless oil. LCMS Calculated for: CnHisBrNO: 331.06; Observed: 332.10 [M+H]+.
Step-6. Synthesis of 3-(4-benzylmorpholin-2-yl)benzonitrile 9 [0310] To a stirred solution of 4-benzyl-2-(3-bromophenyl)morpholine (200 mg, 0.602 mmol, 1.00 equiv) and dicthynylzinc (69.5 mg, 0.602 mmol, 1.00 equiv) in DMF (2.00 mL) was added Pd(PPh3)4 (69.6 mg, 0.0600 mmol, 0.100 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3h at 80°C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (10.0 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous NaiSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-(4-benzylmorpholin-2-yl)benzonitrile (160 mg, 95.5%) as a light-yellow oil. LCMS Calculated for: CisHisNiO: 278.14; Observed: 279.10 [M+H]+.
Step-7. Synthesis of 3-(morpholin-2-yl)benzonitrile (Int-10)
[0311] To a stirred solution of 3-(4-benzylmorpholin-2-yl)benzonitrile (160 mg, 0.575 mmol, 1.00 equiv) in DCE (2.00 mL) was added 1 -chloroethyl carbonochloridate (123 mg, 0.862 mmol, 1.50 equiv). The resulting mixture was stirred for 2h at 80°C. The reaction was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. To the above mixture was added MeOH (2.00 mL). The resulting mixture was stirred for additional 30 min at 70 °C . The resulting mixture was concentrated under reduced pressure to afford 3-
(morpholin-2-yl)benzonitrile (150 mg, 98.4%) as a light-yellow oil. LCMS Calculated for:
C11H12N2O: 188.09; Observed: 189.10 [M+H]+.
Synthesis of 2-(4-(tert-butyl)thiazol-2-yl)-2-methylmorpholine (lnt-11) lnt-11
Step-1. Synthesis of 2-(4-tert-butyl-l,3-thiazol-2-yl)-l-chloropropan-2-ol
[0312] A solution of 2-bromo-4-tcrt-butyl-l,3-thiazolc (500 mg, 2.27 mmol, 1.00 equiv) in EtzO (5.00 ml) was treated with n-BuLi (1.09 mL, 2.72 mmol, 1.20 equiv) for 30 min at -78°C under nitrogen atmosphere followed by the addition of l-chloropropan-2-one (252 mg, 2.72 mmol, 1.20 equiv) drop wise at -78°C. The resulting mixture was stirred for 2h at-78°C. The reaction was quenched with Water at-78°C, Restore the mixture to room temperature. The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous NaiSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-(4-tert-butyl-l,3-thiazol-2-yl)-l-chloropropan-2-ol (198 mg, 37.2%) as a colorless oil. LCMS Calculated for: CioHieCINOS: 233.06; Observed: 234.06 [M+H]+.
Step-2. Synthesis of 2-(4-tert-butyI-l,3-thiazol-2-yl)-l-[(2-hydroxyethyl)amino]propan-2-ol
[0313] A solution of 2-(4-tert-butyl-l,3-thiazol-2-yl)-l-chloropropan-2-ol (198 mg, 0.847 mmol, 1 equiv) and ethanolamine (517 mg, 8.47 mmol, 10.0 equiv) in EtOH (3.00 ml) was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford 2-(4-tert-butyl-l,3-thiazol-2- yl)-l-[(2-hydroxyethyl)amino]propan-2-ol (135 mg, 61.6%) as a white oil. LCMS Calculated for: C12H22N2O2S: 258.14; Observed: 259.14 [M+H]+.
Step-3. Synthesis of tert-butyl V-|2-(4-tert-butyl-L3-thiazol-2-yl)-2-hydroxypropylEV-(2- hydroxyethyl)carbamate
[0314] Into an 8 mL reaction flask were added l-[(2-hydroxyethyl)amino]-2-(4-isopropyl-l,3- thiazol-2-yl)propan-2-ol (135 mg, 0.552 mmol, 1 equiv), TEA (112 mg, 1.10 mmol, 2.0 equiv) resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford tert-butyl A-[2-(4-tert-butyl-l,3-thiazol-2-yl)-2-hydroxypropyl]- /V-(2-hydroxycthyl )carbamatc (140 mg, 70.7%) aass aa white oil. LCMS Calculated for: C17H30N2O4S: 358.19; Observed: 359.19 [M+H]+.
Step-4. Synthesis of tert-butyl 2-(4-tert-butyl-l,3-thiazol-2-yl)-2-methylmorpholine-4- carboxylate
[0315] To a mixture of tert-butyl A-[2-(4-tert-butyl-l,3-thiazol-2-yl)-2-hydroxypropyl]-A-(2- hydroxyethyl)carbamate (130 mg, 0.363 mmol, 1 equiv) and PPI13 (114 mg, 0.436 mmol, 1.20 equiv) in THE (2.00 mL) was added DEAD (75.8 mg, 0.436 mmol, 1.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 : 1) to afford tert-butyl 2-(4-tert-butyl- l,3-thiazol-2-yl)-2-methylmorpholine-4-carboxylate (100 mg, 81.0%) as a yellow oil. LCMS Calculated for: C17H28N2O3S: 340.18; Observed: 341.19 [M+H]+.
Step-5. Synthesis of 2-(4-(tert-butyl)thiazol-2-yl)-2-methylmorpholine (Int-11)
[0316] A solution of tert-butyl 2-(4-tert-butyl-l,3-thiazol-2-yl)-2-methylmorpholine-4- carboxylate (100 mg, 0.294 mmol, 1.00 equiv) and HC1 in 1,4-dioxane (1.50 mL) was stirred for Ih at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 2-(4-(tert-butyl)thiazol-2-yl)-2-methylmorpholine(90 mg, crude) as a white solid. LCMS Calculated for: C12H20N2OS: 240.13; Observed: 241.13 [M+H]+.
Synthesis of (R)-6-(4-(tert-butyl)thiazol-2-yl)-2,2-dimethylmorpholine (Int-12) Step-1. Synthesis of tert-butyl (l?)-6-carbamoyl-2,2-dimethylmorpholine-4-carboxylate
[0317] To a mixture of (2R)-4-(tert-butoxycarbonyl)-6,6-dimethylmorpholine-2-carboxylic acid (500 mg, 1.93 mmol, 1.00 equiv) in THF (5.00 mL) was added 2,2-dimethylpropanoyl chloride (349 mg, 2.89 mmol, 1.50 equiv) and TEA (585 mg, 5.78 mmol, 3.00 equiv) at 0°C. The resulting mixture was stirred for Ih at 0°C. NH3.H2O (5.00 mL) was added at 0°C. The resulting mixture was allowed to stirried at room temperature for Ih. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous NaoSO^. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl (R)-6-carbamoyl-2,2-dimethylmorpholine-4-carboxylate (560 mg, 75.3%) as a yellow oil. LCMS Calculated for: C12H22N2O4: 258.16; Observed: 202.90 [M+H-56]+.
Step-2. Synthesis of tert-butyl (R)-6-carbamothioyl-2,2-dimethylmorpholine-4-carboxylate
[0318] To a mixture of tert-butyl (R)-6-carbamoyl-2,2-dimethyhnorpholine-4-carboxylate (560 mg, 2.17 mmol, 1.00 equiv) in THF (6.00 mL) was added Lawesson Reagent (877 mg, 2.17 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2:1) to afford tert-butyl (R)-6-carbamothioyL2,2-dimethylmorpholine-4-carboxylate (850 mg, 85.7%) as a yellow oil. LCMS Calculated for: C12H22N2O3S: 274.14; Observed: 219.15 [M+H-56]+.
Step-3. Synthesis of (7?)-6-(4-(tert-butyl)thiazol-2-yl)-2,2-dimethylmorpholine (Int-12) [0319] The mixture of tert-butyl (7?)-6-carbamothioyl-2,2-dimethylmorpholine-4-carboxylate (480 mg, 1.75 mmol, 1.00 equiv) and 1-bromopinacolonc (470 mg, 2.62 mmol, 1.50 equiv) in ethanol (5.00 mL) was stirred at 80°C for 2h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford (7?)-6- (4-(tert-butyl)thiazol-2-yl)-2,2-dimethylmorpholine (280 mg, 62.9%) as a yellow oil. LCMS Calculated for: C13H22N2OS: 254.15; Observed: 255.25 [M+H]+.
Synthesis of l-(4-tert-butyl-l,3-thiazol-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (lnt-13) lnt-13
Step-1. Synthesis of tert-butyl l-carbamoyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate
[0320] To a stirred solution of 5-(tert-butoxycarbonyl)-2-oxa-5-azabicyclo[2.2.1]heptane-l- carboxylic acid (400 mg, 1.64 mmol, 1.00 equiv) and EhN (499 mg, 4.93 mmol, 3.00 equiv) in THF (4.00 mL) was added 2,2-dimethylpropanoyl chloride (218 mg, 1.80 mmol, 1.10 equiv) dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 h .To the above mixture was added NH3.H2O (4 .00 mL) drop wise at 0°C. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (1 x 5 mL). The combined organic layers were washed with brine (1x5 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 1 -carbamoyl-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (250 mg, 62.7%) as a white solid.
Step-2. Synthesis of tert-butyl l-carbamothioyl-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate [0321] To a stirred solution of tert-butyl l-carbamoyl-2-oxa-5-azabicyclo[2.2.1 ]heptane-5- carboxylatc (250 mg, 1.03 mmol, l.OOcquiv) in THF (2.00 mL) was added Lawcsson Reagent (626 mg, 1.54 mmol, 1.50 equiv) in portions at room temperature . The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl l-carbamothioyl-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (200 mg, 75.0%) as a white solid.
Step-3. Synthesis of l-(4-tert-butyl-l,3-thiazol-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (Int-13)
[0322] Into a 50 mL round-bottom flask were added tert-butyl l-carbamothioyl-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (200 mg, 0.774 mmol, 1.00 equiv) and 1- bromopinacolone (208 mg, 1.16 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred at 80°C for 3 h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with Et20 (3x1 mL). This resulted in l-(4-tert-butyl-l,3-thiazol-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (60 mg, 28.2%) as a white solid.
Synthesis of (2/?,5/?)-2-(4-(tert-butyl)thiazol-2-yl)-5-methylmorpholine hydrochloride (Int- 14) lnt-14
Step-1. Synthesis of l-(4-(tert-butyl)thiazol-2-yl)-2-chloroethan-l-one [0323] In a 50-mL round bottom flask, to a solution of 2-bromo-4-tert-butyl-l ,3-thiazole (2.00 g, 9.09 mmol, 1.00 equiv) in Et2<) (20.0 mL) was added dropwisc n-butyllithium solution (2.5 M in THE, 7.3 mL, 18.1 mmol) at -78°C under N2 atmosphere. The reaction mixture was stirred at - 78°C for 30 mins. Then a solution of 2-chloro-A-methoxy-A-methylacetamide (1.50 g, 10.9 mmol, 1.20 equiv) in THE (10 mL) was added dropwise and the mixture was stirred for another 2h. The reaction was quenched with water (10 mL), and then the mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatograph PE /EtOAc (5:1) afford to l-(4-(tert-butyl)thiazol-2-yl)-2-chloroethan-l-one (2.00 g, 70.8%).
Step-2. Synthesis of l-(4-(tert-butyl)thiazol-2-yl)-2-chloroethan-l-ol
[0324] To a stirred solution of l-(4-(tcrt-butyl)thiazol-2-yl)-2-chlorocthan-l-onc (2.00 g, 9.19 mmol, 1.00 equiv) in MeOH (20 mL) was added NaBPL (700 mg, 18.4 mmol, 2.00 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for 2h. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford l-(4-(tert- butyl)thiazol-2-yl)-2-chloroethan-l-ol (1.20 g, 59.4%) as a white solid.
Step-3. Synthesis of (2R)-2-((2-(4-(tert-butyl)thiazoL2-yl)-2-hydroxyethyl)amino)propan-l- ol
[0325] A solution of l-(4-( tert butyl)thiazol 2 yl) 2 chloroethan-l-ol (900 mg, 4.10 mmol, 1.00 equiv) and (R)-(-)-2-amino-l -propanol (3.08 g, 40.9 mmol, 10.0 equiv) in EtOH (9 mL) was stirred at 80°C for 24h. The mixture was allowed to cool down to room temperature. The residue silica gel; mobile phase, MeCN in Water (0.1 % FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (2R)-2-([2-(4-tcrt-butyl-l,3-thiazol-2-yl)-2- hydroxyethyl] aminopropan- l-ol (600 mg, 56.7%) as a yellow oil.
Step-4. Synthesis of tert-butyl (2-(4-(tert-butyl)thiazoL2-yl)-2-hydroxyethyl)((R)-l- hydroxypropan-2-yl)carbamat
[0326] A solution of (2R)-2-([2-(4-tert-butyl-l,3-thiazol-2-yl)-2-hydroxyethyl]aminopropan- l-ol (600 mg, 2.32 mmol, 1.00 equiv), (Boc)2O (608 mg, 2.79 mmol, 1.20 equiv) and TEA (705 mg, 6.97 mmol, 3.00 equiv) in DCM (6 mL) was stirred at room temperature for 16h. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl (2-(4-(tert-butyl)thiazol-2-yl)-2-hydroxyethyl)((R)-l-hydroxypropan-2-yl)carbamate (750 mg, 90.1%) as a yellow oil.
Step-5. Synthesis of tert-butyl (2R,5R)-2-(4-(tert-butyl)thiazol-2-yl)-5-methylmorpholine-4- carboxylate
[0327] To a stirred solution of tert-butyl (2-(4-(tert-butyl)thiazol-2-yl)-2-hydroxyethyl)((R)-l- hydroxypropan-2-yl)carbamate (350 mg, 0.976 mmol, 1 equiv) and PPhg (512 mg, 1.95 mmol, 2.00 equiv) in 2-methoxy-2-methylpropane (10.5 mL) wwaass added N- [(ethoxycarbonyl)imino] ethoxy formamide (510 mg, 2.93 mmol, 3.00 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 5h. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /EtOAc (1:1) to afford tert-butyl (2S,5R)-2-(4-(tert-butyl)thiazol- 2-yl)-5-methylmorpholine-4-carboxylate (50.0 mg, 15.04) and tert-butyl (27?,57?)-2-(4-(tert- butyl)thiazol-2-yl)-5-mcthylmorpholinc-4-carboxylatc (50.0 mg, 15.04%) as a yellow oil.
Step-6. Synthesis of (2/?,5/?)-2-(4-(tert-butyl)thiazol-2-yl)-5-methylmorpholine hydrochloride (Int-14)
[0328] A solution of tert-butyl (27?,57?)-2-(4-(tert-butyl)thiazol-2-yl)-5-methylmorpholine-4- carboxylate (50.0 mg, 0.147 mmol, 1.00 equiv) in HCI in 1,4-dioxane (0.5 mL) was stirred at room temperature for Ih. The resulting mixture was concentrated under vacuum. This resulted in (27?,57?)-2-(4-(tert-butyl)thiazol-2-yl)-5-methylmorpholine hydrochloride (25.0 mg, 55.3%) as a white solid.
Synthesis of 7-isobutyl-3,4-dihydro-2H-benzo[Z>][l,4]oxazine (Int-15)
Step-1. Synthesis of 7-(2-methylprop-l-en-l-yI)-3,4-dihydro-2fl-benzo[6][l,4]oxazine
[0329] To a stirred solution of 7-bromo-3,4-dihydro-2H-benzo[£][l,4]oxazine (450 mg, 2.10 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(2-methylprop-l-en-l-yl)-l,3,2-dioxaborolane (459 mg, 2.52 mmol, 1.20 equiv) in 1,4-dioxane (5.00 mL) and H2O (0.500 mL) were added K2CO3 (581 mg, 4.20 mmol, 2.00 equiv) and Pd(dppf)C12 (154 mg, 0.210 mmol, 0.100 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (10.0 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was methylprop-l-en-l-yl)-3,4-dihydro-2/7-benzo[/?][l ,4]oxazine (280 mg, 70.4%) as a yellow oil. LCMS Calculated for: C12H15NO: 189.12; Observed: 190.20 [M+H]+ .
Step-2. Synthesis of 7-isobutyl-3,4-dihydro-27/-benzo[6][l,4]oxazine (Int-15)
[0330] To a stirred solution of 7 -(2-methy Iprop- 1 -en- 1 -y l)-3 ,4-dihy dro-277- benzo[7>][l,4]oxazine (280 mg, 1.48 mmol, 1.00 equiv) and Pd/C (157 mg, 10%) in MeOH (5.00 mL) was stirred at room temperature for 2h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with methanol (3 x 1 mL). The filtrate was concentrated under reduced pressure to afford 7-isobutyl-3,4-dihydro-2H-benzo[&][l,4]oxazine (250 mg, 88.3%) as a light-yellow oil. LCMS Calculated for: C12H17NO: 191.13; Observed: 192.25 [M+H]+.
Synthesis of Example Compounds
Example 1: Synthesis of Compounds 3 and 4: (7?)-2-(4-methylthiazol-2-yl)-4-(tetrazolo[l,5- />]pyridazin-6-yl)morpholine, and (S)-2-(4-methylthiazol-2-yl)-4-(tetrazolo[l,5-6]pyridazin- 6-yl)morpholine
Step-1. Synthesis of tert-butyl 2-carbamoylmorpholine-4-carboxylate [0331] A solution of 4-(tert-butoxycarbonyl)morpholine -2-carboxylic acid (5.00 g, 21.6 mmol, 1.00 cquiv), NH4CI (2.31 g, 43.2 mmol, 2.00 cquiv), DIEA (8.38 g, 64.8 mmol, 3.00 cquiv) and HATH (9.87 g, 25.9 mmol, 1.20 equiv) in DCM (50 mL) was stirred for 14h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:9) to afford tert-butyl 2-carbamoylmorpholine-4-carboxylate (4.00 g, 80.3%) as a white solid. LCMS Calculated for: C10H18N2O4: 230.13; Observed: 231.14 [M+H]+.
Step-2. Synthesis of tert-butyl 2-carbamothioylmorpholine-4-carboxylate
[0332] A solution of tert-butyl 2-carbamoylmorpholine-4-carboxylate (4.00 g, 17.3 mmol, 1.00 equiv) and 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-disulfide (10.5 g, 26.0 mmol, 1.50 equiv) in THE (40.0 mL) was stirred for 20h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:8) to afford tert-butyl 2- carbamothioylmorpholine-4-carboxylate (4.00 g, 93.4%) as a grey solid. LCMS Calculated for: C10H18N2O3S: 246.10; Observed: 247.10 [M+H]+.
Step-3. Synthesis of 2-(4-methylthiazol-2-yl)morpholine
[0333] A solution of tert-butyl 2-carbamothioylmorpholine-4-carboxylate (600 mg, 2.43 mmol, 1.00 cquiv) and l-chloropropan-2-onc (450 mg, 4.87 mmol, 2.00 cquiv) in EtOH (6.00 mL) was stirred for 16h at 80°C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The mixture residue was basified to pH 8 with saturated NaHCO s (aq.). The resulting mixture was extracted with EtOAc (3 x 15 mL). The After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford 2-(4-mcthylthiazol-2- yl)morpholine (250 mg, 36.0%) as a yellow solid.
Step-4. Synthesis of 6-chloro-[l,2,3,4]tetrazolo[l,5-6]pyridazine
[0334] A solution of NaNCh (5.73 g, 83.0 mmol, 1.20 equiv) and 3-chloro-6- hydrazinylpyridazine (10.0 g, 69.1 mmol, 1 equiv) in AcOH (15.0 mL, 261 mmol, 3.78 equiv) and H2O (85.0 mL) was stirred for 2h at 0°C. The precipitated solids were collected by filtration and washed with water (5x10.0 mL). This resulted in 6-chloro-[l,2,3,4]tetrazolo[l,5-&]pyridazine (6.30 g, 58.5%) as a yellow solid.
'H NMR (400 MHz, DMSO-de) 8 8.91 (d, J = 9.6 Hz, 1H), 8.04 (d, J = 9.5 Hz, 1H).
Step-5. Synthesis of 2-(4-methylthiazol-2-yl)-4-(tetrazolo[l,5-b]pyridazin-6-yl)morpholine
[0335] A solution of 2-(4-methyl-l ,3-thiazol-2-yl) morpholine (250 mg, 1.35 mmol, 1.00 equiv), 6-chloro-[l,2,3,4]tetrazolo[l,5-&]pyridazine (211 mg, 1.35 mmol, 1.00 equiv) and EhN (411 mg, 4.07 mmol, 3.00 equiv) in EtOH (2.50 mL) was stirred for 3h at 80°C. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with EtOH (3x3 mL). This resulted in 2-(4-methylthiazol-2-yl)-4-(tetrazolo[l,5- b]pyridazin-6-yl)morpholine (260 mg, 63.1%) as a white solid. LCMS Calculated for: C12H13N7OS: 303.09; Observed: 304.00 [M+H]+.
Step-5. Synthesis of (R)-2-(4-methylthiazol-2-yl)-4-(tetrazolo[l,5-6]pyridazin-6-yl)morpholi ne (Compound 3) and (S)-2-(4-methyl-l,3-thiazol-2-yl)-4-([l,2,3,4]tetrazolo[l,5-6]pyridazin -6-ylmorpholine (Compound 4)
[0336] The 2-(4-methyl-l,3-thiazol-2-yl)-4-([l,2,3,4]tetrazolo[l,5-Z>]pyridazin-6-ylmorphol ine (100 mg, 0.330 mmol, 1.00 equiv) was purified by Prep-HPLC with the following conditions
(Column: XA CHIRALPAK IA, 2*25 cm, 5 pm; Mobile Phase A: Hex-HPLC, Mobile Phase B:
ETOH(0.1% 2M NH3-MEOH); Flow rate: 25 mL/min; Gradient: isocratic 50; Wave Length: 254 nm; RTl(min): 6.2; RT2(min): 10.1; Sample Solvent: ETOH: DCM=1:1; Injection Volume: 1 mL;
Number Of Runs: 9) to afford (S)-2-(4-methylthiazol-2-yl)-4-(tetrazolo[l,5-&]pyridazin-6- yljmorpholine (Compound 4, 48 mg, 47.95%) as a white solid and (2R)-2-(4-methyl-l,3-thiazol-
2-yl)-4-([l,2,3,4]tetrazolo[l,5-/?]pyridazin-6-ylmorpholine (Compound 3, 49 mg, 48.95%) as a white solid.
[0337] The following compounds were prepared using similar procedures to those described for the preparation of Compounds 3 and 4: Example 2: Synthesis of methyl 3-(([l,2,3,4]tetrazolo[l,5-6]pyridazin-6- ylaminomethyl)benzoate (Compound 130)
Compound 130
[0338] A solution of N-ethyltetrahydro-2H-pyran-4-amine (50 mg, 0.387 mmol, 1.00 equiv),
6-chloro-[l,2,3,4]tetrazolo[l,5-&]pyridazine (60.2 mg, 0.387 mmol, 1.0 equiv) and EhN (101.20 mg, 1.16 mmol, 3.0 equiv) in DMF (1 mL) was stirred for 3h at 80°C. The mixture was allowed to cool down to room temperature. The crude product was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 OBD Column, 19*150 mm, Sum; mobile phase, water (10 mmol/L NH4HCO3 + 0.1%NH3 H2O) and MeCN (12% MeCN up to 24% in 6 min); Detector, UV
254 nm.) to afford methyl 3-(([l,2,3,4]tetrazolo[l,5-h]pyridazin-6-ylaminomethyl)benzoate
(Compound 130, 20 mg, 23%) as a white solid.
[0339] The following compounds were prepared using similar procedures to those described for the preparation of Compound 130:
Example 3: Synthesis of A-methyl-A-(2-(4-methylthiazol-2-yl)ethyl)tetrazolo[l,5-
/>]pyridazin-6-amine (Compound 48)
[0340] A solution of N-(2-(4-methylthiazol-2-yl)ethyl)tetrazolo[l,5-Z>]pyridazin-6-amine (130 mg, 0.497 mmol, 1.00 equiv) in THF (3.00 mL) was treated with NaH (17.9 mg, 1.50 equiv, 60%
) for 30min at room temperature followed by the addition of CH3I (70.6 mg, 0.497 mmol, 1.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was diluted with water (5.00 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous NaiSO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (130 mg) was purified by Prep-HPLC with the following conditions (Column: Ultimate XB-C18, 30*250, 10 pm; Mobile Phase A: Water(0.1%NH3H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min mL/min; Gradient: isocratic 5% - 25% 14min; Wave
Length: 254nm/220nm nm; RTl(min): 8) to afford N-methyl-N-(2-(4-methylthiazol-2- yl)ethyl)tetrazolo[l,5-&]pyridazin-6-amine (Compound 48, 50.0 mg, 36.5%) as a white solid. 1H NMR (300 MHz, DMSO-rf6) 5 8.36 (d, J = 9.9 Hz, 1H), 7.56 (d, J = 9.9 Hz, 1H), 7.09 (s, 1H), 4.00 (t, J = 7.2 Hz, 2H), 3.33 - 3.27 (m, 2H), 3.13 (s, 3H), 2.28 (s, 3H). HPLC purity: 99.8%;
LCMS Calculated for: C11H13N7S: 275.10; Observed: 276.00 [M+H]+.
Example 4: Synthesis of 4-(lH-imidazo[4,5-6]pyrdin-5-yl)-2-(4-methylthiazol-2- yl)morpholine (Compound 45), 4-(l-methyl-LH-imidazo[4,5-6]pyridin-5-yl)-2-(4- methylthiazol-2-yl)morpholine (Compound 49), and 4-(3-methyl-3H-imidazo[4,5-b]pyridin- 5-yl)-2-(4-methylthiazol-2-yl)morpholine (Compound 52).
Compound 45 Compound 49 Compound 52
Step-1. Synthesis of 6-(2-(4-methylthiazol-2-yl)morpholino)-3-nitropyridin-2-amine
[0341] To a stirred solution of 2-(4-methylthiazoL2-yl)morpholine (500 mg, 2.71 mmol, 1.00 equiv) and 6-chloro-3-nitropyridin-2-amine (518 mg, 2.99 mmol, 1.10 equiv) in DMF (5.00 mL) was added K2CO3 (1.12 g, 8.14 mmol, 3.00 equiv). The resulting mixture was stirred for 2h at diluted with water (10.0 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford 6-(2-(4-methylthiazol-2- yl)morpholino)-3-nitropyridin-2-amine (600 mg, 68.8%) as a yellow oil.
LCMS Calculated for: C13H15N5O3S: 321.09; Observed: 322.20 [M+H]+.
Step-2. Synthesis of 6-(2-(4-methylthiazol-2-yl)morpholino)pyridine-2,3-diamine
[0342] To a stirred solution of 6-(2-(4-methylthiazol-2-yl)morpholino)-3-nitropyridin-2- amine (400 mg, 1.25 mmol, 1.00 equiv) in MeOH (5.00 mL) was added 10% Pd/C (132 mg, 1.25 mmol, 1.00 equiv) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 3 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to afford 6-(2-(4- methylthiazol-2-yl)morpholino)pyridine-2,3-diamine (350 mg, 96.5%) as a light-yellow oil.
LCMS Calculated for: C13H17N5OS: 291.12; Observed: 292.20 [M+H]+.
Step-3. Synthesis of 4-(lH-imidazo[4,5-6]pyrdin-5-yl)-2-(4-methylthiazol-2-yl)morpholine (
Compound 45)
[0343] The mixture of 6-[2-(4-methyl-l,3-thiazol-2-yl)morpholin-4-yl]pyridine-2,3-diamine (200 mg, 0.686 mmol, 1.00 equiv) in triethyl orthoformate (2.00 mL) was stirred for 15h at 120°C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum The crude product was purified by Prep HPLC with the following conditions (Column: CsH Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 5%-40%B in 8min; Wave
Length: 254nm/220nm; RTl(min): 4.7) to afford 4-(lH-imidazo[4,5-b]pyridin-5-yl)-2-(4- methylthiazol-2-yl)morpholine (Compound 45, 5.00 mg, 2.42%) as a yellow solid. 1H NMR (400 MHz, DMSO-t/e) 5 12.61 (s, 1H), 8.35-8.21 (m, 1H), 7.87 (d, 7 = 8.6 Hz, 1H), 7.29 (d, 7= 1.1 Hz, 1H), 6.86 (d, 7 = 8.9 Hz, 1H), 4.89 (dd, 7 = 10.3, 2.9 Hz, 1H), 4.66 (d, 7 = 13.1 Hz, 1H), 4.13 (d, 7 = 12.3 Hz, 1H), 4.09 - 4.00 (m, 1H), 3.86 (td, J = 11.4, 2.7 Hz, 1H), 3.04 (s, 1H), 2.87 (t, 7 = 11.4 Hz, 1H), 2.40 (s, 3H). HPLC purity: 92.3%; LCMS Calculated for: C14H15N5OS: 301.10; Observed: 302.20 [M+H]+.
Step-4. Synthesis of 4-(l-methyl-l/7-imidazo[4,5-6]pyridin-5-yl)-2-(4-methylthiazol-2-yl)mo rpholine (Compound 49) and 4-(3-methyl-3H-imidazo[4,5-6]pyridin-5-yl)-2-(4-methylthiaz ol-2-yl)morpholine (Compound 52)
Compound 49 Compound 52
[0344] To a stirred mixture of 4-(177-imidazo[4,5-/>]pyridin-5-yl-2-(4-methyl-l,3-thiazol-2- yl)morpholine (140 mg, 0.465 mmol, 1.00 equiv) in THF (2.00 mL) was added NaH (22.3 mg, 2.00 equiv, 60%) in portions at 0°C. The mixture was stirred at this temperature for 30 min. Mel (39.6 mg, 0.279 mmol, 0.600 equiv) was added. The resulting mixture was stirred for Ih at room temperature. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XB ridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: water (0.1% NH3H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 15%-40%B in 13min;
Wave Length: 254nm/220nm; RTl(min): 7.62) to afford 4-(l-methyl-lH-imidazo[4,5-/?]pyridin- 5-yl)-2-(4-methylthiazol-2-yl)morpholine (Compound 49, 35.0 mg, 23.9%) as a yellow solid *H NMR (300 MHz, Methanol-^) 5 8.09 (s, IH), 7.84 (d, 7= 9.0 Hz, IH), 7.13 (q, 7= 0.9 Hz, IH), 6.96 (d, 7 = 9.0 Hz, IH), 4.93 (d, 7 = 3.0 Hz, IH), 4.56 - 4.54 (m, IH), 4.28 - 4.12 (m, 2H), 3.97 - 3.86 (m, IH), 3.86 (s, 3H), 3.10 - 3.09 (m, IH), 2.96 (dd, 7 = 12.9, 10.2 Hz, IH), 2.45 (d, 7= 0.9 [M+H]+ and 4-(3-methyl-377-imidazo[4,5-/>]pyridin-5-yl)-2-(4-methylthiazol-2-yl)morpholine (Compound 52, 4.00 mg, 2.73%) as a yellow solid. XH NMR (300 MHz, Methanol-^) 8 8.03 (s, 1H), 7.86 (d, 7= 8.9 Hz, 1H), 7.16 (d, J= 1.1 Hz, 1H), 6.91 (d, 7= 8.9 Hz, 1H), 4.93 (dd, 7 = 10.3, 3.0 Hz, 1H), 4.76 (d, J = 13.3 Hz, 1H), 4.22 (d, 7 = 13.1 Hz, 2H), 3.95 (td, 7= 11.6, 3.0 Hz, 1H), 3.84 (s, 3H), 3.15 (td, 7= 12.3, 3.5 Hz, 1H), 2.98 (dd, 7= 12.9, 10.3 Hz, 1H), 2.47 (d, 7 = 1.0 Hz, 3H). HPLC purity: 99.2%; LCMS Calculated for: C15H17N5OS: 315.12; Observed: 316.35 [M+H]+
Example 5: Synthesis of 6-((3-ethyloxetan-3-yl)methoxy)tetrazolo[l,5-Z>]pyridazine (Compound 63)
[0345] A solution of (3-ethyloxetan-3-yl)methanol (50.0 mg, 0.430 mmol, 1.00 equiv) in THF (0.500 mL) was treated with NaH (20.7 mg, 0.860 mmol, 2.00 equiv) for 30 min at room temperature followed by the addition of 6-chloro-[l,2,3,4]tetrazolo[l,5-b]pyridazine (73.6 mg, 0.473 mmol, 1.10 equiv) in portions at 0°C. The resulting mixture was stirred for additional 3h at room temperature. The mixture was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 OBD Column, 19*150 mm, Sum; mobile phase, water(10 mmol/L NH4HCO3+0.1%NH3.H2O) and ACN (12% ACN up to 24% in 6 min); Detector, UV 254 nm.) to afford 6-[(3-ethyloxetan-3-yl)methoxy]-[l,2,3,4]tetrazolo[l,5-&]pyridazine (Compound 63, 50.0 mg, 49%) as a white solid.
[0346] The following compounds were prepared using similar procedures to those described for the preparation of Compound 63:
Example 6: Synthesis of (2S,6/?)-2-(4-( terl-butyl )tliiazol-2-yl)-6-niethyl-4-(tetrazolo| 1.5- a]pyridin-6-yl)morpholine (Compound 170) [0347] The mixture of (2S,6/?)-2-(4-(tert-butyl)thiazol-2-yl)-6-methylmorpholine hydrobromidc (120 mg, 0.502 mmol, 2.00 cquiv), 6-bromo-[l,2,3,4]tctrazolo[l,5-a]pyridinc (50.0 mg, 0.251 mmol, 1.00 equiv), EPhos Pd G6 TES (23.7 mg, 0.0250 mmol, 0.100 equiv) and sodium trimethylsilanolate (84.5 mg, 0.753 mmol, 3.00 equiv) in THF (1.00 mL) was stirred for 3h at
60°Cunder nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep RP
C18 Column, 30*150 mm, 5pm; Mobile Phase A: water (lOmmol/L NH4HC03+0.05%NH3.H20),
Mobile Phase B: MeCN; Flow rate: 35mL/min; Gradient: 48% to 68% B in lOmin; Wave Length:
254nm/220nm; RTl(min): 7.18) to afford (2S,6R)-2-(4-(tert-butyl)thiazol-2-yl)-6-methyl-4- (tetrazolo[l,5-a]pyridin-6-yl)morpholine (Compound 170, 25.0 mg, 27.8%) as a white solid. 1H NMR (300 MHz, DMSO-de) 8 8.73 - 8.59 (m, 1H), 8.10 (d, 7 = 9.7 Hz, 1H), 7.88 (dd, 7 = 9.8,
2.2 Hz, 1H), 7.26 (s, 1H), 5.31 (t, 7= 3.4 Hz, 1H), 4.14 (d, 7 = 13.5 Hz, 2H), 3.56 (d, 7= 12.1 Hz,
1H), 3.40 (dd, 7 = 12.6, 3.9 Hz, 1H), 2.85 (dd, 7 = 12.3, 8.9 Hz, 1H), 1.25 (d, 7 = 2.3 Hz, 12H).
HPLC purity: 99.6%; LCMS Calculated for: C17H22N6OS: 358.16; Observed: 359.20 [M+H]+
The following compounds were prepared using similar procedures to those described for the preparation of Compound 170:
Example 7: Synthesis of 6-(4-ethynylphenyl)tetrazolo[l,5-/>]pyridazine (Compound 137)
Step-1. Synthesis of 6-(4-((trimethylsilyl)ethynyl)phenyl)tetrazolo[l,5-Z>]pyridazine
[0348] The mixture of 6-chloro-[l,2,3,4]tetrazolo[l,5-Z>]pyridazine (150 mg, 0.964 mmol,
1.00 equiv), trimethyl((2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethynyl)silane
(347 mg, 1.16 mmol, 1.20 equiv), PdAmphos (68.3 mg, 0.0960 mmol, 0.100 equiv) and K2CO3
(266 mg, 1.93 mmol, 2.00 equiv) in dioxane (2.00 mL) and H2O (0.200 mL) was stirred for 2h at
100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature.
The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted wwiitthh PE / EEAA (2:1) to aaffffoorrdd 6-(4- ((trimcthylsilyl)cthynyl)phcnyl)tctrazolo[l,5-b]pyridazinc (150 mg, 53.0%) as a yellow solid.
LCMS Calculated for: CisHisNsSi: 293.11; Observed: 294.10 [M+H]+.
Step-2. Synthesis of 6-(4-ethynylphenyl)tetrazolo[l,5-Z>]pyridazine (Compound 137)
[0349] To a mixture of 6-(4-((trimethylsilyl)ethynyl)phenyl)tetrazolo[l,5-b]pyridazine (150 mg, 0.511 mmol, 1.00 equiv) in MeOH (2.00 mL) was added KF (59.4 mg, 1.02 mmol, 2.00 equiv). The resulting mixture was stirred for 2h at room temperature. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Ultimate XB-C18, 30*250, lOum; Mobile Phase A: water (lOmmol/L NH4HCO3+0.1%NH3H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 25%-45%B in 30min; Wave Length: 254nm/220nm; RTl(min): 15) to afford 6-(4-ethynylphenyl)tetrazolo[l,5-Z>]pyridazine (Compound 137, 50.0 mg, 44.2%) as a yellow solid. 'H NMR (300 MHz, DMSO-J6) 5 8.92 (d, J = 9.6 Hz, 1H), 8.49 (d, J = 9.6 Hz, 1H), 8.26 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 4.49 (s, 1H). HPLC purity: 99.3%; LCMS Calculated for: C12H7N5: 221.07; Observed: 222.15 [M+H]+
Biological Evaluation
Example 8: APMAP lactonase activity assay
[0350] Exemplary compounds were evaluated for activity in a lactonase assay. Experimental procedures and results are provided below.
Experimental Procedure
[0351] The APMAP lactonase activity assay was run using recombinant full length human
APMAP expressed in Expi293F cells in a buffer containing 50 mM Tris-HCl,7.4, 150 mM NaCl, 5 C C12 001% di i i 0 01% SA ll l l f i hibi i f h l activity, 200 nanoliters of compound in 100% DMSO was added to a 384 well plate (PE Cat# 6008590) using an Echo acoustic dispenser. Next, 18 microliters of 5.55 nM enzyme was added to the plate, centrifuged at 1000 RPM for 1 min and then shaken for 1 minute. Compound and enzyme were preincubated at 25 °C for 30 minutes. To initiate the lactonase reaction, 2 microliters of 500 pM substrate (Delta tetradecalactone Sigma W359009) was added to the plate, sealed, centrifuged at 1000 RPM for 1 minute and then shaken for 1 minute. The incubation reaction was performed at 37 °C for 1 hour and then terminated with 40 microliters acetonitrile/0.15% formic acid/750 nM internal standard; internal standard (IS) is 3-hydroxytetradecanoic acid [d5] purchased from Cambridge Isotope Labs (DLM-2922-PK). Once terminated, the plate was sealed, shaken for 5 minutes at 4 °C and spun for 15 minutes at 2350 RPM. The terminated reaction plate was further diluted by taking 16 microliters of terminated reaction and adding it to 65 microliters of HPLC grade water, centrifuged and sealed. Final concentration in the 20-microliter reaction volume of enzyme was 5 nM, substrate was 50 pM with 1% DMSO.
[0352] To detect product (5-hydroxytetradecanoic acid) and IS, a Rapidfire 365 system coupled with an Agilent 6459 QQQ mass spectrometer was used with a Cl 8 SPE cartridge, water as mobile phase A wash and 80% acetonitrile as mobile phase B elution. The MRM transition used to detect IS was 248.39/61.2 and product was 243.37/197.3. The following setting were used for the Rapidfire pump flow rate; 1.5 ml/min for pump 1 , 1.25 ml/min for pump 2 and 1.25 ml/min for pump 3. Rapidfire cycle times were 250/3000/4000/1000 for aspirate, load/wash, elute and reequilibrate steps. The MS conditions were the following; ESI source in negative mode, 16 L/min gas flow, 50 psi nebulizer, 3500 v capillary, 5500 v ion spray voltage, 200 °C gas temperature, 350 °C sheath gas temperature, 11 L/min sheath gas flow and 1500 v nozzle voltage. The ratio of product signal area to IS signal area was used to calculate percent inhibition; DMSO control was equal to 0% inhibition and the molecule undecanoic gamma- Lactone (BLD Pharma BD 17400) was used at 200 pM for the 100% inhibition control.
Results
[0353] Table 5 shows the activity observed for exemplary compounds in the APMAP lactonase assay using the protocol described above. Compounds having an activity designated as “A” provided an ICso of 0.01-0.5 pM; compounds having an activity designated as “B” provided an ICso of 0.501-5 pM; compounds having an activity designated as “C” provided an ICso of 5.01- Table 5
Example 9: APMAP Phagocytosis activity assay
[0354] Exemplary compounds were evaluated for activity in a phagocytosis assay. Experimental procedures and results are provided below. This Example describes coculture assays using J774A.1 mouse macrophages and Ramos lymphoma cells to measure antibody-dependent cellular phagocytosis (ADCP) induced by anti-CD47 clone B6H12. Experimental procedures and results are provided below.
Experimental Procedure
[0355] The day prior to the coculture assay, 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 pg/ml streptomycin) were plated in assay plates at 10,000 cells/well in 40pl HI-DMEM + lOOng/ml LPS media. The next day, Ramos lymphoma cells (ATCC CRL- 1596) cultured in complete RPMI media (containing 10% HI FBS, GlutaMAX, 100 units/ml penicillin, 100 pg/ml streptomycin) were harvested, counted, and resuspended in 1 ml PBS per 1 million cells. Cells were stained with pHrodo-Red-SE dye (WOnM final concentration) for 20 minutes at 37C. Dye quenching was performed by addition of 0.5X media volume of HI-DMEM and incubation at 37C for 5 min Labeled tumor cells were washed HI-DMEM and resuspended to a stock concentration of 5 million cells/ml. Tumor cells were then opsonized with 10 pg/ml anti- CD47 clone B6H12 (BioXccll BE0019-1) without and with tested compound at 50000 nM, 16667 nM, 5556 nM, 1852 nM, 617 nM, 206 nM, 69 nM, 23 nM, 8 nMor with 10 pg/ml mouse IgGl isotype control (BioXcell BEOO83) alone in each experiment, for 30 minutes at 37°C. These samples were then placed in coculture with the J774A.1 mouse macrophages at a 1:2 E:T ratio, resulting in final coculture concentrations of 2 pg/ml anti-CD47 clone B6H12 or mlgGl control; 10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 14 nM, 4.6 nM, 1.5 nM tested compound; and 0.08% DMSO. The coculture assay was imaged over multiple timepoints using an Incucyte S3 imager. Data from the 6-hour timepoint were processed.
Results
[0356] Table 6 shows the activity observed for exemplary compounds in the APMAP phagocytosis assay using the protocol described above. Compounds having an activity designated as “A” provided an IC50 of 1.00-5.00 nM; compounds having an activity designated as “B” provided an ICso of 5.01-20.00 nM; compounds having an activity designated as “C” provided an ICso of 20.01-100.00 nM; compounds having an activity designated as "D" provided an ICso of 100.01-1000 nM; and compounds having an activity designated as “E” provided an ICso of >1000.01 nM.
Table 6
Example 10: APMAP Inhibitor Enhancement of Rituximab-induced ADCP of Ramos lymphoma cells by mouse macrophages
[0357] This Example describes coculture assays using J774A.1 mouse macrophages and Ramos lymphoma cells to measure antibody-dependent cellular phagocytosis (ADCP) induced by anti-CD20 (rituximab). Experimental procedures and results are provided below.
Experimental Procedure
[0358] The day prior to the coculture assay, 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 pg/ml streptomycin) were plated in assay plates at 10,000 cells/well in 40pl HI-DMEM + lOOng/ml EPS media. The next day, Ramos lymphoma cells (ATCC CRL- 1596) cultured in complete RPMI media (containing 10% HI FBS, GlutaMAX, 100 units/ml penicillin, 100 pg/ml streptomycin) were harvested, counted, and resuspended in 1 ml PBS per 1 million cells. Cells were stained with pHrodo-Red-SE dye (lOOnM final concentration) for 20 minutes at 37C. Dye quenching was performed by addition of 0.5X media volume of HI-DMEM and incubation at 37C for 5 min. Labeled tumor cells were washed HI-DMEM and resuspended to a stock concentration of 5 million cells/ml. Tumor cells were then opsonized with 5 pg/ml anti- CD20 rituximab (BioXcell #SIM0008) without and with Compound 4 at 5000 nM, 1665 nM, 550 M 185 M 62 M 21 M 7 M 2 3 M ith 5 / l h I Gl i t t l (hl Gl BioXcell #BE0297) alone in each experiment, for 30 minutes at 37°C. These samples were then placed in coculturc with the J774A.1 mouse macrophages at a 1:2 E:T ratio, resulting in final coculture concentrations of 1 pg/ml anti-CD20 rituximab or hlgGl control; 1000 nM, 333 nM, 110 nM, 37 nM, 12 nM, 4.2 nM, 1.37 nM, or 0.46 nM Compound 4; and 0.08% DMSO. The coculture assay was imaged over multiple timepoints using an Incucyte S3 imager. Data from the 6-hour timepoint were processed.
Results
[0359] Experimental results are shown in FIG. 1. Induction of phagocytosis as imaged by pHrodo-Red integrated intensity is enhanced by the addition of the APMAP inhibitor (hlgGl control, anti-CD20 rituximab alone, and a dose-response series of Compound 4 with anti-CD20 rituximab are shown in FIG. 1, with statistical significance indicated (using unpaired t-test, p < 0.05 (*), < 0.01 (**), < 0.0001 (***))). The final antibody concentration of anti-CD20 rituximab was Ipg/ml.
[0360] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of anti-CD20 rituximab in Ramos lymphoma cells under the conditions tested.
Example 11: APMAP Inhibitor Enhancement of Cetuximab-induced ADCP of MDA-MB- 231 breast cancer cells by mouse macrophages
[0361] Coculture assays were conducted as described in Example 10, except that MDA-MB- 231 adenocarcinoma tumor cells (ATCC HTB-26) were used instead of Ramos lymphoma cells, an anti-EGFR antibody (Cetuximab) was used instead of an anti-CD20 antibody, and a single final Compound 4 coculture concentration of 300nM was used instead of a dose-response series.
[0362] Experimental results are shown in FIG. 2. Induction of phagocytosis as imaged by pHrodo-Red integrated intensity is enhanced by the addition of Compound 4 (hlgGl control, anti- EGFR cetuximab alone, and anti-EGFR cetuximab with 300nM Compound 4, are shown in FIG. 2, with statistical significance indicated (using unpaired t-test, p < 0.005 (**))). The final antibody concentration of anti-EGFR cetuximab was lOpg/ml. [0363] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of anti-EGFR cetuximab in MDA-MB-231 breast cancer cells under the conditions tested.
Example 12: APMAP Inhibitor Enhancement of TTI-622-induced ADCP of A375 melanoma cells by mouse macrophages
[0364] Coculture assays were conducted as described in Example 11, except that A375 melanoma cells (ATCC CRL-1619) were used instead of MDA-MB-231 breast cancer cells, and TTI-662 fusion protein (human SIRPa CD47-binding domain fused to IgG4 Fc) was used instead of cetuximab.
[0365] Experimental results are shown in FIG. 3. Induction of phagocytosis as imaged by pHrodo-Red integrated intensity is enhanced by the addition of Compound 4 (hIgG4 control, TTI- 622, and TTI-622 with 300nM Compound 4 are shown in FIG. 3, with statistical significance indicated (using unpaired t-test, p < 0.0001 (****))). The final antibody concentration of TTI-622 was lOpg/ml.
[0366] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of TTI-622 in A375 melanoma cells under the conditions tested.
Example 13: APMAP Inhibitor Enhancement of Cetuximab-induced ADCP of A375 melanoma cells by mouse macrophages
[0367] Coculture assays were conducted as described in Example 11, except that A375 melanoma cells (ATCC CRL-1619) were used instead of MDA-MB-231 breast cancer cells.
[0368] Experimental results are shown in FIG. 4. Induction of phagocytosis as imaged by pHrodo-Red integrated intensity is enhanced by the addition of Compound 4 (hlgGl control, anti- EGFR cetuximab, and anti-EGFR cetuximab with 300nM Compound 4, are shown in FIG. 4, with statistical significance indicated (using unpaired t-test, p < 0.005 (**))). The final antibody concentration of anti-EGFR cetuximab was lOpg/ml. [0369] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of anti-EGFR cetuximab in A375 melanoma cells under the conditions tested.
Example 14: APMAP Inhibitor Enhancement of Rituximab-induced ADCP of Ramos lymphoma cells by primary human macrophages
[0370] This Example describes coculture assays using human monocyte-derived macrophages and Ramos lymphoma cells to measure antibody-dependent cellular phagocytosis (ADCP) induced by anti-CD20 (rituximab). Experimental procedures and results are provided below.
Experimental Procedure
[0371] The day prior to the coculture assay, human monocyte-derived macrophages differentiated for 6 days in complete HI-RPMI media (containing 10% heat-inactivated (HI) FBS, GlutaMAX, 100 units/ml penicillin, 100 pg/ml streptomycin) with the addition of 40ng/ml hM- CSF were plated in assay plates at 10,000 cells/well in 40pl HI-RPMI + 40ng/ml hM-CSF media. The next day, Ramos lymphoma cells (ATCC CRL-1596) cultured in HI-RPMI media were harvested, counted, and resuspended in 1 ml PBS per 1 million cells. Cells were stained with pHrodo-Red-SE dye (lOOnM final concentration) for 20 minutes at 37C. Dye quenching was performed by addition of 0.5X media volume of HI-RPMI and incubation at 37C for 5 min. Labeled tumor cells were washed HI-RPMI and resuspended to a stock concentration of 5 million cells/ml. Tumor cells were then opsonized with 0.05 pg/ml anti-CD20 rituximab (BioXcell #SIM0008) without and with Compound 4 at 5 pM, or with 0.05 pg/ml human IgGl isotype control (hlgGl, BioXcell #BE0297) alone in each experiment, for 30 minutes at 37°C. These samples were then placed in coculture with the human monocyte-derived macrophages at a 1:2 E:T ratio, resulting in final coculture concentrations of 0.01 pg/ml anti-CD20 rituximab or hlgGl control; 1 pM final coculture concentration of Compound 4; and 0.08% DMSO. The coculture assay was imaged over multiple timepoints using an Incucyte S3 imager. Data from the 6-hour timepoint were processed.
Results
[0372] Experimental results are shown in FIG. 5. Induction of phagocytosis as imaged by pHrodo-Red integrated intensity is enhanced by the addition of Compound 4 (hlgGl control anti- CD20 rituximab, and the highest-activity condition, anti-CD20 rituximab with I pM Compound 4, arc shown in FIG. 5, with statistical significance indicated (using unpaired t-test, p < 0.005 (**))). This experiment uses primary human macrophages differentiated from Donor 63 human monocytes. The final concentration of anti-CD20 rituximab was O.Olpg/ml.
[0373] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of anti-CD20 rituximab in Ramos lymphoma cells under the conditions tested.
Example 15: APMAP Inhibitor Enhancement of Cetuximab-induced ADCP of FaDu squamous cell carcinoma cells by primary human macrophages
[0374] Coculture assays were conducted as described in Example 14, except that FaDu head and neck squamous cell carcinoma cells (HNSCC) (ATCC HTB-43) were used instead of Ramos lymphoma cells; an anti-EGFR antibody (Cetuximab) was used instead of an anti-CD20 antibody; primary human macrophages pooled from three individual donors were used; and four final coculture concentrations of Compound 4 were tested: 1 pM, 333 nM, 110 nM, and 37 nM. [0375]
[0376] Experimental results are shown in FIG. 6. Induction of phagocytosis as imaged by pHrodo-Red integrated intensity is enhanced by the addition of Compound 4 (hlgGl control, anti- EGFR cetuximab, and the highest-activity condition, anti-EGFR cetuximab with 1 pM Compound 4, are shown in FIG. 6, with statistical significance indicated (using unpaired t-test, p < 0.05 (*))). The final concentration of anti-EGFR cetuximab was lOpg/ml.
[0377] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of anti-EGFR cetuximab in FaDu HNSCC cells under the conditions tested.
Example 16: APMAP Inhibitor Enhancement of Trastuzumab-induced ADCP of SKOV-3 ovarian cancer cells by primary human macrophages
[0378] Coculture assays were conducted as described in Example 15, except that SKOV-3 ovarian cancer cells (ATCC HTB-77) were used instead of FaDu HNSCC cells, and an anti-HER2 [0379] Experimental results are shown in FIG. 7. Induction of phagocytosis as imaged by pHrodo-Red integrated intensity is enhanced by the addition of Compound 4 (hlgGl control, anti- HER2 trastuzumab, and the highest-activity condition, anti-HER2 trastuzumab with IpM Compound 4, are shown in FIG. 7, with statistical significance indicated (using unpaired t-test, p < 0.001 (***))). The final concentration of anti-HER2 trastuzumab was lp.g/ml.
[0380] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of anti-HER2 trastuzumab in SKOV-3 breast cancer cells under the conditions tested.
Example 17: APMAP Inhibitor Enhancement of Trastuzumab-induced ADCP of BT-474 breast cancer cells by primary human macrophages
10381] Coculture assays were conducted as described in Example 15, except that BT-474 breast cancer cells (ATCC HTB-20) were used instead of FaDu HNSCC cells.
[0382] Experimental results are shown in FIG. 8. Induction of phagocytosis as imaged by pHrodo-Red integrated intensity is enhanced by the addition of Compound 4 (hlgGl control, anti- HER2 trastuzumab, and the highest-activity condition, anti-HER2 trastuzumab with IpM Compound 4, are shown in FIG. 8, with statistical significance indicated (using unpaired t-test, p < 0.001 (***))). The final concentration of anti-HER2 trastuzumab was lpg/ml.
[0383] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of anti-HER2 trastuzumab in BT-474 breast cancer cells under the conditions tested.
Example 18: APMAP Inhibitor Enhancement of Avelumab-induced ADCP of RKO colon carcinoma cells by primary human macrophages from three individual donors
[0384] Coculture assays were conducted as described in Example 15, except that RKO colon carcinoma cells (ATCC CRL-2577) were used instead of FaDu HNSCC cells; an anti-PD-Ll antibody (Avelumab) was used instead of cetuximab; and primary human macrophages from three individual donors were used.
[0385] Experimental results are shown in FIG. 9. Induction of phagocytosis as imaged by PD-L1 avelumab, and the highest-activity condition, anti-PD-Ll avelumab with 333nM Compound 4 arc shown in FIG. 9, with statistical significance indicated (using unpaired t-test, p < 0.05 (*); using unpaired t-test, p < 0.005 (**)). The final concentration of anti-PD-Ll avelumab was Ipg/ml.
[0386] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-inducing effect of anti-PD-Ll avelumab in RKO colon cancer cells under the conditions tested.
Example 19: APMAP Inhibitor impact on cytokine/chemokine production
[0387] Coculture assays were conducted as described in Example 15, except that SK-BR-3 breast cancer cells (for Figs. 10A-10D) or RKO colon carcinoma cells (for Figs. 11A-11C) were used instead of FaDu HNSCC cells, an anti-HER2 antibody (Trastuzumab) (for Figs. 10A-10D) or an anti-PD-Ll antibody (Avelumab) (for Figs. 11A-11C) was used instead of cetuximab, and a single final Compound 4 coculture concentration of 200nM was used in each experiment. Supernatant from these assays were analyzed for the desired cytokine/chemokine concentration by MSD analysis according to the manufacturer’s protocol.
[0388] Experimental results are shown in FIGS. 10A-10D and FIGS. 11A-11C. Induction of cytokines/chemokines, specifically TNFa (Fig. 10A and 11 A), IL-6 (Fig. 10B), IL- 10 (Fig. 10C and 1 IB), IFNy (Fig. 10D), and MIP- la (Fig. 1 1C), observed upon presence of antibody in coculture were not further enhanced or were mildly suppressed by the addition of 200nM Compound 4 (unpaired t-test, p > 0.05 (n.s.), p < 0.05 (*)).
[0389] Results of this experiment show that APMAP inhibition by Compound 4 does not substantially impact the concentration of measured cytokines/chemokines in the cell culture media under the conditions tested.
Example 20: APMAP Inhibitor impact on cytokine/chemokine production
[0390] Coculture assays were conducted as described in Example 15, except that Ramos lymphoma cells were used instead of FaDu HNSCC cells, an anti-CD20 antibody (Rituximab) . was used instead of cetuximab, and a single final Compound 4 coculture concentration of 200nM cytokine/chemokine concentration by MSD analysis according to the manufacturer’s protocol. For this experiment, the induction of cytokines/chemokines was measured upon addition of Compound 4 (200nM final concentration) or an anti-CD47 antibody (clone B6H12, 2ug/ml final concentration) to the rituximab-opsonized Ramos cells and primary human macrophage cell coculture. APMAP_knockout Ramos cells opsonized with rituximab were used as a reference sample.
[0391] Experimental results are shown in FIGS. 12A-12D. Induction of cytokines/chemokines, specifically IL- 10 (Fig. 12A), IP- 10 (Fig. 12B), MCP-1 (Fig. 12C), and MIP-la (Fig. 12D), observed upon presence of rituximab or isotype control in coculture, were not significantly further enhanced by the addition of 200nM Compound 4. In contrast, addition of 2 pg/ml of the anti-CD47 antibody B6H12 induced a significant increase in IL- 10, MCP-1, and MIP- la relative to rituximab alone in coculture (unpaired t-test, p > 0.05 (n.s.), p < 0.005 (**), p < 0.0001 (****)).
[0392] Results of this experiment show that APMAP inhibition by Compound 4 does not substantially impact the concentration of measured cytokines/chemokines in the cell culture media under the conditions tested, in contrast to CD47 blockade by B6H12. The relative lack of pro- inflammatory activity of Compound 4 under the conditions tested in this Example as well as Example 19 may be beneficial, for example, for treatment of diseases or conditions in which additional pro-inflammatory activity is not desirable.
Example 21: Tumor Depletion Enhancement of Rituximab-induced ADCP of Ramos lymphoma cells by mouse macrophages
[0393] Coculture assays were conducted as described in Example 10, except that a single final Compound 4 coculture concentration of 200nM was used instead of a dose-response series, and an additional sample including isotype control plus 200nM Compound 4 (without rituximab) was tested. Ramos cells were also labeled with luM CFSE dye prior to coculture. Final Ramos lymphoma cell count was measured by flow cytometry for each condition tested. Briefly, tumor cells and macrophages were harvested from the well using accutase. Cell population was then counterstained with an anti-CDllb antibody conjugated to APC to mark macrophages. Tumor cell count was determined by quantification of CD1 Ib-negative, CFSE-positive cells within a defined volume using an Attune flow cytometer.
[0394] Experimental results are shown in FIG. 13. Depletion of tumor cells stimulated by opsonization with anti-CD20 rituximab is enhanced by the addition of Compound 4, statistical significance indicated (using unpaired t-test, p < 0.05 (*), p < 0.0001 (***), p < 0.00001 (****)). The final antibody concentration of rituximab was 1 pg/ml.
[0395] Results of this experiment show that APMAP inhibition by Compound 4 significantly enhances the ADCP-mediated depletion of Ramos lymphoma cells by rituximab under the conditions tested.
Example 22: APMAP Enhancement of ADCP of Various Cancer Cells Induced by Various
Agents (Mouse Macrophage System)
[0396] The APMAP enhancement of ADCP of various cancer cells induced by an agent may be evaluated using an assay based on that described in Example 10, 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 7, and the final coculture concentration of the ADCP-inducing agent may be, for example, 0.1, 1, or 10 pg/ml.
Table 7
[0397] Exemplary agents that may be evaluated for APMAP inhibitor enhancement of ADCP of various cancer cells include any of compounds 1 through 213; or another APMAP inhibitor, e.g., another APMAP inhibitor recited herein. Each row of Table 7 corresponds to a separate set of coculture experiments.
Example 23: APMAP inhibitor Enhancement of ADCP of Various Cancer Cells Induced by Various Agents (Human Macrophage System)
[0398] The APMAP inhibitor enhancement of ADCP of various cancer cells induced by an agent may be evaluated using an assay based on that described in Example 10 or 22, except that human monocyte-derived macrophages may be used in place of J774A mouse macrophages. To differentiate monocyte derived macrophages, CD 14+ monocycles from human donor samples may be cultured in complete HI-RPMI media (containing 10% heat-inactivated (HI) FBS, GlutaMAX, 100 units/ml penicillin, 100 pg/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 24: APMAP Inhibitor Enhancement of Tumor Cell Depletion by ADCP induced by Various Agents (Human or Mouse Macrophage Coculture System)
[0399] The APMAP inhibitor enhancement of ADCP of various cancer cells induced by an agent may be evaluated using an assay based on that described in one of the preceding examples, prior to the coculture assay. Human macrophages may be derived as described in Example 23, and mouse macrophages may be treated as described in Example 22. Tumor cell lines chosen from Table 7 may be additionally stained with CFSE (ThermoFisher #C34554, final concentration of IpM) for 20 minutes at the time of labeling with pHrodo-Red-SE. After 24 hours of coculture, the contents of each well may be harvested and counterstained with anti-CDl lb-APC antibody (BioLegend, clone #IRF44 for human macrophages and clone #M1/7O for mouse macrophages). Samples may then be analyzed using a flow cytometer to quantify the number of CFSE-positive, CD1 Ib-negative cells that are remaining in the population.
Example 25: APMAP Inhibitor Enhancement of ADCP of Various Cancer Cells Induced by Various Agents readout by Flow Cytometry (Human or Mouse Macrophage Coculture System)
[0400] The APMAP inhibitor enhancement of ADCP of various cancer cells induced by an agent may be evaluated using an assay based on that described in Example 24. At the end of the assay, phagocytosis may be quantified as the %pHrodo-Red-SE positive of the CDllb-positive population.
Example 26: Use of an APMAP Inhibitor to Stimulate Phagocytosis of Ap Plaques and
Treat Alzheimer’s Disease
[0401] An APMAP inhibitor, e.g., a brain-permeant APMAP inhibitor, e.g., one of Compounds 1-213 or a compound of any of Formulas I to III-5, may be evaluated for stimulation of phagocytosis of Ap plaques, e.g., by microglia or macrophages, and/or for reduction of the number or size of Ap plaques, in an in vitro system. For example, in a mouse study, Compound 142 was demonstrated to be a brain-permeant APMAP inhibitor, as it exhibits good passive penetration to the brain, with the equilibrium ratio of unbound drug in the brain to unbound drug in the plasma, Kp,uu, brain, equal to approximately 0.5 (data not shown). Optionally, the APMAP inhibitor may be administered in combination with an anti-amyloid beta (AP) antibody such as ABBV-916, Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK-6640, Lecanemab
(e.g., Lecanemab-irmb), MEDI-1814, NS-101, PMN-310, PRX-012, Remtemetug, Sabimetug, may be conducted in vivo, e.g., by using the Tg2576 mouse model (APPSWE Model 1349; Taconic Bioscicnccs) of Alzheimer’s disease to evaluate administration of the brain-permeant APMAP inhibitor, optionally in combination with an anti-Ap antibody such as ABBV-916, Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK-6640, Lecanemab (e.g., Lecanemab-irmb), MEDI-1814, NS-101, PMN-310, PRX-012, Remternetug, Sabirnetug, SHR-1707, or Trontinemab, and compared to administration of anti-Ap alone. Additionally, an APMAP inhibitor, e.g., a brain-permeant APMAP inhibitor, e.g., one of Compounds 1-213 or a compound of any of Formulas I to III-5, optionally in combination with an anti-Ap antibody such as ABBV- 916, Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK-6640, Lecanemab (e.g., Lecanemab-irmb), MEDI-1814, NS-101, PMN-310, PRX-012, Remternetug, Sabirnetug, SHR- 1707, or Trontinemab, may be evaluated in human subjects for stimulation of phagocytosis of Ap plaques, for reduction of the number or size of Ap plaques, and/or for treatment of Alzheimer’s disease.
[0402] The embodiments of the disclosure described above are intended to be merely exemplary, numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.
[0403] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entireties and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.
[0404] Other embodiments are provided within the following claims.

Claims

1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:
X1 is CRX or N;
X2 is C or N;
X3 is CRX or N;
Ring Y is optionally substituted 4- to 6-mcmbcrcd hctcroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S; each Rx is independently selected from the group consisting of hydrogen, halogen, -CN, -OR, optionally substituted Ci-Ce aliphatic, and optionally substituted C3-C7 cycloaliphatic,
A is -iJ-A1-*, where * represents a point of attachment to B;
L1 is a bond, -O-, -S-, -N(R)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or optionally substituted Ci-Ce aliphatic;
A1 is selected from the group consisting of -optionally substituted Ci-Ce aliphatic, optionally substituted -C3-C12 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cw aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
B is selected from the group consisting of a bond, optionally substituted -Ci-Ce aliphatic, optionally substituted -C3-C7 cycloaliphatic, optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
R1 is selected from the group consisting of hydrogen, halogen, -CN, -O(R), -N(R)2, - optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 hctcroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and each R is independently hydrogen or optionally substituted Ci-Ce aliphatic.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is not a racemate selected from:
3. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1 is CH.
4. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1 is N.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Ring Y is optionally substituted 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
6. The compound of any one of claims 1-5, wherein Ring Y is: wherein
X4 is O, S, N, NRX, or CRX, as valency permits;
X5 is O, S, N, NRX, or CRX, as valency permits; and X6 is O, S, N, NRX, or CRX, as valency permits.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein:
(i) X1 is N, X2 is N, X3 is CRX, X4 is N, X5 is N, and X6 is N; or
(ii) X1 is CRX, X2 is N, X3 is CRX, X4 is N, X5 is N, and X6 is N.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Rx is hydrogen or optionally substituted Ci-Ce aliphatic.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein Rx is hydrogen.
10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein Rxis optionally substituted Ci-Ce aliphatic.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein Rx I "S methyl.
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein moiety is selected from the group consistin g of:
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein moiety is
14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt thereof, wherein i t is
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein L1 is a bond, -O-, or -N(R)-.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein A1 is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein L1 is a bond, and A1 is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered hctcroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein L1 is -O- or -N(R)- and A1 is Ci-Ce aliphatic.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein the moiety B is connected to moiety A at a chiral carbon atom on moiety A.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein the connection between moiety B and moiety A is in a single stereochemical configuration.
21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein the connection is in the S configuration.
22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein the connection is in the (R) configuration.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein the moiety is selected from the group consisting of:
R , and R
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the moiety is selected from the group consisting of:
25. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the moiety is selected from the group consisting of:
R1
26. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the moiety is: wherein each RA is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl.
27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein the moiety is: wherein carbon atom a is chirally pure.
28. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein the moiety is:
29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the moiety is: wherein carbon atom a is chirally pure.
30. The compound of claims 27 or 29, or a pharmaceutically acceptable salt thereof, wherein the connection between moiety B and carbon atom a is in the (S) stereochemical configuration.
31. The compound any one of claims 1-30, or a pharmaceutically acceptable salt thereof, 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-mcmbcrcd hctcroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein B is a bond.
33. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted -Ci-Ce aliphatic.
34. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted 4- to 12- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted 5- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from halogen, -CN, -O(R), -N(R)2, -OC(O)(R), -C(O)O(R), -C(0)N(R)2, - S(R), -S(O)R, -S(O)2R, -N(R)C(O)R, =NC(O)R, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, -CN, -O(R), -N(R)2, -OC(O)(R), -C(O)O(R), -C(0)N(R)2, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
38. The compound of claim 36 or 37, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted 5- to 10-mcmbcrcd hctcroaryl comprising 1 to 3 hctcroatoms selected from N, O, and S.
39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R1 is wherein R1a is optionally substituted -Ci-Ce aliphatic, C3-C7 cycloaliphatic, or 4- to 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
40. The compound of claim 36 or 37, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted Ce-Cio aryl.
41. The compound of claim 36 or 37, or a pharmaceutically acceptable salt thereof, wherein R1 is -C(O)N(R)2.
42. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula II- 1: wherein:
X1 is N or CH; each RA is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl; and,
R1 is hydrogen, -C(O)O(R), -C(O)N(R)2, optionally substituted Ci-Ce aliphatic, optionally substituted C3-C7 cycloaliphatic, optionally substituted 4- to 7- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Cr.-Cio aryl, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula II-2:
Formula II-2, wherein carbon atom a is a chirally pure carbon atom.
44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula II-3:
Formula 11-3.
45. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula II-4:
46. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula III- 1 : Formula III-l wherein:
X1, X2, X3, X4, X5, and X6 are each independently selected from N, NH, C, and CH, as valency permits; each RA i is independently Ci-Ce aliphatic or C3-C7 cycloaliphatic; or two RA, together with the atoms to which each is attached, form an optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted Ce-Cio aryl; and R1a is hydrogen, Ci-Ce aliphatic, or optionally substituted 3- to 7-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula III-2:
Formula III-2, wherein carbon atom a is a chirally pure carbon atom.
48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula III-3: wherein: carbon atom a is a chirally pure carbon atom; and X1 is N or CH.
49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula III-4:
50. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula III-5:
51. The compound of claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
52. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
53. The compound of claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
54. A pharmaceutical composition comprising the compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
55. A composition comprising the compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein the composition comprises a single enantiomer of the compound in an enantiomeric excess of about 90% or greater.
56. The composition of claim 55, wherein the composition comprises a single enantiomer of the compound in an enantiomeric excess of about 95% or greater.
57. The composition of claim 56, wherein the composition comprises a single enantiomer of the compound in an enantiomeric excess of about 99% or greater.
58. The composition of any one of claims 55-57, wherein the single enantiomer is the (S) enantiomer.
59. The composition of any one of claims 55-57, wherein the single enantiomer is the (R) enantiomer.
60. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 54, or the composition of any one of claims 55-59, to treat the cancer.
61. The method of claim 60, wherein the cancer is a solid tumor.
62. The method of claim 60 or 61, wherein 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.
63. The method of claim 60 or 61, wherein 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 Sezary syndrome.
64. The method of claim 60, wherein the cancer is a hematological cancer.
65. The method of claim 64, wherein the cancer is lymphoma, leukemia, or myeloma.
66 The method of any one of claims 60 65 wherein the subject is a human
67. The method of any one of claims 60-66, further comprising administering a CAR-T therapy.
68. The method of claim 67, wherein the CAR-T therapy is idecabtagene vicleucel or lisocabtagene maraleucel.
69. A method for inhibiting the activity of APMAP in a subject or a biological sample, the method comprising administering to the subject or the biological sample the compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 54, or the composition of claims 55-59, to thereby inhibit the activity of APMAP.
70. The method of claim 69, wherein inhibiting APMAP in the subject treats a disease, disorder, or condition.
71. A method for treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 54, or the composition of any one of claims 55-59 to treat the disease, disorder, or condition.
72. The method of claim 71, wherein the APMAP inhibitor is delivered to the subject’s brain.
73. A method for treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of (i) an APMAP inhibitor and (ii) an additional therapeutic agent that binds to a target selected from amyloid beta (A0), BCMA, CCR4, CD19, CD20, CD22, CD24, CD30, CD33, CD38, CD47, CD52, CD79b, CEACAM5, CEACAM6, Claudin 6, Claudin 18.2, CTLA-4, DLL3, EGER, FGFR2, GD2, GPRC5D, GUCY2C, HER2, LAG3, Mesothelin, MET, Nectin-4, PDGFRa, PD-1,
PD-L1, PSMA, RANKE, SLAMF7, SMAGP, TF, TREM2, TROP2, VEGF, VEGFR, VEGFR2, or epidermal growth factor receptor with exon 20 insertion mutations, to treat the disease, disorder, or condition.
74. The method of claim 73, wherein the additional therapeutic agent is an inhibitor.
75. The method of claim 73 or 74, wherein the additional therapeutic agent is an agonist.
76. The method of any one of claims 73-75, wherein the additional therapeutic agent is an antibody.
77. The method of any one of claims 73-76, wherein the additional therapeutic agent is Alemtuzumab, Amivantamab, Avelumab, Bemarituzumab, Bevacizumab, Cetuximab,
Cosibelimab, Daratumumab, Denosumab, Dinutiximab, Elotuzumab, Isatuximab, Magrolizumab, Margetuximab, Mogamulizumab, Naxitamab, Necitumumab, Obinutuzumab, Ofatumumab, Olaratumab, Panitumumab, Pertuzumab, Ramucirumab, Rituximab, Tafasitamab, Trastuzumab,
TTI-622, a SIRPaFc fusion protein, or Zolbetuximab.
78. The method of any one of claims 73-77, wherein the additional therapeutic agent is ABBV-
916, Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK-6640, Lecanemab, MEDI-
1814, NS-101, PMN-310, PRX-012, Remtemetug, Sabirnetug, SHR-1707, or Trontinemab.
79. The method of any one of claims 73-78, wherein the additional therapeutic agent is an antibody -drug-conjugate.
80. The method of any one of claims 73-78, wherein 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.
81. A method for treating a disease, disorder, or condition responsive to APMAP inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of (i) an APMAP inhibitor and (ii) CAR-T therapy, to treat the disease, disorder, or condition.
82. The method of claim 81, wherein the CAR-T therapy is idecabtagene vicleucel or lisocabtagene maraleucel.
83. The method of any one of claims 71-82, wherein the disease, disorder, or condition is cancer.
85. The method of claim 83 or 84, wherein 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.
86. The method of any claim 83 or 84, wherein 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, gastroesophageal 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 Sezary syndrome.
87. The method of claim 83, wherein the cancer is a hematological cancer.
88. The method of claim 87, wherein the cancer is lymphoma, leukemia, or myeloma.
89. The method of any one of claims 71-81, wherein the disease, disorder, or condition responsive to APMAP inhibition is an autoimmune and/or inflammatory disease, disorder, or condition.
90. The method of claim 89, wherein the autoimmune and/or inflammatory disease, disorder, or condition is rheumatoid arthritis.
91. The method of any one of claims 71-81, wherein the disease, disorder, or condition responsive to APMAP inhibition is an infectious disease, disorder, or condition; or a neurological or neurodegenerative disease, disorder, or condition.
92. The method of claim 91, wherein the disease, disorder, or condition responsive to APMAP inhibition is a neurological or neurodegenerative disease, disorder, or condition.
93. The method of claim 92, wherein the neurological or neurodegenerative disease, disorder, or condition is multiple sclerosis, Huntington’s disease, or Parkinson’s disease.
94. The method of claim 92, wherein the neurological or neurodegenerative disease, disorder, or condition is a disease, disorder, or condition involving amyloid beta (AP) deposit formation or a disease, disorder, or condition involving frontal neuronal degeneration.
95. The method of claim 94, wherein the disease, disorder, or condition involving amyloid beta (Ap) deposit formation is Alzheimer’s disease.
96. The method of claim 95, further comprising administering to the subject an anti-amyloid beta (AP) antibody.
97. The method of claim 96, wherein the anti-amyloid beta ( AP) antibody is selected from the group consisting of ABBV-916, Aducanumab, Crenezumab, Donanemab, Ganterenumab, KHK- 6640, Lecanemab (e.g., Lecanemab-irmb), MEDI-1814, NS-101, PMN-310, PRX-012, Remternetug, Sabimetug, SHR-1707, and Trontinemab.
98. The method of claim 94, wherein the disease, disorder, or condition involving frontal neuronal degeneration is frontotemporal dementia.
99. The method of claim 73, wherein the method is further characterized by: a) the additional therapeutic agent is Rituximab, and the disease, disorder, or condition is:
• B-Cell Non-Hodgkin Lymphoma;
• Relapsed or refractory, low grade or follicular, B-Cell Non-Hodgkin Lymphoma (B-NHL) as a single agent;
• First line (IL) B-NHL in patients achieving a complete response or partial response as single-agent maintenance therapy, and wherein the Rituximab is administered in combination with a first line chemotherapy;
• Diffuse large B-cell lymphoma;
• Non-progressing (including stable disease), low-grade, B-NHL as a single agent after IL cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; • IL DLBCL, where the Rituximab is administered in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimen;
• IL advanced stage, CD20-positive, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL), wherein the Rituximab is administered in combination with chemotherapy;
• Chronic Lymphocytic Leukemia;
• Chronic Lymphocytic Leukemia; or
• Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC); b) the additional therapeutic agent is Ofatumumab, and the disease, disorder, or condition is:
• Chronic lymphocytic leukemia; or
• Chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab; c) the additional therapeutic agent is Obinutuzumab, and the disease, disorder, or condition is:
• Chronic lymphocytic leukemia;
• previously untreated CLL (sp. if del(17p)/TP53 mutation), wherein the Obinutuzumab is administered in combination with chlorambucil;
• Follicular lymphoma;
• follicular lymphoma, wherein the Obinutuzumab is administered in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients who relapsed after, or are refractory to, a rituximab-containing regimen; or
• previously untreated stage II bulky, III or IV follicular lymphoma, wherein the Obinutuzumab is administered in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission; d) the additional therapeutic agent is Ibritumomab tiuxetan, and the disease, disorder, or condition is:
• Follicular lymphoma; or
• Relapsed or refractory follicular lymphoma; e) the additional therapeutic agent is Tafasitamab, and the disease, disorder, or condition is:
• Diffuse large B cell lymphoma; or • Relapsed or refractory DLBCL, wherein the Tafasitamab is administered in combination with lenalidomide; f) the additional therapeutic agent is Alemtuzumab, and the disease, disorder, or condition is Chronic lymphocytic leukemia; g) the additional therapeutic agent is Mogamulizumab, and the disease, disorder, or condition is:
• Mycosis fungoides;
• Sezary syndrome; or
• Relapsed or refractory mycosis fungoides or Sezary syndrome; h) the additional therapeutic agent is Daratumumab, and the disease, disorder, or condition is:
• Multiple myeloma;
• Multiple myeloma (MM), wherein the Daratumumab is administered in combination with bortezomib, melphalan and prednisone (VMP) in newly diagnosed patients who are ineligible for ASCT ;
• Multiple myeloma, wherein the Daratumumab is administered in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for ASCT and in patients with RR-MM (second line (2L));
• Multiple myeloma, wherein the Daratumumab is administered in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for ASCT;
• Multiple myeloma, wherein the Daratumumab is administered in combination with bortezomib and dexamethasone in a patient who has received at least one prior therapy;
• Multiple myeloma, wherein the Daratumumab is administered in combination with pomalidomide and dexamethasone in a patient who has received at least one prior line of therapy including lenalidomide and a proteasome inhibitor;
• Multiple myeloma, wherein the Daratumumab is administered in combination with carfilzomib and dexamethasone in a patient with RR-MM who has received one to three prior lines of therapy;
• Multiple myeloma, wherein the patient has received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who is doublerefractory to a PI and an immunomodulatory agent; • Light chain amyloidosis; or
• Light chain amyloidosis, wherein the Daratumumab is administered in combination with bortezomib, cyclophosphamide and dexamethasone in a patient newly diagnosed with Light chain amyloidosis; i) the additional therapeutic agent is Isatuximab, and the disease, disorder, or condition is:
• Multiple myeloma;
• Multiple myeloma for the treatment of adult patients, wherein the Isatuximab is administered in combination with pomalidomide and dexamethasone, wherein patient has received at least 2 prior therapies including lenalidomide and a proteasome inhibitor; or
• RR-Multiple myeloma in an adult patient who has received 1 to 3 prior lines of therapy, wherein the Isatuximab is administered in combination with carfilzomib and dexamethasone; j) the additional therapeutic agent is Elotuzumab, and the disease, disorder, or condition is:
• Multiple myeloma;
• RR-Multiple myeloma is an adult patient who has received one to three prior therapies, wherein the Elotuzumab is administered in combination with lenalidomide and dexamethasone; or
• RR-Multiple myeloma in a patient who has received at least two prior therapies including lenalidomide and a proteasome inhibitor, wherein the Elotuzumab is administered in combination with pomalidomide and dexamethasone; k) the additional therapeutic agent is Cetuximab, and the disease, disorder, or condition is:
• Head and Neck Cancer;
• Squamous cell carcinoma;
• Locally or regionally advanced squamous cell carcinoma of head and neck (SCCHN), wherein the Cetuximab is administered in combination with radiation therapy;
• Recurrent locorcgional disease or metastatic SCCHN, wherein the Cetuximab is administered in combination with platinum-based therapy with fluorouracil;
• Recurrent or metastatic SCCHN progressing after platinum-based therapy;
• Colorectal cancer; • K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test;
• Cancer, wherein the Cetuximab is administered in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or
• Cancer, wherein the Cetuximab is administered as a single-agent in a patient who has failed oxaliplatin- and irinotecan-based chemotherapy or who is intolerant to irinotecan;
1) the additional therapeutic agent is Panitumumab, and the disease, disorder, or condition is:
• Colorectal cancer;
• RAS WT metastatic CRC;
• Cancer characterized by disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy; m) the additional therapeutic agent is Necitumumab, and the disease, disorder, or condition is:
• Non-small cell lung cancer; or
• Metastatic squamous NSCLC, wherein the Necitumumab is administered in combination with gemcitabine and cisplatin, for first-line treatment of patients; n) wherein the additional therapeutic agent is Amivantamab, and the disease, disorder, or condition is:
• Non-small cell lung cancer; or
• Locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, where the disease has progressed on or after platinum-based chemotherapy; o) wherein the additional therapeutic agent is Trastuzumab, and the disease, disorder, or condition is:
• Breast cancer;
• HER2 overexpressing breast cancer, wherein the Trastuzumab is administered as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and cither paclitaxel or docetaxel, with docetaxel and carboplatin, or as a single agent following multi-modality anthracy cline based therapy;
• mBrCa, wherein the Trastuzumab is administered in combination with paclitaxel for first- line treatment of HER2-overexpressing mBrCa or as a single agent for treatment of HER2- overexpressing BrCa in patients who have received one or more chemotherapy regimens for metastatic disease;
• Gastric or gastroesophageal junction adenocarcinoma; or
• HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, wherein the Trastuzumab is administered in combination with cisplatin and capecitabine or 5 -fluorouracil; p) wherein the additional therapeutic agent is Pertuzumab, and the disease, disorder, or condition is:
• Breast cancer;
• HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy, wherein the Pertuzumab is administered in combination with trastuzumab and docetaxel;
• HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive); or
• HER2-positive early breast cancer at high risk of recurrence, wherein the Pertuzumab is administered in combination with trastuzumab and chemotherapy; q) wherein the additional therapeutic agent is Margetuximab, and the disease, disorder, or condition is:
• Breast cancer; or
• metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease, wherein the Margetuximab is administered in combination with chemotherapy; r) wherein the additional therapeutic agent is Zolbetuximab, and the disease, disorder, or condition is:
• Gastro-esophageal junction adenocarcinoma; or
• Previously untreated, locally advanced unresectable or metastatic HER2-/Claudin 18.2+ gastric or gastro-esophageal junction adenocarcinoma; s) wherein the additional therapeutic agent is Ramucirumab, and the disease, disorder, or condition is:
• Metastatic gastric or gastro-esophageal junction adenocarcinoma; • Advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy, wherein the Ramucirumab is administered as a single agent or in combination with paclitaxel;
• Non-small cell lung cancer;
• first-line treatment of metastatic NSCLC with EGFR ex 19 deletions or ex21 (L858R) mutations, wherein the Ramucirumab is administered in combination with erlotinib;
• metastatic NSCLC with disease progression on or after platinum-based chemotherapy, wherein the Ramucirumab is administered in combination with docetaxel;
• EGFR or ALK genomic tumor aberrations should have disease progression on FDA- approved therapy for these aberrations prior to receiving CYRAMZA;
• Colorectal cancer;
• Metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine, wherein the Ramucirumab is administered in combination with FOLFIRI;
• Hepatocellular carcinoma; or
• HCC in patients who have an alpha fetoprotein of >400 ng/mL and have been treated with sorafenib; t) wherein the additional therapeutic agent is Bemarituzumab, and the disease, disorder, or condition is:
• Gastric cancer; or
• FGFR2 OE Gastric cancer IL with FOLFOX6 or chemotherapy + nivolumab; or u) wherein the additional therapeutic agent is Olaratumab, and the disease, disorder, or condition is soft tissue sarcoma, wherein the is Olaratumab is administered in combination with doxorubicin therapy for patients who do not have a curative option with surgery or radiation; v) wherein the additional therapeutic agent is Cosibelimab, and the disease, disorder, or condition is Cutaneous squamous cell carcinoma (cSCC); w) wherein the additional therapeutic agent is Avelumab, and the disease, disorder, or condition is:
• Urothelial cancer; or • Renal cancer; x) wherein the additional therapeutic agent is Magrolimab, and the disease, disorder, or condition is:
• Triple negative breast cancer, wherein the Magrolimab is administered alone and in combination with standard of care;
• Metastatic colorectal cancer, wherein the Magrolimab is administered alone and in combination with standard of care and bevacizumab;
• Urothelial cancer, wherein the Magrolimab is administered alone and in combination with standard of care;
• Head and neck squamous cell carcinoma, wherein the Magrolimab is administered alone and in combination with standard of care and/or cetuximab;
• Low and high Myelodysplastic syndrome with azacytidine;
• Acute myeloid leukemia, wherein the Magrolimab is administered alone and with standard of care and or venetoclax;
• Diffuse large B cell lymphoma, wherein the Magrolimab is administered alone and with standard of care, including rituximab, or Obinutuzumab; or
• Multiple myeloma, wherein the Magrolimab is administered alone and with standard of care including daratumumab, elotuzumab and Isatuximab; y) wherein the additional therapeutic agent is TTI-622, and the disease, disorder, or condition is:
• Multiple myeloma, wherein the TTI-622 is administered alone and with standard of care including daratumumab, elotuzumab and Isatuximab;
• Diffuse large B cell lymphoma, wherein the TTI-622 is administered alone and with standard of care, including rituximab, or Obinutuzumab or lenalidomide or Tafasitamab;
• Ovarian cancer, wherein the TTI-622 is administered alone and in combination with Pegylated liposomal doxorubicin;
• Low and high Myelodysplastic syndrome, wherein the TTI-622 is administered with azacytidine; or
• Acute myeloid leukemia, wherein the TTI-622 is administered alone or with standard of care and/or venetoclax; z) wherein the additional therapeutic agent is Bevacizumab, and the disease, disorder, or condition is:
• Metastatic colorectal cancer, wherein the Bevacizumab is administered in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment;
• Metastatic colorectal cancer, wherein the Bevacizumab is administered in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second- line treatment in patients who have progressed on a first- line bevacizumab productcontaining regimen;
• Unresectable, locally advanced, recurrent, or metastatic non-squamous non-small cell lung cancer, wherein the Bevacizumab is administered in combination with carboplatin and paclitaxel for first-line treatment;
• Recurrent glioblastoma in adults;
• Metastatic renal cell carcinoma, wherein the Bevacizumab is administered in combination with interferon alfa;
• Persistent, recurrent, or metastatic cervical cancer, wherein the Bevacizumab is administered in combination with paclitaxel and cisplatin, or paclitaxel and topotecan;
• Epithelial ovarian, fallopian tube, or primary peritoneal cancer, wherein the Bevacizumab is administered: a) in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection; b) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum- resistant recurrent disease who received no more than 2 prior chemotherapy regimens; or c) in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Avastin as a single agent, for platinum-sensitive recurrent disease; or
• Hepatocellular Carcinoma (HCC), wherein the Bevacizumab is administered in combination with atezolizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy; aa) wherein the additional therapeutic agent is Denosumab, and the disease, disorder, or condition is:
• bone metastases from solid tumors for prevention of skeletal-related events in patients; or • giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity; ab) wherein the additional therapeutic agent is Dinutiximab, and the disease, disorder, or condition is:
• Neuroblastoma; or
• high-risk neuroblastoma in pediatric patients who achieve at least a partial response to prior first-line multiagent, multimodality therapy, wherein the Dinutiximab is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA); ac) wherein the additional therapeutic agent is Naxitamab, and the disease, disorder, or condition is:
• Neuroblastoma; or
• relapsed or refractory high-risk neuroblastoma in the bone or bone marrow in pediatric patients 1 year of age and older and adult patients who have demonstrated a partial response, minor response, or stable disease to prior therapy, wherein the Naxitamab is administered in combination with granulocyte-macrophage colony-stimulating factor (GMCSF); ad) wherein the additional therapeutic is Aducanumab, and the disease, disorder, or condition is:
• Alzheimer’s disease; or
• mild cognitive impairment or mild dementia stage of disease; or ae) wherein the additional therapeutic is Lecanemab, and the disease, disorder, or condition is:
• Alzheimer’s disease; or
• mild cognitive impairment or mild dementia stage of disease.
100. The method of any one of claims 73-99, wherein the APMAP inhibitor is or comprises the compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 54, or the composition of claims 55-59.
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