WO2024022332A1 - Fap inhibitors - Google Patents

Fap inhibitors Download PDF

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Publication number
WO2024022332A1
WO2024022332A1 PCT/CN2023/109106 CN2023109106W WO2024022332A1 WO 2024022332 A1 WO2024022332 A1 WO 2024022332A1 CN 2023109106 W CN2023109106 W CN 2023109106W WO 2024022332 A1 WO2024022332 A1 WO 2024022332A1
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Prior art keywords
compound
ring
heterocyclyl
mmol
cancer
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PCT/CN2023/109106
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French (fr)
Inventor
Yun Jin
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Shanghai Sinotau Biotech. Co., Ltd
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Publication of WO2024022332A1 publication Critical patent/WO2024022332A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • fibroblast activation protein FAP
  • Fibroblast activation protein alpha (FAP, also named seprase, EC 3.4.21. B28) , encoded by the FAP gene, also known as prolyl endopeptidase FAP, is a 760 amino acid type II transmembrane glycoprotein. It contains a short intracellular domain of 6 amino acids at the N-terminal, a transmembrane section of 22 amino acids and a large extracellular region at the C-terminal. The extracellular domain consists of a beta propeller domain, which functions as a substrate selectivity gatekeeper, and an alpha/beta hydrolase domain. FAP is not enzymatic active until it forms homodimer or heterodimer with DPP4.
  • FAP Fibroblast activation protein alpha
  • FAP is a serine protease. It belongs to the propyl dipeptidyl peptidase family, which also includes DPP4, DPP7, DPP8, DPP9, prolyl carboxypeptidase, and prolyl endopeptidase (PREP) . It mostly resembles DDP4, with which shares 84%amnio acid homology and 51%identity. In addition to a post-proline exopeptidase, which is similar to DPP4, FAP is also an endopeptidase.
  • FAP knockout mice are normal, fertile and healthy (Niedermeyer et al 2000) , suggesting that its function could be fully compensated by proteins with similar activity. Echoing with what is observed with FAP knockout mice, loss of function SNP variant in a Vietnamese family was not associated with any phenotype (Osborne et al 2014) .
  • FAP is found upregulated in 90%of carcinoma. It promotes cancer cell proliferation, migration and invasion (An et al 2022) .
  • FAP is profoundly known as a marker of cancer associated fibroblast (CAF) , which plays a pro-tumorigenic role in a broad spectrum of cancers, breast cancer, colorectal, pancreatic, lung, bladder, ovarian, head and neck, glioblastoma et al, just to name a few (Kratochwil et al 2019, Windisch et al 2020) .
  • CAF cancer associated fibroblast
  • targeting FAP is a promising strategy for cancer therapy. Multiple approaches targeting FAP have been intensively exploited and developed as noted.
  • FAP enzymatic inhibition and functional block by small molecular inhibitors, vaccination, antibody against FAP Those could be clustered into: 1) FAP enzymatic inhibition and functional block by small molecular inhibitors, vaccination, antibody against FAP; 2) FAP protein depletion by PROTACs and oligonucleotide drugs of miRNA, shRNA, siRNA; 3) FAP (+) cell depletion, such as CAR-T and CAR-NK; 4) FAP directed prodrug and micelle (Chai et al 2018, Teng et al 2020) ; 5) FAP ligand mediated therapy, such as FAP ligand mediated radiotherapy or chemotoxicity and antibody-conjugated chemotherapy.
  • FAP ligand mediated therapy such as FAP ligand mediated radiotherapy or chemotoxicity and antibody-conjugated chemotherapy.
  • FAP is involved in varying diseases, including but not limited to cardiovascular, infection, arthritis, inflammation, fibrosis, metabolic and autoimmune diseases (Tillmanns et al 2015, Croft et al 2019, Lay et al 2019, Schmidkonz et al 2020, Hoffmann et al 2021, Windisch et al 2021) .
  • FAP imaging is being exploited in delineating tumor volume, diagnosis and staging of FAP-associated diseases (Dendl et al 2021, Kratochwil et al 2019, Luo et al 2021) .
  • FAP mediates tumor growth and FAP associated diseases in both enzymatic activity dependent and independent way.
  • Breast cancer cell line that expressed enzymatic inactive FAP is more invasive and produces tumor that grow rapidly (Huang et al 2011) , which is likely through activating PI3K and MMP2/9 pathways (Lv et al 2016) .
  • ligands binding/targeting FAP provides great potential of clinical value in therapy or diagnosis.
  • provided herein are some chemical entities which demonstrate potent FAP enzymatic inhibition, great tumor uptake and/or retention.
  • small animal PET/CT delineate the tumor volume with great tumor-to-blood, tumor-to-kidney ratio, and long-term tumor retention, and resulting in completely tumor inhibition in the in vivo efficacy study.
  • Also provided herein is a complex formed by a compound provided herein and a divalent or trivalent metal cation.
  • a liposome comprising the compound provided herein.
  • a virus-like particle comprising the compound provided herein.
  • composition comprising a compound provided herein, a liposome provided herein, or a virus-like particle (VLP) provided herein, and a pharmaceutically acceptable excipient.
  • VLP virus-like particle
  • Also provided herein is a method for the diagnosis of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a diagnostically effective amount of a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein.
  • FAP fibroblast activation protein
  • Also provided herein is a method for the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein.
  • FAP fibroblast activation protein
  • kits comprising a compound provided herein, a complex provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein, and instructions for the diagnosis or treatment of a disease.
  • VLP virus-like particle
  • the terms “comprising” and “including” can be used interchangeably.
  • the terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of” . Consequently, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.
  • the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C” . An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.
  • phrase “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone) ; and B (alone) .
  • phrase “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated.
  • the alkyl group has, for example, from one to twenty-four carbon atoms (C 1 -C 24 alkyl) , four to twenty carbon atoms (C 4 -C 20 alkyl) , six to sixteen carbon atoms (C 6 -C 16 alkyl) , six to nine carbon atoms (C 6 -C 9 alkyl) , one to fifteen carbon atoms (C 1 -C 15 alkyl) , one to twelve carbon atoms (C 1 -C 12 alkyl) , one to eight carbon atoms (C 1 -C 8 alkyl) or one to six carbon atoms (C 1 -C 6 alkyl) and which is attached to the rest of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl) , n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) , 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specified, an alkyl group is optionally substituted.
  • alkenyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds.
  • alkenyl also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations, as appreciated by those of ordinary skill in the art.
  • the alkenyl group has, for example, from two to twenty-four carbon atoms (C 2 -C 24 alkenyl) , four to twenty carbon atoms (C 4 -C 20 alkenyl) , six to sixteen carbon atoms (C 6 -C 16 alkenyl) , six to nine carbon atoms (C 6 -C 9 alkenyl) , two to fifteen carbon atoms (C 2 -C 15 alkenyl) , two to twelve carbon atoms (C 2 -C 12 alkenyl) , two to eight carbon atoms (C 2 -C 8 alkenyl) or two to six carbon atoms (C 2 -C 6 alkenyl) and which is attached to the rest of the molecule by a single bond.
  • alkenyl groups include, but are not limited to, ethenyl, prop-1-enyl, but- 1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like. Unless otherwise specified, an alkenyl group is optionally substituted.
  • alkynyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon triple bonds.
  • the alkynyl group has, for example, from two to twenty-four carbon atoms (C 2 -C 24 alkynyl) , four to twenty carbon atoms (C 4 -C 20 alkynyl) , six to sixteen carbon atoms (C 6 -C 16 alkynyl) , six to nine carbon atoms (C 6 -C 9 alkynyl) , two to fifteen carbon atoms (C 2 -C 15 alkynyl) , two to twelve carbon atoms (C 2 -C 12 alkynyl) , two to eight carbon atoms (C 2 -C 8 alkynyl) or two to six carbon atoms (C 2 -C 6 alkynyl) and which is attached to the
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specified, an alkynyl group is optionally substituted.
  • cycloalkyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which is saturated. Cycloalkyl group may include fused, bridged, or spiro ring systems. In one embodiment, the cycloalkyl has, for example, from 3 to 15 ring carbon atoms (C 3 -C 15 cycloalkyl) , from 3 to 10 ring carbon atoms (C 3 -C 10 cycloalkyl) , or from 3 to 8 ring carbon atoms (C 3 -C 8 cycloalkyl) .
  • the cycloalkyl is attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • polycyclic cycloalkyl radicals include, but are not limited to, adamantyl, norbornyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, spiro [3, 3] heptyl, spiro [3, 4] octyl, spiro [4, 3] octyl, spiro [3, 5] nonyl, spiro [5, 3] nonyl, spiro [3, 6] decyl, spiro [6, 3] decyl, spiro [4, 5] decyl, spiro [5, 4] decyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and the like. Unless otherwise specified, a cycloalkyl group is optionally substituted.
  • heteroalkyl refers to a saturated straight or branched carbon chain that is interrupted one or more times with the same or different heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur.
  • heteroalkyl include, but are not limited to, -O-CH 3 , -S-CH 3 , -CH 2 -O-CH 3 , -CH 2 -O-C 2 H 5 , -CH 2 -S-CH 3 , -CH 2 -S-C 2 H 5 , -C 2 H 4 -O-CH 3 , -C 2 H 4 -O-C 2 H 5 , -C 2 H 4 -S-CH 3 , -C 2 H 4 -S-CH 3 , -C 2 H 4 -S-C 2 H 5 , and the like.
  • a heteroalkyl group is optionally substituted.
  • heterocyclyl refers to a non-aromatic radical monocyclic or polycyclic moiety that contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom.
  • a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other polycyclic ring system, wherein the polycyclic ring systems can be a fused, bridged or spiro ring system.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or more rings.
  • a heterocyclyl group can be saturated or partially unsaturated.
  • Saturated heterocycloalkyl groups can be termed “heterocycloalkyl” .
  • Partially unsaturated heterocycloalkyl groups can be termed “heterocycloalkenyl” if the heterocyclyl contains at least one double bond, or “heterocycloalkynyl” if the heterocyclyl contains at least one triple bond.
  • the heterocyclyl has, for example, 3 to 18 ring atoms (3-to 18-membered heterocyclyl) , 4 to 18 ring atoms (4-to 18-membered heterocyclyl) , 5 to 18 ring atoms (3-to 18-membered heterocyclyl) , 4 to 8 ring atoms (4-to 8-membered heterocyclyl) , or 5 to 8 ring atoms (5-to 8-membered heterocyclyl) .
  • a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heterocyclyl group can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to and including 18 ring atoms.
  • heterocyclyl groups include, but are not limited to, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and piperidinyl.
  • heterocyclyl groups also include, but are not limited to, 1- (1, 2, 5, 6-tetrahydropyridyl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1, 8 diazo-spiro- [4, 5] decyl, 1, 7 diazo-spiro- [4, 5] decyl, 1, 6 diazo-spiro- [4, 5] decyl, 2, 8 diazo-spiro [4, 5] decyl, 2, 7 diazo-spiro [4, 5] decyl, 2, 6 diazo-spiro [4, 5] decyl, 1, 8 diazo-spiro- [5, 4] decyl, 1, 7 diazo-spiro- [5, 4] decyl, 2, 8 diazo-spiro-[5, 4] decyl, 2, 7 diazo-spiro [5, 4] decyl, 3, 8 diazo-spiro [5, 4
  • aryl refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring.
  • the aryl has from 6 to 18 ring carbon atoms (C 6 -C 18 aryl) , from 6 to 14 ring carbon atoms (C 6 -C 14 aryl) , or from 6 to 10 ring carbon atoms (C 6 -C 10 aryl) .
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • aryl also refers to bicyclic, tricyclic, or other multicyclic hydrocarbon rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) . Unless otherwise specified, an aryl group is optionally substituted.
  • heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from O, S, and N.
  • the heteroaryl may be attached to the main structure at any heteroatom or carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • heteroaryl also refers to bicyclic, tricyclic, or other multicyclic rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N.
  • Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.
  • tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. Unless otherwise specified, a heteroaryl group is optionally substituted.
  • alkylene or “alkylene chain” refers to a straight or branched multivalent (e.g., divalent or trivalent) hydrocarbon chain linking the rest of the molecule to a radical group (or groups) , consisting solely of carbon and hydrogen, which is saturated.
  • the alkylene has, for example, from one to twenty-four carbon atoms (C 1 -C 24 alkylene) , one to fifteen carbon atoms (C 1 -C 15 alkylene) , one to twelve carbon atoms (C 1 -C 12 alkylene) , one to eight carbon atoms (C 1 -C 8 alkylene) , one to six carbon atoms (C 1 -C 6 alkylene) , two to four carbon atoms (C 2 -C 4 alkylene) , one to two carbon atoms (C 1 -C 2 alkylene) .
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group (s) can be through one carbon or any two (or more) carbons within the chain. Unless otherwise specified, an alkylene chain is optionally substituted.
  • alkynylene is a multivalent (e.g., divalent or trivalent) alkynyl group
  • cycloalkylene is a multivalent (e.g., divalent or trivalent) cycloalkyl group
  • heterocyclylene is a multivalent (e.g., divalent or trivalent) heterocyclyl group
  • arylene is a multivalent (e.g., divalent or trivalent) aryl group
  • heteroarylene is a multivalent (e.g., divalent or trivalent) heteroaryl group.
  • Other “ylene” terms can be constructed similarly from the corresponding “yl” terms.
  • a “yl” term as used herein includes and can be replaced by the corresponding “ylene” term, if proper based on the valence of the group.
  • the ring moiety is also heterocyclylene if it is multivalent (e.g., divalent or trivalent) , i.e., it is connected to multiple parts of the compound.
  • aralkyl refers to an alkyl moiety, which is substituted by aryl.
  • An example is the benzyl radical.
  • heteroaryl refers to an alkyl moiety, which is substituted by heteroaryl. Unless otherwise specified, the terms for other similar composite moieties can be constructed similarly.
  • the substituent is a C 1 -C 12 alkyl group. In other embodiments, the substituent is a cycloalkyl group. In other embodiments, the substituent is a halo group, such as fluoro. In other embodiments, the substituent is an oxo group. In other embodiments, the substituent is a hydroxyl group. In other embodiments, the substituent is an alkoxy group (-OR’) . In other embodiments, the substituent is a carboxyl group. In other embodiments, the substituent is an amino group (-NR’R’) .
  • optionally substituted means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted alkyl means that the alkyl radical may or may not be substituted and that the description includes both substituted alkyl radicals and alkyl radicals having no substitution.
  • halo refers to a halogen residue selected from the group consisting of F, Cl, Br, and I.
  • linker refers to any chemically suitable linker.
  • a linker is not or only slowly cleaved under physiological conditions.
  • the linker does not comprise recognition sequences for proteases or recognition structures for other degrading enzymes.
  • the linker when the compounds provided herein are administered systemically to allow broad access to all compartments of the body and subsequently enrichment of the compounds provided herein wherever in the body the tumor is located, the linker is chosen in such that it is not or only slowly cleaved in blood. In one embodiment, the cleavage is considered slowly, if less than 50%of the linkers are cleaved 2 h after administration of the compound to a human patient.
  • Suitable linkers include, but are not limited to, optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aralkyl, heteroaralyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, sulfonyl, amines, ethers, thioethers phosphines, phosphoramidates, carboxamides, esters, imidoesters, amidines, thioesters, sulfonamides, 3-thiopyrrolidine-2, 5-dion, carbamates, ureas, guanidines, thioureas, disulfides, oximes, hydrazines, hydrazides, hydrazones, diaza bonds, triazoles, triazolines, tetrazines, platinum complexes and amino acids, or combinations
  • the linker can also be a cleavable linker such as a peptide motif that is cleaved by cathepsin. Any suitable linker that is cleavable by cathepsin can be used. Certain suitable cleavable peptide linkers are described in Peterson et al., Bioconjugate Chem., 1998.
  • Suitable cleavable linkers comprises optionally substituted NO 2 Tyr-Gln-Gly-Val-Gln-Phe-Lys (Aminobenzoyl) , NO 2 Tyr-Asn-Gly-Thr-Gly-Phe-Lys (Aminobenzoyl) , NO 2 Tyr-Ser-Val-Val-Phe-Phe-Lys (Aminobenzoyl) , NO 2 Tyr-Val-Gln-Ser-Ala-Phe, Multiple-Val-Gln-Phe-Val, NO 2 Tyr-Gly-Val-Phe-Gln-Phe, NO 2 Tyr-Gly-Thr-Val-Ala-Phe-Lys (Aminobenzoyl) , NO 2 Tyr-Ala-Thr-Ala-Phe-Phe-Lys (Aminobenzoyl) , NO 2 Tyr-Gly-Ser-Val-Gln-Phe-Lys (Aminobenzo
  • amino acid refers to any organic acid containing one or more amino substituents, e.g., ⁇ -, ⁇ -or ⁇ -amino, derivatives of aliphatic carboxylic acids.
  • amino substituents e.g., ⁇ -, ⁇ -or ⁇ -amino, derivatives of aliphatic carboxylic acids.
  • polypeptide notation e.g., Xaa1Xaa2Xaa3Xaa4Xaa5
  • the left hand direction is the amino terminal direction
  • the right hand direction is the carboxy terminal direction, in accordance with standard usage and convention.
  • conventional amino acid refers to the twenty naturally occurring amino acids, and encompasses all stereomeric isoforms, i.e., D, L-, D-and L-amino acids thereof.
  • These conventional amino acids can herein also be referred to by their conventional three-letter or one-letter abbreviations and their abbreviations follow conventional usage (see, for example, Immunology-ASynthesis, 2nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer Associates, Sunderland Mass. (1991) ) .
  • non-conventional amino acid refers to unnatural amino acids or chemical amino acid analogues, e.g. ⁇ , ⁇ -disubstituted amino acids, N-alkyl amino acids, homo-amino acids, dehydroamino acids, aromatic amino acids (other than phenylalanine, tyrosine and tryptophan) , and ortho-, meta-or para-aminobenzoic acid.
  • Non-conventional amino acids also include compounds which have an amine and carboxyl functional group separated in a 1, 3 or larger substitution pattern, such as ⁇ -alanine, ⁇ -amino butyric acid, Freidinger lactam, the bicyclic dipeptide (BTD) , amino-methyl benzoic acid and others known in the art.
  • BTD bicyclic dipeptide
  • Statine-like isosteres, hydroxyethylene isosteres, reduced amide bond isosteres, thioamide isosteres, urea isosteres, carbamate isosteres, thioether isosteres, vinyl isosteres and other amide bond isosteres known to the art may also be used.
  • analogues or non-conventional amino acids may improve the stability and biological half-life of the added peptide since they are more resistant to breakdown under physiological conditions.
  • the person skilled in the art will be aware of similar types of substitution which may be made.
  • a non-limiting list of non-conventional amino acids which may be used as suitable building blocks for a peptide and their standard abbreviations (in brackets) is as follows: ⁇ -aminobutyric acid (Abu) , L-N-methylalanine (Nmala) , ⁇ -amino- ⁇ -methylbutyrate (Mgabu) , L-N-methylarginine (Nmarg) , aminocyclopropane (Cpro) , L-N-methylasparagine (Nmasn) , carboxylate L-N-methylaspartic acid (Nmasp) , aniinoisobutyric acid (Aib) , L-N-methylcysteine (Nmcys) , amino
  • radioactive moiety refers to a molecular assembly which carries a radioactive nuclide.
  • the nuclide is bound either by covalent or coordinate bonds which remain stable under physiological conditions. Examples are [ 113 I] -3-iodobenzoic acid or 68 Ga-DOTA.
  • fluorescent isotope refers to an isotope that emits electromagnetic radiation after excitation by electromagnetic radiation of a shorter wavelength.
  • radioisotope is a radioactive isotope of an element (included by the term “radionuclide” ) emitting ⁇ -, ⁇ -, and/or ⁇ -radiation.
  • radioactive drug refers to a biologic active compound which is modified by a radioisotope.
  • intercalating substances can be used to deliver the radioactivity to direct proximity of DNA (e.g. a 131 I-carrying derivative of Hoechst-33258) .
  • the terms “chelating agent” or “chelator” are used interchangeably and refer to a molecule, often an organic one, and often a Lewis base, having two or more unshared electron pairs available for donation to a metal ion.
  • the metal ion is usually coordinated by two or more electron pairs to the chelating agent.
  • the terms “bidentate chelating agent” , “tridentate chelating agent” , and “tetradentate chelating agent” refer to chelating agents having, respectively, two, three, and four electron pairs readily available for simultaneous donation to a metal ion coordinated by the chelating agent.
  • the electron pairs of a chelating agent forms coordinate bonds with a single metal ion; however, in certain examples, a chelating agent may form coordinate bonds with more than one metal ion, with a variety of binding modes being possible.
  • fluorescent dye refers to a compound that emits visible or infrared light after excitation by electromagnetic radiation of a shorter and suitable wavelength. It is understood by the skilled person that each fluorescent dye has a predetermined excitation wavelength.
  • contrast agent refers to a compound which increases the contrast of structures or fluids in medical imaging.
  • the enhancement is achieved by absorbing electromagnetic radiation or altering electromagnetic fields.
  • paramagnetic refers to paramagnetism induced by unpaired electrons in a medium.
  • a paramagnetic substance induces a magnetic field if an external magnetic field is applied.
  • the direction of the induced field is the same as the external field and unlike ferromagnetism the field is not maintained in absence of an external field.
  • nanoparticle refers to particles, such as particles of spheric shape, with diameters of sizes between 1 and 100 nanometers. Depending on the composition, nanoparticles can possess magnetical, optical or physico-chemical qualities that can be assessed. Additionally surface modification is achievable for many types of nanoparticles.
  • a “pharmaceutically acceptable salt” includes both acid and base addition salts.
  • Suitable pharmaceutically acceptable salts of the compound provided herein include acid addition salts which may, for example, be formed by mixing a solution of choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts) ; alkaline earth metal salts (e.g., calcium or magnesium salts) ; and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counter anions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate) .
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counter anions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and
  • compositions include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphor sulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentane propionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes provided herein.
  • prodrugs of a compound readily undergoes chemical changes under physiological conditions to provide the compound.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound provided herein following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds provided herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds provided herein when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are known by those skilled in the art.
  • esters for example, methyl, ethyl
  • cycloalkyl for example, cyclohexyl
  • aralkyl for example, benzyl, p-methoxybenzyl
  • alkylcarbonyloxyalkyl for example, pivaloyloxymethyl
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989) ) .
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985) ) .
  • Hydroxyl groups have been masked as esters and ethers.
  • EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • Certain compounds provided herein possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are intended to be encompassed within the scope of this application.
  • the compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) . All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of this application.
  • the term “pharmaceutical composition” refers to a substance and/or a combination of substances being used for the identification, prevention or treatment of a tissue status or disease.
  • the pharmaceutical composition is formulated to be suitable for administration to a patient in order to prevent and/or treat disease.
  • a pharmaceutical composition refers to the combination of an active agent with a carrier, inert or active, making the composition suitable for therapeutic use.
  • Pharmaceutical compositions can be formulated for oral, parenteral, topical, inhalative, rectal, sublingual, transdermal, subcutaneous or vaginal application routes according to their chemical and physical properties.
  • Pharmaceutical compositions comprise solid, semisolid, liquid, transdermal therapeutic systems (TTS) .
  • Solid compositions are selected from the group consisting of tablets, coated tablets, powder, granulate, pellets, capsules, effervescent tablets or transdermal therapeutic systems. Also comprised are liquid compositions, selected from the group consisting of solutions, syrups, infusions, extracts, solutions for intravenous application, solutions for infusion or solutions of the carrier systems provided herein.
  • Semisolid compositions provided herein comprise emulsion, suspension, creams, lotions, gels, globules, buccal tablets and suppositories.
  • the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • a saline solution is a carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include 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.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • cytotoxic effect refers to the depletion, elimination and/or the killing of a target cell (s) .
  • cytotoxic agent refers to an agent that has a cytotoxic and/or cytostatic effect on a cell.
  • the term is intended to include chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant, or animal origin, and fragments thereof.
  • cytostatic effect refers to the inhibition of cell proliferation.
  • cytostatic agent refers to an agent that has a cytostatic effect on a cell, thereby inhibiting the growth and/or expansion of a specific subset of cells.
  • cytokine refers to small proteins ( ⁇ 5-20 kDa) that are involved in autocrine signaling, paracrine signaling and endocrine signaling as immunomodulating agents. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors but generally not hormones or growth factors.
  • immunomodulatory molecule refers to substance that stimulates or suppresses the immune system and may help the body fight cancer, infection, or other diseases.
  • Specific immunomodulating molecules can be monoclonal antibodies, cytokines, and vaccines, which affect specific parts of the immune system.
  • amphiphilic substance refers to compounds with both hydrophilic and lipophilic properties. Common amphiphilic substances are phospholipids, cholesterol, glycolipids, fatty acids, bile acids, saponins, pediocins, local anesthetics, Ab proteins and antimicrobial peptides.
  • protein and polypeptide are used interchangeably herein and refer to any peptide-bond-linked chain of amino acids, regardless of length or post-translational modification.
  • the amino acid is any of the amino acids provided herein.
  • Proteins provided herein can be further modified by chemical modification. This means such a chemically modified polypeptide comprises other chemical groups than the 20 naturally occurring amino acids. Examples of such other chemical groups include without limitation glycosylated amino acids and phosphorylated amino acids. Chemical modifications of a polypeptide may provide advantageous properties as compared to the parent polypeptide, e.g., one or more of enhanced stability, increased biological half-life, or increased water solubility.
  • nucleic acid and “polynucleotide” are used interchangeably herein and refer to polymeric or oligomeric macromolecules, or large biological molecules, essential for all known forms of life.
  • Nucleic acids which include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) , are made from monomers known as nucleotides. Most naturally occurring DNA molecules consist of two complementary biopolymer strands coiled around each other to form a double helix. The DNA strand is also known as polynucleotides consisting of nucleotides.
  • Each nucleotide is composed of a nitrogen-containing nucleobase as well as a monosaccharide sugar called deoxyribose or ribose and a phosphate group.
  • Naturally occurring nucleobases comprise guanine (G) , adenine (A) , thymine (T) , uracil (U) or cytosine (C) .
  • the nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone.
  • the sugar is desoxyribose
  • the polymer is DNA.
  • the sugar is ribose
  • the polymer is RNA.
  • nucleic acid includes but is not limited to ribonucleic acid (RNA) , deoxyribonucleic acid (DNA) , and mixtures thereof such as RNA-DNA hybrids (within one strand) , as well as cDNA, genomic DNA, recombinant DNA, cRNA and mRNA.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • a nucleic acid may consist of an entire gene, or a portion thereof, the nucleic acid may also be a miRNA, siRNA, piRNA or shRNA.
  • miRNAs are short ribonucleic acid (RNA) molecules, which are on average 22 nucleotides long but may be longer and which are found in all eukaryotic cells, i.e., in plants, animals, and some viruses, which functions in transcriptional and post-transcriptional regulation of gene expression. miRNAs are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts (mRNAs) , usually resulting in translational repression and gene silencing. Small interfering RNAs (siRNAs) , sometimes known as short interfering RNA or silencing RNA, are short ribonucleic acid (RNA molecules) , between 20-25 nucleotides in length.
  • siRNAs small interfering RNAs
  • RNA interference RNA interference
  • shRNA short hairpin RNA
  • shRNA small hairpin RNA
  • RNAi RNA interference
  • Expression of shRNA in cells is typically accomplished by delivery of plasmids or through viral or bacterial vectors.
  • piRNAs are also short RNAs which usually comprise 26-31 nucleotides and derive their name from so-called piwi proteins they are binding to.
  • the nucleic acid can also be an artificial nucleic acid.
  • Artificial nucleic acids include polyamide or peptide nucleic acid (PNA) , morpholino and locked nucleic acid (LNA) , as well as glycol nucleic acid (GNA) and threose nucleic acid (TNA) . Each of these is distinguished from naturally-occurring DNA or RNA by changes to the backbone of the molecule.
  • the nucleic acids can, e.g., be synthesized chemically, e.g., in accordance with the phosphotriester method (see, for example, Uhlmann, E. &Peyman, A. (1990) Chemical Reviews, 90, 543-584) .
  • VSP viral structural protein
  • VCP viral coat proteins
  • VAG viral envelope glycoproteins
  • VCP viral coat protein
  • VCP refers to a structural virus capsid protein of a virus.
  • the virus is a double-stranded DNA virus, single-stranded DNA virus, double-stranded RNA virus, single-stranded RNA virus, negative-sense single-stranded RNA virus, single-stranded RNA reverse transcribing virus, double-stranded RNA reverse transcribing virus.
  • the VCP can comprise major capsid proteins of adeno-associated virus (AAV) .
  • AAV adeno-associated virus
  • viral envelope glycoproteins refers to viral proteins that are part of the viral envelope.
  • the viral envelope is typically derived from portions of the host cell membrane, e.g., comprises phospholipids, and additionally comprise viral glycoproteins that, e.g., help the virus to avoid the immune system.
  • Enveloped viruses comprise DNA viruses, such as Herpesviruses, Poxviruses, and Hepadnaviruses; RNA viruses, such as Flavivirus, Togavirus, Coronavirus, Hepatitis D, Orthomyxovirus, Paramyxovirus, Rhabdovirus, Bunyavirus, Filovirus and Retroviruses.
  • the viral envelop glycoprotein is derived from any of these viruses.
  • liposome refers to uni-or multilamellar (e.g., 2, 3, 4, 5, 6, 7, 8, 9, and 10 lamellar) lipid structures enclosing an aqueous interior, depending on the number of lipid membranes formed.
  • Lipids, which are capable of forming a liposomes include all substances having fatty or fat-like properties. Such lipids comprise an extended apolar residue (X) and usually a water soluble, polar, hydrophilic residue (Y) , which can be characterized by the basic formula
  • lipids which can make up the lipids in the liposomes provided herein are selected from the group consisting of glycerides, glycerophospholipids, sulfolipids, sphingolipids, phospholipids, isoprenolides, steroids, stearines, steroles and carbohydrate containing lipids.
  • VLP virus like particle
  • VSP is a multimer of VSP, such as VCPs and/or VEPs that does not comprise polynucleotides but which otherwise has properties of a virus, e.g., binds to cell surface receptors, is internalized with the receptor, is stable in blood, and/or comprises glycoproteins etc.
  • VLPs are typically assembled of multimers of VCPs and/or VEPs, in particular of VCPs.
  • VLPs are known in the art and have been produced from a number of viruses including Parvoviridae (e.g., adeno-associated virus) , Retroviridae (e.g., HIV) , Flaviviridae (e.g., Hepatitis C virus) and bacteriophages (e.g., QP, AP205) .
  • Parvoviridae e.g., adeno-associated virus
  • Retroviridae e.g., HIV
  • Flaviviridae e.g., Hepatitis C virus
  • bacteriophages e.g., QP, AP205
  • Fibroblast activation protein As used herein, and unless otherwise specified, the term “fibroblast activation protein (FAP) ” as used herein is also known under the term “seprase” . Both terms can be used interchangeably herein. Fibroblast activation protein is a homodimeric integral protein with dipeptidyl peptidase IV (DPPIV) -like fold, featuring an alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain.
  • DPPIV dipeptidyl peptidase IV
  • Ring C is 1-naphthyl, 5-to 10-membered N-containing heteroaryl, or 5-to 10-membered N-containing heterocyclyl;
  • each instance of R 2 , R 3 , or R 4 is independently -OH, halo, C 1 -C 6 alkyl, -O- (C 1 -C 6 alkyl) , -N (R 5 ) 2, or -S- (C 1 -C 6 alkyl) , each of said C 1 -C 6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo;
  • G 1 is absent, C 1 -C 5 alkylene, or C 2 -C 5 alkynylene, wherein said C 1 -C 5 alkylene and C 2 -C 5 alkynylene are optionally substituted with one or more substituents independently selected from -OH, oxo, halo, C 1 -C 3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
  • each instance of G is independently C 1 -C 5 alkylene or C 2 -C 5 alkynylene, wherein said C 1 -C 5 alkylene and C 2 -C 5 alkynylene are optionally substituted with one or more substituents independently selected from -OH, oxo, halo, C 1 -C 3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
  • Ring B is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
  • L is absent or a linker
  • Ring A is 5 to 10-membered N-containing heteroaryl or 5 to 10-membered N-containing heterocyclyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, or 3;
  • s is 1, 2, or 3;
  • each instance of R 5 is independently -H or C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from -OH, oxo, and halo;
  • Z is a radioactive moiety, a chelating agent, a fluorescent dye, or a contrast agent.
  • At least three of Q 1 to Q 7 are present. In one embodiment, exactly three of Q 1 to Q 7 are present. In one embodiment, at least four of Q 1 to Q 7 are present. In one embodiment, exactly four of Q 1 to Q 7 are present. In one embodiment, at least five of Q 1 to Q 7 are present. In one embodiment, exactly five of Q 1 to Q 7 are present. In one embodiment, at least six of Q 1 to Q 7 are present. In one embodiment, exactly six of Q 1 to Q 7 are present. In one embodiment, all of Q 1 to Q 7 are present.
  • Q 1 is piperidin-1-yl. In one embodiment, Q 1 is azepan-1-yl. In one embodiment, Q 1 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring (i.e., ) .
  • Q 2 is piperidin-1-yl. In one embodiment, Q 2 is azepan-1-yl. In one embodiment, Q 2 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
  • Q 3 is piperidin-1-yl. In one embodiment, Q 3 is azepan-1-yl. In one embodiment, Q 3 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
  • Q 4 is piperidin-1-yl. In one embodiment, Q 4 is azepan-1-yl. In one embodiment, Q 4 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
  • Q 5 is piperidin-1-yl. In one embodiment, Q 5 is azepan-1-yl. In one embodiment, Q 5 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
  • Q 6 is piperidin-1-yl. In one embodiment, Q 6 is azepan-1-yl. In one embodiment, Q 6 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
  • Q 7 is piperidin-1-yl. In one embodiment, Q 7 is azepan-1-yl. In one embodiment, Q 7 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
  • Q 1 , Q 2 , Q 3 , and Q 4 are each independently absent or CH 2 ;
  • Q 5 is 5-to 6-membered N-containing heterocyclyl;
  • Q 6 is CHR 5 ; and
  • Q 1 is O or NR 5 , and -Q 2 -Q 3 -Q 4 -Q 5 -Q 6 -Q 7 -is wherein *refers to the direction toward Ring C.
  • Q 1 is O , and -Q 2 -Q 3 -Q 4 -Q 5 -Q 6 -Q 7 -is In one embodiment, Q 1 is O, and -Q 2 -Q 3 -Q 4 -Q 5 -Q 6 -Q 7 -is In one embodiment, Q 1 is NH , and -Q 2 -Q 3 -Q 4 -Q 5 -Q 6 -Q 7 -is In one embodiment, Q 1 is NH , and -Q 2 -Q 3 -Q 4 -Q 5 -Q 6 -Q 7 -is
  • Ring C is 1-naphthyl.
  • Ring C is 5-to 10-membered N-containing heteroaryl. In one embodiment, Ring C is 5-membered N-containing heteroaryl. In one embodiment, Ring C is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, 1, 2, 3-triazolyl, or 1, 2, 4-triazolyl. In one embodiment, Ring C is 6-membered N-containing heteroaryl. In one embodiment, Ring C is pyridyl, pyrimidinyl, pyridazinyl, or triazinyl.
  • the 5-or 6-membered N-containing heteroaryl is fused to a phenyl or another 5-or 6-membered N-containing heteroaryl.
  • Ring C is quinolinyl, 1, 8-naphthyridinyl, pyrido [2, 3-b] pyrazinyl, or quinazolinyl. In one embodiment, Ring C is quinolinyl.
  • Ring C is 5-to 10-membered N-containing heterocyclyl. In one embodiment, Ring C is 5-membered N-containing heterocyclyl. In one embodiment, Ring C is pyrrolidinyl. In one embodiment, Ring C is 6-membered N-containing heterocyclyl. In one embodiment, Ring C is piperidinyl. In one embodiment, the 5-or 6-membered N-containing heterocyclyl is fused to a phenyl or another 5-or 6-membered N-containing heteroaryl. In one embodiment, Ring C is 1, 2, 3, 4-tetrahydroquinolinyl.
  • Ring C is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring C is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring C is wherein the shown point of attachment is toward Q 1 .
  • X 1 is O.
  • X 1 is NR 5 .
  • X 1 is NH.
  • X 1 is N (CH 3 ) .
  • G 1 is absent. In one embodiment, G 1 is C 1 -C 5 alkylene. In one embodiment, G 1 is C 2 -C 5 alkylene. In one embodiment, G 1 is C 1 alkylene. In one embodiment, G 1 is C 2 alkylene. In one embodiment, G 1 is C 3 alkylene. In one embodiment, G 1 is C 4 alkylene. In one embodiment, G 1 is C 5 alkylene. In one embodiment, G 1 is C 2 -C 5 alkynylene. In one embodiment, G 1 is C 2 alkynylene. In one embodiment, G 1 is C 3 alkynylene. In one embodiment, G 1 is C 4 alkynylene. In one embodiment, G 1 is C 5 alkynylene.
  • G 1 is unsubstituted. In one embodiment, G 1 is substituted with one or more substituents independently selected from -OH, oxo, halo, C 1 -C 3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl. In one embodiment, G 1 is substituted with one or more halo (e.g., one or more fluoro) .
  • substituents independently selected from -OH, oxo, halo, C 1 -C 3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl. In one embodiment, G 1 is substituted with one or more halo (e.g., one or more fluoro) .
  • s is 1. In one embodiment, s is 2. In one embodiment, s is 3.
  • X 2 is absent.
  • X 2 is O.
  • X 2 is NR 5 .
  • X 2 is NH.
  • X 2 is N (CH 3 ) .
  • each instance of X is independently absent.
  • each instance of G is independently C 1 -C 5 alkylene. In one embodiment, each instance of G is independently C 1 -C 3 alkylene. In one embodiment, each instance of G is independently C 1 alkylene. In one embodiment, each instance of G is independently C 2 alkylene. In one embodiment, each instance of G is independently C 3 alkylene. In one embodiment, each instance of G is independently C 4 alkylene. In one embodiment, each instance of G is independently C 5 alkylene. In one embodiment, each instance of G is independently C 2 -C 5 alkynylene. In one embodiment, each instance of G is independently C 2 alkynylene. In one embodiment, each instance of G is independently C 3 alkynylene.
  • each instance of G is independently C 4 alkynylene. In one embodiment, each instance of G is independently C 5 alkynylene. In one embodiment, G is unsubstituted. In one embodiment, G is substituted with one or more substituents independently selected from -OH, oxo, halo, C 1 -C 3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl. In one embodiment, G is substituted with one or more halo (e.g., one or more fluoro) .
  • -X 2 - [G-X- (Ring B) -X] s -G 1 -X 1 -is -G- (Ring B) -G 1 -X 1 -, wherein G is C 1 -C 2 alkylene, G 1 is C 1 -C 2 alkylene, and X 1 is O, NR 5 , or - (C O) NR 5 -*.
  • G is C 1 -C 2 alkylene
  • G 1 is C 1 -C 2 alkylene
  • X 1 is O.
  • G is C 1 -C 2 alkylene
  • G 1 is C 1 -C 2 alkylene
  • X 1 is NH.
  • G is C 1 -C 2 alkylene
  • G 1 is C 1 -C 2 alkylene
  • X 1 is N (CH 3 ) .
  • -X 2 - [G-X- (Ring B) -X] s -G 1 -X 1 -is -G- (Ring B) -X 1 -, wherein G is C 1 -C 2 alkylene, and X 1 is O, NR 5 , or - (C O) NR 5 -*.
  • G is C 1 -C 2 alkylene, and X 1 is O.
  • L is absent. In one embodiment, L is a linker. In one embodiment, the linker is a peptide comprising 2 to 5 amino acids.
  • the compound is a compound of Formula (II-A) :
  • n is 1.
  • the one R 2 is attached to 5-position of quinolinyl. In one embodiment, the one R 2 is attached to 7-position of quinolinyl. In one embodiment, the one R 2 is attached to 8-position of quinolinyl.
  • the compound is a compound of Formula (III-A) :
  • the compound is a compound of Formula (IV-A) :
  • the compound is a compound of Formula (II-B) :
  • n is 1.
  • the one R 2 is attached to 5-position of quinolinyl. In one embodiment, the one R 2 is attached to 6-position of quinolinyl. In one embodiment, the one R 2 is attached to 7-position of quinolinyl.
  • the compound is a compound of Formula (III-B) :
  • the compound is a compound of Formula (IV-B) :
  • the compound is a compound of Formula (II-A) (including sub-formulas such as (III-A) and (IV-A) ) , except that X 1 is attached to the 5-position of quinolinyl.
  • the compound is a compound of Formula (II-A) (including sub-formulas such as (III-A) and (IV-A) ) , except that X 1 is attached to the 7-position of quinolinyl.
  • each instance of Ring B is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl.
  • Ring B is C 3 -C 10 cycloalkyl. In one embodiment, Ring B is C 3 -C 8 cycloalkyl. In one embodiment, the cycloalkyl is a monocyclic cycloalkyl. In one embodiment, the cycloalkyl is a bridged cycloalkyl. In one embodiment, the cycloalkyl is a spiro cycloalkyl. In one embodiment, the cycloalkyl is cyclopropyl. In one embodiment, the cycloalkyl is cyclobutyl. In one embodiment, the cycloalkyl is cyclopentyl. In one embodiment, the cycloalkyl is cyclohexyl.
  • the cycloalkyl is In one embodiment, the cycloalkyl is In one embodiment, the cycloalkyl is In one embodiment, the cycloalkyl is In one embodiment, the cycloalkyl is In one embodiment, the cycloalkyl is In one embodiment, the cycloalkyl is
  • Ring B is C 6 -C 10 aryl. In one embodiment, the aryl is
  • Ring B is 5 to 10-membered heteroaryl. In one embodiment, Ring B is 5 to 6-membered heteroaryl. In one embodiment, the heteroaryl is pyridyl. In one embodiment, the heteroaryl is In one embodiment, the right side point of attachment of these groups (as shown here) is toward Ring C.
  • Ring B is 5 to 10-membered heterocyclyl. In one embodiment, Ring B is 3 to 8-membered heterocyclyl. In one embodiment, the heterocyclyl is a monocyclic heterocyclyl. In one embodiment, the heterocyclyl is a bridged heterocyclyl. In one embodiment, the heterocyclyl is a spiro heterocyclyl. In one embodiment, the heterocyclyl is azetidinyl. In one embodiment, the heterocyclyl is pyrrolidinyl. In one embodiment, the heterocyclyl is piperidinyl.
  • the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the right side point of attachment of these groups (as shown here) is toward Ring C.
  • Ring A is absent. In one embodiment, Ring A is 5 to 10-membered N-containing heteroaryl. In one embodiment, Ring A is 5 to 6-membered N-containing heteroaryl.
  • Ring A is 5 to 10-membered N-containing heterocyclyl. In one embodiment, Ring A is 5 to 8-membered N-containing heterocyclyl.
  • the heterocyclyl is a monocyclic heterocyclyl. In one embodiment, the heterocyclyl is a bridged heterocyclyl. In one embodiment, the heterocyclyl is a spiro heterocyclyl. In one embodiment, the heterocyclyl is a fused heterocyclyl. In one embodiment, the heterocyclyl is azetidinyl. In one embodiment, the heterocyclyl is pyrrolidinyl. In one embodiment, the heterocyclyl is piperidinyl. In one embodiment, the heterocyclyl is azepanyl.
  • the heterocyclyl is azocanyl. In one embodiment, the heterocyclyl is piperazinyl. In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the heterocyclyl is In one embodiment, the right point of attachment of these groups (as shown here) is toward Ring B.
  • n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.
  • each instance of R 2 is independently -OH, halo, C 1 -C 6 alkyl, -O- (C 1 -C 6 alkyl) , -N (R 5 ) 2, or -S- (C 1 -C 6 alkyl) , each of said C 1 -C 6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo.
  • each instance of R 2 is independently halo, C 1 -C 6 alkyl, -O- (C 1 -C 6 alkyl) , or -N (R 5 ) 2 .
  • m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • each instance of R 3 is independently -OH, halo, C 1 -C 6 alkyl, -O- (C 1 -C 6 alkyl) , -N (R 5 ) 2, or -S- (C 1 -C 6 alkyl) , each of said C 1 -C 6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo.
  • each instance of R 3 is independently halo, C 1 -C 6 alkyl, -O- (C 1 -C 6 alkyl) , or -N (R 5 ) 2 .
  • p is 0. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, p is 3.
  • each instance of R 4 is independently -OH, halo, C 1 -C 6 alkyl, -O- (C 1 -C 6 alkyl) , -N (R 5 ) 2, or -S- (C 1 -C 6 alkyl) , each of said C 1 -C 6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo.
  • each instance of R 4 is independently halo, C 1 -C 6 alkyl, -O- (C 1 -C 6 alkyl) , or -N (R 5 ) 2 .
  • Z is a radioactive moiety.
  • the radioactive moiety is a fluorescent isotope, a radioisotope, or a radioactive drug.
  • the radioactive moiety is selected from the group consisting of alpha radiation emitting isotopes, beta radiation emitting isotopes, gamma radiation emitting isotopes, Auger electron emitting isotopes, X-ray emitting isotopes, and fluorescence emitting isotopes.
  • the radioactive moiety is 177 Lu-DOTA, 177 Lu-DOTAGA, 68 Ga-DOTA, 90 Y-DOTA, Al 18 F-NOTA. 203 Pb-TCMC, 212 Pb-TCMC, 64 Cu-DOTA, or 225 Ac-DOTA. In one embodiment, the radioactive moiety is 177 Lu-DOTA. In one embodiment, the radioactive moiety is 177 Lu-DOTAGA. In one embodiment, the radioactive moiety is 68 Ga-DOTA.
  • the radioactive moiety is 11 C, 18 F, 72 As, 72 Se, 123 I, 124 I, 131 I, or 211 At.
  • Z is a fluorescent dye.
  • the fluorescent dye is an Xanthene, an Acridine, an Oxazine, an Cyanine, a Styryl dye, a Coumarin, a Porphine, a Metal-Ligand-Complex, a Fluorescent protein, a Nanocrystals, a Perylene, a Boron-dipyrromethene, or a Phthalocyanine, or a conjugate or combination thereof.
  • Z is a chelating agent.
  • the chelating agent is a chelating agent that forms a complex with a divalent or trivalent metal cation.
  • the chelating agent is 1, 4, 7, 10-tetraazacyclododecane-N, N', N, N'-tetra acetic acid (DOTA) , ethylenediaminetetraacetic acid (EDTA) , 1, 4, 7-triazacyclononane-l, 4, 7-triacetic acid (NOTA) , 1, 4, 7, 10-tetraazacyclododecane-1- (glutaric acid) -4, 7, 10-triacetic acid (DOTAGA) , 2- [4, 7, 10-tris (2-amino-2-oxoethyl) -1, 4, 7, 10-tetrazacyclododec-1-yl] acetamide (TCMC) , triethylenetetramine (TETA) , iminodiacetic acid, diethylenetriamine
  • TCMC triethylene
  • the chelating agent is a chelating agent in Table 1.
  • Z is a contrast agent.
  • the contrast agent comprises a paramagnetic agent.
  • the paramagnetic agent comprises paramagnetic nanoparticles.
  • Z is a cytostatic and/or cytotoxic agent.
  • the cytostatic and/or cytotoxic agent is selected from the group consisting of alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs) , inhibitors of cyclooxygenases and/or lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthrac
  • the cytostatic and/or cytotoxic agent is selected from the group consisting of doxorubicin, ⁇ -amanitin and monomethyl auristatin E.
  • Z is doxorubicin.
  • Z is a cytokine.
  • the cytokine is a chemokine molecule.
  • the chemokine molecule is selected from the group consisting of CXCL9, CXCL10 and CX3CL1.
  • Z is CXCL9.
  • Z is CXCL10.
  • Z is CX3CL1.
  • Z is an immunomodulatory molecule.
  • the immunomodulatory molecule is selected from the group consisting of CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, interleukin-2, interferon alpha and interferon gamma.
  • the immunomodulatory molecule is selected from the group consisting of CXCL3, interleukin
  • Z is an amphiphilic substance.
  • the amphiphilic substance is selected from the group consisting of a lipid, a phospholipid and other highly lipophilic moiety conjugated to a polar group such as an ammonium ion or inositol triphosphate.
  • the lipid is selected from the group consisting of saccharolipids, prenol lipids, sterol lipids, glycerolipids, polyketides and fatty acids and the phospholipid is selected from the group consisting of plasmalogens, sphingo lipids, phophatidates and phosphoinositides.
  • the amphiphilic substance is a lipid or a phospholipid.
  • the amphiphilic substance is N-PEGylated l, 2-disteaorylglycero-3-phosphoethanolamine.
  • Z is a lipid. In one embodiment, Z is a phospholipid. In one embodiment, Z is N-PEGylatcd l, 2-disteaorylglycero-3-phosphoethanolamine.
  • Z is a nucleic acid.
  • the nucleic acid is selected from the group consisting of DNA, RNA, siRNA, mRNA, PNA and cDNA.
  • the nucleic acid encodes a cytokine and/or an immunomodulatory molecule provided herein.
  • the nucleic acid is a siRNA or PNA.
  • Z is a viral structural protein.
  • the viral structural protein is of a virus selected from the group consisting of
  • double-stranded DNA virus such as Myoviridae, Siphoviridae, Podoviridae, Herpesviridae, Adenoviridae, Baculoviridae, Papillomaviridae, Polydnaviridae, Polyomaviridae, Poxviridae;
  • RNA virus such as Reoviridae
  • RNA virus such as Coronaviridae, Picomaviridae, Caliciviridae, Togaviridae, Flaviviridae, Astroviridae, Arteriviridae, Hepeviridae;
  • RNA virus such as Arenaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Bunyaviridae, Orthomyxoviridae, Bomaviridae;
  • the viral structural protein such as VCP is derived from a virus selected from the group consisting of double-stranded DNA virus, such as Myoviridae, Siphoviridae, Podoviridae, Herpesviridae, Adenoviridae, Baculoviridae, Papillomaviridae, Polydnaviridae, Polyomaviridae, Poxviridae; single-stranded DNA virus, such as Anelloviridae, Inoviridae, Parvoviridae; double-stranded RNA virus, such as Reoviridae; single-stranded RNA virus, such as Coronaviridae, Picomaviridae, Caliciviridae, Togaviridae, Flaviviridae, Astroviridae, Arteriviridae, Hepeviridae; negative-sense single-stranded RNA vims, such as Arenaviridae, Filoviridae, Paramy
  • the VCP is from a family of the Parvoviridae, such as from adeno-associated vims.
  • the VCP is human AAV, bovine AAV, caprine AAV, avian AAV, canine parvovirus (CPV) , mouse parvovirus; minute vims of mice (MVM) ; parvovirus B19 (B19) ; parvovirus Hl (Hl) ; human bocavims (HBoV) ; feline panleukopenia vims (FPV) ; or goose parvovirus (GPV) .
  • CPV parvovirus
  • the VCP is from a certain AAV-serotype, such as AAV-l, AAV-2, AAV-2-AAV-3 hybrid, AAV-3a, AAV-3b, AAV-4, AAV-5, AAV-6, AAV-6.2, AAV-7, AAV-8, AAV-9, AAV-10, AAVrh. 10, AAV-11, AAV-12, AAV-13 or AAVrh32.33.
  • the VCP is from AAV-2 or a variant thereof that is capable of assembling into a VLP.
  • Z is protein.
  • the protein is selected from the group consisting of a membrane bound protein and unbound protein. Examples of the protein include but are not limited to CEA, CA19-9, Macrophage Migration Inhibition Factor (MIF) , IL-8 (interleukin 8) , AXL, MER and c-MET.
  • MIF Macrophage Migration Inhibition Factor
  • IL-8 interleukin 8
  • Z is biotin.
  • provided herein is a liposome comprising a compound provided herein, wherein Z is an amphiphilic substance.
  • the liposomes provided herein can be various types of liposomes, for example, as described in Alavi et al., Adv Pharm Bull, 2017.
  • the liposomes provided herein is a stealth liposome.
  • Stealth liposomes are known in the art and are for example reviewed by Immordino et al., Int J Nanomedicine, 2006.
  • the liposome provided herein can be positively charged, negatively charged or neutral liposomes.
  • the charge of a liposome is determined by the lipid composition and is the average of all charges of the lipids comprised in the liposome. For example, a mixture of a negatively charged phospholipid and cholesterol will yield a negatively charged liposome.
  • lipids/phospholipids to be used in liposomes include but are not limited to glycerides, glycerophospholipides, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, phospholipids, isoprenolides, steroids, stearines, steroles and carbohydrate containing lipids.
  • the negatively charged lipid/phospholipid is selected from the group consisting of phosphatidylserine (PS) , phosphatidylglycerol (PG) and phosphatidic acid (PA) .
  • PS and PG are collective terms for lipids sharing a similar phosphatidylserine and phosphatidylglycerol, respectively, head group.
  • many different apolar residues can be attached to these head groups.
  • PSs and PGs isolated from different natural sources vary substantially in the length, composition and/or chemical structure of the attached apolar residues and naturally occurring PS and PG usually is a mixture of PSs and PGs with different apolar residues.
  • the PS employed in the liposomes provided herein is selected from the group consisting of palmitoyloleoylphosphatidylserine, palmitoyllinoeoyl- phosphatidylserine, palmitoylarachidonoylphosphatidylserine, palmitoyldocosahexaenoyl-phosphatidylserine, stearoyloleoylphosphatidylserine, stearoyllinoleoylphosphatidylserine, stearoyl-arachidonoylphosphatidylserine, stearoyldocosahexaenoylphosphatidylserine, dicaprylphosphatidylserine, dilauroylphosphatidylserine, dimyristoylphosphatidylserine, diphytanoylphosphatidylserine, dih
  • the PG employed in the liposome provided herein is selected from the group consisting of palmitoyloleoylphosphatidylglycerol, palmitoyl-linoleoylphosphatidylglycerol, palmitoylarachidonoylphosphatidylglycerol, palmitoyl-docosahexaenoylphosphatidylglycerol, stearoyloleoylphosphatidylglycerol, stearoyl-linoleoylphosphatidylglycerol, stearoylarachidonoylphosphatidylglycerol, stearoyldocosa-hexaenoylphosphatidylglycerol, dicaprylphosphatidylglycerol dilauroylphosphatidylglycerol, diheptadecanoylphosphatidylglycerol, diphy
  • PE is also a generic term for lipids sharing a phosphatidylethanolamine head group.
  • the PE is selected from the group consisting of palmitoyloleoylphosphatidylethanolamine, palmitoyllinoleoylphosphatidylethanolamine, palmitoylarachidonoylphosphatidylethanolamine, palmitoyldocosahexaenoylphosphatidyl-ethanolamine, stearoyloleoylphosphatidylethanolamine, stearoyllinoleoylphosphatidyl-ethanolamine, stearoylarachidonoylphosphatidylethanolamine, stearoyldocosahexaenoyl-phosphatidylethanolamine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidyl-ethanolamine, diphytanoylphosphatidylethanolamine, dipalmit
  • the liposome provided herein can comprise at least one further component selected from the group consisting of an adjuvant, additive, and auxiliary substance.
  • adjuvants are selected from the group consisting of unmethylated DNA, such as unmethylated DNA comprising CpG dinucleotides (CpG motif) , such as CpG ODN with phosphorothioate (PTO) backbone (CpG PTO ODN) or phosphodiester (PO) backbone (CpG PO ODN) ; bacterial products from the outer membrane of Gram-negative bacteria, such as monophosphoryl lipid A (MPLA) , lipopolysaccharides (LPS) , muramyl dipeptides and derivatives thereof; synthetic lipopeptide derivatives, such as ParmCys; lipoarabinomannan; peptidoglycan; zymosan; heat shock proteins (HSP) , such as HSP 70; dsRNA and synthetic derivatives thereof, such as Poly Epoly C; polycationic
  • adjuvants which can be comprised in the liposome provided herein are selected from the group unmethylated DNA, such as unmethylated DNA comprising CpG dinucleotides (CpG motif) , such as CpG ODN with phosphorothioate (PTO) backbone (CpG PTO ODN) or phosphodiester (PO) backbone (CpG PO ODN) , bacterial products from the outer membrane of Gram-negative bacteria, such as monophosphoryl lipid A (MPLA) and synthetic lipopeptide derivatives, such as ParmCys.
  • CpG motif such as CpG ODN with phosphorothioate (PTO) backbone (CpG PTO ODN) or phosphodiester (PO) backbone (CpG PO ODN)
  • PTO phosphorothioate
  • PO phosphodiester
  • bacterial products from the outer membrane of Gram-negative bacteria such as monophosphoryl lipid A (MPLA) and synthetic lipopeptide derivatives, such as Par
  • the term “additive” comprises substances, which stabilize any component of the liposome or of the liquid medium like, for example, antioxidants, radical scavengers or the like.
  • stabilizers are selected from the group consisting of a-tocopherol or carbohydrates, such as glucose, sorbitol, sucrose, maltose, trehalose, lactose, cellubiose, raffmose, maltotriose, or dextran.
  • the stabilizers can be comprised in the lipid membranes of the liposomes, the interior of the liposomes and/or within the liquid medium surrounding the liposomes.
  • Liposomes provided herein can have a diameter between 10 and 1000 nm. In one embodiment, they have a diameter of between 30 and 800 nm, between 40 and 500 nm, between 50 and 300 nm, or between 100 and 200 nm.
  • the diameter of the liposomes can be affected, for example, by extrusion of the liposomal composition through sieves or meshes with a known pore size. This and further methods of controlling the size of liposomes are known in the art and are described, for example, in Mayhew et al. (1984) Biochim. Biophys. Acta 775: 169-174 or Olson et al. (1979) Biochim. Biophys. Acta 557: 9-23.
  • the liposome or the mixture of liposomes provided herein are comprised in a liquid medium.
  • liquid medium comprises all biocompatible, physiological acceptable liquids and liquid compositions such as FLO, aqueous salt solutions, and buffer solutions like, for example, PBS, Ringer solution and the like.
  • the liposome is loaded with a substance selected from the group consisting of an agent and a nucleic acid.
  • the agent that the liposome is loaded with is a cytostatic and/or cytotoxic agent provided herein.
  • the nucleic acid that the liposome is loaded with is a nucleic acid provided herein.
  • a variety of methods are available in the art to “load” a liposome with a given therapeutic agent.
  • the therapeutic agent (s) is (are) admixed with the lipid components during formation of the liposomes.
  • Other passive loading methods include dehydration-rehydration (Kirby & Gregoriadis (1984) Biotechnology 2: 979) , reverse-phase evaporation (Szoka & Papahadjopoulos (1978) Proc. Natl. Acad. Sci.
  • the compound is a compound in Table 2, or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  • provided herein is a complex formed by a compound provided herein and a divalent or trivalent metal cation.
  • the complex is formed when Z is a chelating agent.
  • the metal cation is a cation of Cr, Ga, In, Tc, Re, La, Yb, Sm, Ho, Y, Pm, Dy, Er, Lu, Sc, Pr, Gd, Bi, Ru, Pd, Rh, Sb, Ba, Hg, Eu, Tl, Pb, Cu, Re, Au, Ac, Th, or Ag.
  • the metal cation is a cation of Ga.
  • the metal cation is a cation of Lu.
  • the metal cation is a cation of 51 Cr, 67 Ga, 68 Ga, 111 In, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 188 Re, 186 Re, 198 Au, 225 Ac, 227 Th, or 199 Ag.
  • the metal cation is a cation of 68 Ga.
  • the metal cation is a cation of 177 Lu.
  • a compound or complex provided herein exhibit suitable cellular uptake in FAP transfected cells, as well as tumor uptake in FAP-positive tumors.
  • provided herein is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound provided herein or a complex provided herein and a pharmaceutically acceptable excipient.
  • virus-like particle comprising a compound provided herein, wherein Z is a viral structural protein.
  • the virus-like particle is loaded with a substance selected from the group consisting of an agent and a nucleic acid.
  • the agent that the virus-like particle is loaded with is a cytostatic and/or cytotoxic agent provided herein.
  • the nucleic acid that the virus-like particle is loaded with is a nucleic acid provided herein.
  • provided herein is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound provided herein, a liposome provided herein, or a virus-like particle provided herein, and a pharmaceutically acceptable excipient.
  • provided herein is a method for the diagnosis of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a diagnostically effective amount of a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein.
  • a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein is for use in the diagnosis of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.
  • provided herein is a method for the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.
  • a compound provided herein or a pharmaceutical composition provided herein is for use in the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.
  • provided herein is a method for the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein.
  • a compound provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein is for use in the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.
  • the disease characterized by overexpression of fibroblast activation protein is cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling, or keloid disorder.
  • the disease is cancer.
  • the cancer is breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocellular carcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary) , thymus carcinoma, desmoid tumors, glioma, astrocytoma, cervix carcinoma, or prostate cancer.
  • the cancer is glioma, breast cancer, colon cancer, lung cancer, head and neck cancer, liver cancer, or pancreatic cancer.
  • the cancer is glioma.
  • the cancer is colon cancer.
  • the disease is chronic inflammation.
  • the chronic inflammation is rheumatoid arthritis, osteoarthritis, or Crohn's disease.
  • the chronic inflammation is rheumatoid arthritis.
  • the disease is fibrosis.
  • the fibrosis is pulmonary fibrosis, such as idiopathic pulmonary fibrosis, or liver cirrhosis.
  • the disease is tissue remodeling. In one embodiment, the tissue remodeling occurs after myocardial infarction.
  • the disease is a keloid disorder.
  • the keloid disorder is scar formation, keloid tumors, or keloid scar.
  • the subject is an animal. In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.
  • kits comprising a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein and instructions for the diagnosis or treatment of a disease provided herein.
  • a kit comprising a compound provided herein, a complex provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein, and instructions for the treatment of a disease.
  • VLP virus-like particle
  • any embodiment of the compounds provided herein, as set forth above, and any specific substituent and/or variable in the compounds provided herein, as set forth above, may be independently combined with other embodiments and/or substituents and/or variables of the compounds to form embodiments not specifically set forth above.
  • substituents and/or variables may be listed for any particular group or variable, it is understood that each individual substituent and/or variable may be deleted from the particular embodiment and/or claim and that the remaining list of substituents and/or variables will be considered to be within the scope of embodiments provided herein.
  • Prep-HPLC Purification Method 1 The compound was purified on Shimadzu LC-20AP and UV detector. The column used was Shim-pack GIS C18 (250*20) mm, 10 ⁇ m. Column flow was 20 ml/min. Mobile phase were used (A) 0.1%TFA in water and (B) acetonitrile. Purification were carried out employing a linear gradient from 5%to 30%of (B) acetonitrile for 20 min. The UV spectra were recorded at 202 nm&254 nm.
  • Prep-HPLC Purification Method 2 The compound was purified on Shimadzu LC-20AP and UV detector. The column used was Shim-pack GIS C18 (250*20) mm, 10 ⁇ m. Column flow was 20 ml/min. Mobile phase were used (A) 0.1%NH 3 in water and (B) acetonitrile. Purification were carried out employing a linear gradient from 5%to 35%of (B) acetonitrile for 20 min. The UV spectra were recorded at 202 nm&254 nm.
  • Step 1 To a solution of D1-1 (20.00 g, 79.34 mmol) in t-BuOH (2-methylpropan-2-ol) (200 mL) was added di-tert-butyl dicarbonate (20.75 g, 95.21 mmol) and DMAP (N, N-dimethylpyridin-4-amine) (96.51 mg, 0.79 mmol) . The mixture was stirred at 30 °C overnight. The reaction mixture was quenched by water (100 ml) and extracted with EtOAc (ethyl acetate) (100 mL ⁇ 3) .
  • Step 2 To a solution of D1-2 (23.00 g, 74.63 mmol) in 1, 4-dioxane (230 mL) was added 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2- dioxaborolane (22.74 g, 89.56 mmol) , potassium acetate (21.97 g, 223.89 mmol) and Pd(dppf) Cl 2 (6.05 g, 7.46 mmol ) at r.t., and the reaction mixture was stirred at 100 °C under nitrogen overnight.
  • Step 3 To a solution of D1-3 (25.00 g, 70.37 mmol) in DMSO (50 mL) and EtOH (200 mL) was added 2.0 mol/L NaOH in water (106 mL) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 0.5 h, then 30%H 2 O 2 (23.93 mL, 211.11 mmol) was added dropwise at 0 °C. The solution was stirred at r.t. for 2 h. The reaction was quenched by addition of water (100 mL) and extracted with EtOAc (50 mL ⁇ 3) .
  • Step 1 To a stirred solution of D2-1 (19.00 g, 78.19 mmol) in DCM (150 mL) was added DAST (26.83 mL, 203.29 mmol) dropwise at 0 °C over a period of 30 min, and the reaction mixture was stirred at r.t. overnight. The reaction was quenched by water (500 mL) . The resulting solution was extracted with DCM (500 mL ⁇ 3) .
  • Step 2 To a stirred solution of D2-2 (12.00 g, 45.28 mmol) in MeOH (60 mL) was added a solution of NH 3 in methanol (300 mL, 7.0 M) dropwise at 0 °C. The mixture was allowed to stir at 60 °C for 12 h. After completion of reaction, the solvent was concentrated to give a crude, which was recrystallized from hexane: pentane (1: 1, 200 mL) to afford the title compound D2-3 (10.00 g, 40.00 mmol, yield: 88.34%) as an off-white solid.
  • LC-MS (ESI) 251 [M+H] + .
  • Step 3 To a stirred solution of D2-3 (10.00 g, 40.00 mmol) in DCM (100 mL) was added DIPEA (26.39 mL, 160.00 mmol) dropwise at 0 °C. The reaction mixture was allowed to stir for 15 min at 0 °C. Trifluoroacetic anhydride (11.12 mL, 80.00 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at r.t. for 5 h. The resulting mixture was quenched by water (500 mL) , extracted with DCM (300 mL ⁇ 3) .
  • Step 4 To a stirred solution of D2-4 (6.2 g, 26.72 mmol) in acetonitrile (60 mL) was added TsOH (13.79 g, 80.16 mmol) . The resulting reaction mixture was allowed to stir at r.t. for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude, which was triturated with ethyl acetate (20 mL) to afford the title compound D2-5 (4.2 g, crude) as a colorless oil. LC-MS (ESI) : 133 [M+H] + .
  • Step 5 To a stirred solution of (tert-butoxycarbonyl) glycine (7.01 g, 40.08 mmol) and HATU (20.31 g, 53.44 mmol) in DMF (10 mL) was added D2-5 (4.2 g, crude) and stirred for 10 min, followed by addition of DIPEA (17.63 mL, 106.88 mmol) and the reaction mixture was allowed to stir at r.t. for 16 h. The reaction mixture was quenched by cold water (500 mL) and extracted with ethyl acetate (500 mL ⁇ 3) .
  • Step 6 To a stirred solution of D2-7 (100 mg, 0.35 mmol) in DCM (2 mL) was added TFA (0.5 mL) dropwise at 0 °C. The mixture was allowed to stir at r.t. for 1 h. The solvent was concentrated under reduced pressure to obtain residue which was triturated with ethyl acetate (10 mL) to afford the compound D2 (80 mg, crude) as a colorless oil.
  • LC-MS (ESI) 190 [M+H] + .
  • Step 1 To a solution of D3-1 (30.00 g, 119.01 mmol) in MeOH (300 mL) was added thionyl chloride (25.90 mL, 357.04 mmol) . The mixture was stirred at 60 °C for 24 h and then concentrated to give a residue, to which was added DCM (300 mL) . Adjust the reaction solution to alkaline with saturated sodium bicarbonate aqueous solution, extracted with DCM (50 mL ⁇ 2) and washed with brine (300 mL) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound D3-2 (37.80 g, crude) as a white solid. LC-MS (ESI) : 266 [M+H] + .
  • Step 2 To a solution of D3-2 (37.8 g, crude) in 1, 4-dioxane (400 mL) was added 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (36.27 g, 142.81 mmol) , potassium acetate (34.99 g, 357.03 mmol) and Pd(dppf) Cl 2 (9.67 g, 11.90 mmol) at r.t. and the reaction mixture was stirred at 100 °C for 16 h.
  • Example 1 (Method A) : E1: (S) -2, 2', 2” - (10- (2- (3- (2- (3- ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) (methyl) amino) azetidin-1-yl) ethyl) azetidin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
  • Step 1 To a solution of D3-2 (4.00 g, 15.09 mmol) in dioxane (40 mL) was added tert-butyl 3- (methylamino) azetidine-1-carboxylate (2.95 g, 15.84 mmol) , Cs 2 CO 3 (14.76 g, 45.27 mmol) , Pd 2 (dba) 3 (1.38 g, 1.51 mmol) and Xantphos (4, 5-Bis (diphenylphosphino) -9, 9-dimethylxanthene) (1.74 g, 3.02 mmol) . The reaction mixture was stirred at 100 °C overnight.
  • Step 2 To a solution of E1-1 (2.00 g, 5.39 mmol) in DCM (16 mL) was added TFA (4 mL) . The reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E1-2 (2.30 g, crude) as a yellow oil. LC-MS (ESI) : 272 [M+H] + .
  • Step 3 To a solution of E1-2 (271.00 mg, 1.00 mmol) in DMF (N, N-Dimethylformamide) (4 mL) was added Cs 2 CO 3 (977.46 mg, 3.00 mmol) and tert-butyl 3- (2-bromoethyl) azetidine-1-carboxylate (289.30 mg, 1.10 mmol) . The mixture was stirred at 60 °C overnight. The reaction mixture was quenched by water (25 ml) and extracted with EtOAc (25 mL ⁇ 2) .
  • Step 4 To a solution of E1-3 (145.00 mg, 0.32 mmol) in THF (2 mL) was added MeOH (0.50 mL) , H 2 O (1 mL) . Then the mixture was cooled to 0 °C, slowly add aq. NaOH (0.48 mL, 2N) dropwise at this temperature. Then the reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E1-4 (150.00 mg, 0.34 mmol, yield: 106.25%) as a yellow solid. LC-MS (ESI) : 441 [M+H] + .
  • Step 5 To a solution of E1-4 (150.00 mg, 0.34 mmol) in DMF (2 mL) under nitrogen was added D2 (70.69 mg, 0.37 mmol) , HATU (258.40 mg, 0.68 mmol) and DIEA (0.28 mL, 1.70 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (15 mL) and extracted with EtOAc (15 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E1-5 (110.00 mg, 0.18 mmol, yield: 52.94%) as a yellow oil. LC-MS (ESI) : 612 [M+H] + .
  • Step 6 To a solution of E1-5 (110.00 mg, 0.18 mmol) in ACN (acetonitrile) (3 mL) was added TsOH (4-methylbenzenesulfonic acid) (92.88 mg, 0.54 mmol) , and the reaction mixture was stirred at 60 °C for 2 h. The mixture was then evaporated under reduced pressure to give crude, which was dissolved in DMF (2 mL) , followed by addition of DOTA-PNP (94.50 mg, 0.18 mmol) and DIEA (0.21 mL, 1.26 mmol) . The reaction mixture was stirred at r.t.
  • Example 2 (Method B) : E2: (S) -2, 2', 2” - (10- (2- (4- ( (3- ( ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) methyl) oxetan-3-yl) methyl) piperazin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
  • Step 1 To a solution of D1 (1.50 g, 6.12 mmol) in DMF (N, N-Dimethylformamide) (20 mL) was added Cs 2 CO 3 (5.99 g, 18.36 mmol) and 3, 3-bis (bromomethyl) oxetane (1.04 g, 4.28 mmol) . The mixture was stirred at 60 °C overnight. The reaction mixture was quenched by water (100 ml) and extracted with EtOAc (50 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E2-1 (2.20 g, 5.41 mmol, yield: 88.40%) as a yellow oil. LC-MS (ESI) : 408 [M+H] + .
  • Step 2 To a solution of E2-1 (2.20 g, 5.41 mmol) in DMF (25 mL) was added Cs 2 CO 3 (5.29 g, 16.23 mmol) and tert-butyl piperazine-1-carboxylate (1.11 g, 5.95 mmol) . The reaction mixture was stirred at 60 °C overnight. The reaction mixture was quenched by water (150 ml) and extracted with EtOAc (100 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E2-2 (1.40 g, 2.73 mmol, yield: 50.46%) as a white solid. LC-MS (ESI) : 514 [M+H] + .
  • Step 3 To a solution of E2-2 (1.40 g, 2.73 mmol) in TFA (Trifluoroacetic acid) (12.60 mL) was added TfOH (Trifluoromethanesulfonic acid) (0.70 mL) , TES (Triethylsilane) (0.35 mL) and H 2 O (0.70 mL) . The mixture was stirred at r.t. for 2 h. The resulting mixture was evaporated under reduced pressure to give crude, which was dissolved in DCM (10 mL) , followed by addition of di-tert-butyl dicarbonate (0.81 mL, 3.55 mmol) and TEA (1.14 mL, 8.19 mmol) .
  • TFA Trifluoroacetic acid
  • TfOH Trifluoromethanesulfonic acid
  • TES Triethylsilane
  • H 2 O 0.70 mL
  • Step 4 To a solution of E2-3 (450.00 mg, 0.98 mmol) in DMF (5 mL) under nitrogen was added D2 (204.12 mg, 1.08 mmol) , HATU (744.80 mg, 1.96 mmol) and DIEA (0.81 mL, 4.90 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (50 mL) and extracted with EtOAc (25 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E2-4 (360.00 mg, 0.57 mmol, yield: 58.16%) as a colorless oil. LC-MS (ESI) : 629 [M+H] + .
  • Step 5 To a solution of E2-4 (360.00 mg, 0.57 mmol) in ACN (acetonitrile) (4 mL) was added TsOH (4-methylbenzenesulfonic acid) (294.12 mg, 1.71 mmol) , and the reaction mixture was stirred at 60 °C for 2 h. The mixture was then evaporated under reduced pressure to give crude, which was dissolved in DMF (3 mL) , followed by addition of DOTA-PNP (299.25 mg, 0.57 mmol) and DIEA (0.56 mL, 3.42 mmol) . The reaction mixture was stirred at r.t.
  • Example 3 (Method C) : E3: (S) -2, 2', 2” - (10- (2- (4- ( (6- ( ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) methyl) pyridin-3-yl) methyl) piperazin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
  • Step 1 To a solution of D1 (2.00 g, 8.16 mmol) in DMF (N, N-Dimethylformamide) (20 mL) was added K 2 CO 3 (3.38 g, 24.48 mmol) and methyl 6- (bromomethyl) nicotinate (2.06 g, 8.98 mmol) . The mixture was stirred at 60 °C overnight. The reaction mixture was quenched by water (100 ml) and extracted with EtOAc (50 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E3-1 (400.00 mg, 5.41 mmol, yield: 88.40%) as a yellow oil. LC-MS (ESI) : 408 [M+H] + .
  • Step 2 To a solution of E3-1 (400.00 mg, 1.02 mmol) in THF: H 2 O: MeOH (2.80 mL: 1.40 mL: 0.70 mL) was added aq. LiOH (5.10 mL, 1N, 5.10 mmol) at 0°C, and the reaction mixture was stirred at r.t. for 2 h. Then the reaction mixture was concentrated, quenched by addition of water (15 mL) , adjust the pH to 4 with 2N aqueous hydrochloride, extracted with EtOAc (20 mL ⁇ 2) . The combined organic layer was dried and concentrated to give compound E3-2 (260.00 mg, 0.68 mmol, yield: 67.08%) as a white solid.
  • LC-MS (ESI) 381 [M+H] + .
  • Step 3 To a solution of E3-2 (260.00 mg, 0.68 mmol) in DMF (3 mL) under nitrogen was added tert-butyl 1-piperazinecarboxylate (126.48 mg, 0.68 mmol) , HATU (387.60 mg, 1.02 mmol) and DIEA (0.67 mL, 4.08 mmol) . The reaction mixture was stirred at r.t. 12 h. The resulting mixture was quenched by water (25 mL) and extracted with EtOAc (25 mL ⁇ 2) .
  • Step 4 To a mixture E3-3 (80.00 mg, 0.15 mmol) in anhydrous tetrahydrofuran (2 mL) was added a tetrahydrofuran solution of borane-tetrahydrofuran complex (1 M, 1.50 mL, 1.50 mmol) under nitrogen at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The mixture was quenched by MeOH (10 mL) slowly at 0 °C. The resulting mixture was evaporated under reduced pressure to afford the compound, which was purified by flash chromatography to afford the title compound E3-4 (70.00 mg, 0.13 mmol, yield: 87.39%) as a white solid. LC-MS (ESI) : 535 [M+H] + .
  • Step 5 To a solution of E3-4 (70.00 mg, 0.13 mmol) in TFA (0.63 mL) was added TfOH (0.04 mL) , TES (0.02 mL) and H 2 O (0.04 mL) . The reaction mixture was stirred at r.t. for 2 h. The resulting mixture was evaporated under reduced pressure to give crude residue, which was dissolved in DCM (10 mL) , followed by addition of di-tert-butyl dicarbonate (0.05 mL, 0.20 mmol) and TEA (0.05 mL, 0.39 mmol) . The mixture was stirred at r.t. for 24 h.
  • Step 6 To a solution of E3-5 (40.00 mg, 0.08 mmol) in DMF (1 mL) under nitrogen was added D2 (18.14 mg, 0.10 mmol) , HATU (45.60 mg, 0.12 mmol) and DIEA (0.08 mL, 0.48 mmol) . The reaction mixture was stirred at r.t. 12 h. The resulting mixture was quenched by water (10 mL) and extracted with EtOAc (10 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E3-6 (20.00 mg, 0.03 mmol, yield: 36.83%) as a yellow solid. LC-MS (ESI) : 650 [M+H] + .
  • Step 7 To a solution of E3-6 (20.00 mg, 0.03 mmol) in ACN (1 mL) was added TsOH (15.48 mg, 0.09 mmol) and the reaction mixture was stirred at 60 °C for 2 h. The solution was evaporated under reduced pressure to give crude, which was dissolved in DMF (1 mL) , followed by addition of DOTA-PNP (15.75 mg, 0.03 mmol) and DIEA (0.03 mL, 0.18 mmol) . The reaction mixture was stirred at r.t. for 2 h.
  • Example 4 (Method D) : E4: (S) -2, 2', 2” - (10- (2- (4- (2- (3- ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) azetidin-1-yl) ethyl) piperidin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
  • Step 1 To a solution of D3 (1.00 g, 4.93 mmol) in ACN (Acetonitrile) (10 mL) was added K 2 CO 3 (2.04 g, 14.79 mmol) and tert-butyl 3-bromoazetidine-1-carboxylate (1.28 g, 5.42 mmol) . The mixture was stirred at 60 °C overnight. The reaction mixture was filtered with diatomite and evaporated to dryness to give a crude product, which was purified by flash chromatography to afford the compound E4-1 (623.00 mg, 1.74 mmol, yield: 35.30%) as a yellow solid. LC-MS (ESI) : 359 [M+H] + .
  • Step 2 To a solution of E4-1 (623.00 mg, 1.74 mmol) in DCM (4 mL) was added TFA (1 mL) . The reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E4-2 (570.00 mg, 2.21 mmol, yield: 126.97%) as a yellow oil.
  • LC-MS (ESI) 259 [M+H] + .
  • Step 3 To a solution of E4-2 (570.00 mg, 2.21 mmol) in DMF (N, N-dimethylformamide) (10 mL) was added Cs 2 CO 3 (2.16 g, 6.63 mmol) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (707.13 mg, 2.43 mmol) . The mixture was stirred at 60 °C overnight. The reaction mixture was quenched by water (60 ml) and extracted with EtOAc (60 mL ⁇ 2) .
  • Step 4 To a solution of E4-3 (400.00 mg, 0.85 mmol) in THF (4 mL) was added MeOH (1 mL) , H 2 O (2 mL) . Then the mixture was cooled to 0 °C, slowly add aq. NaOH (1.28 mL, 2N, 2.55 mmol) dropwise at this temperature. Then the reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E4-4 (345.00 mg, 0.76 mmol, yield: 89.20%) as a yellow solid.
  • LC-MS (ESI) 456 [M+H] + .
  • Step 5 To a solution of E4-4 (345.00 mg, 0.76 mmol) in DMF (3 mL) under nitrogen was added D2 (171.99 mg, 0.91 mmol) , HATU (433.20 mg, 1.14 mmol) and DIEA (0.50 mL, 3.04 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (15 mL) and extracted with EtOAc (15 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E4-5 (230.00 mg, 0.37 mmol, yield: 48.34%) as a yellow solid. LC-MS (ESI) : 627 [M+H] + .
  • Step 6 To a solution of E4-5 (230.00 mg, 0.37 mmol) in ACN (acetonitrile) (3 mL) was added TsOH (4-methylbenzenesulfonic acid) (190.92 mg, 1.11 mmol) , and the reaction mixture was stirred at 60 °C for 2 h. The mixture was then evaporated under reduced pressure to give crude residue, which was dissolved in DMF (2 mL) , followed by addition of DOTA-PNP (194.25 mg, 0.37 mmol) and DIEA (0.37 mL, 2.22 mmol) . The reaction mixture was stirred at r.t.
  • Example 5 (Method E) : E5: (S) -2, 2', 2” - (10- (2- (4- ( (6- ( ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) methyl) spiro [3.3] heptan-2-yl) methyl) piperazin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
  • Step 1 To a solution of E5-1 (2.00 g, 10.87 mmol) in MeOH (30 mL) was added SOCl 2 (2.37 mL, 32.61 mmol) at 0 °C. Then the mixture was stirred at r.t. overnight. The reaction mixture was concentrated to afford the compound d E5-2 (2.10 g, crude) as a brown solid. LC-MS (ESI) : 213 [M+H] + .
  • Step 2 To a solution of E5-2 (2.10 g, crude) in THF (12 mL) was added MeOH (3 mL) , H 2 O (6 mL) . Then the mixture was cooled to 0 °C, slowly add aq. NaOH (16.31 mL, 2N, 32.61 mmol) dropwise at this temperature. Then the reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E5-3 (1.30 g, 6.57 mmol, yield: two steps 60.44%) as a yellow solid.
  • LC-MS (ESI) 199 [M+H] + .
  • Step 3 To a solution of E5-3 (1.30 g, 6.57 mmol) in DMF (13 mL) under nitrogen was added tert-butyl piperazine-1-carboxylate (1.47 g, 7.88 mmol) , HATU (3.75 g, 9.86 mmol) and DIEA (6.50 mL, 39.42 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (80 mL) and extracted with EtOAc (80 mL ⁇ 2) .
  • Step 4 To a solution of E5-4 (1.40 g, 3.83 mmol) in THF (20 mL) under nitrogen was added LiAlH 4 (436.62 mg, 11.49 mmol) at 0 °C. The reaction mixture was stirred at r.t. for 2 h. The resulting mixture was quenched by Sodium sulfate decahydrate. The suspension was then filtered through a celite and the filter cake was washed with DCM (40 mL ⁇ 2) , to which was added water (20 mL) and separated.
  • Step 5 To a solution of E5-5 (830.00 mg, 2.56 mmol) in DCM (10 mL) was added triethylamine (1.42 mL, 10.24 mmol) . Then the mixture was cooled to 0 °C, slowly add MsCl (0.39 mL, 5.12 mmol) dropwise at this temperature. Then the mixture was stirred at r.t. for 2 h. The reaction mixture was quenched by water (30 mL) and extracted with DCM (30 mL ⁇ 2) . The combined organic layer was dried and concentrated to afford the compound d E5-6 (830.00 mg, crude) as a yellow oil. LC-MS (ESI) : 403 [M+H] + .
  • Step 6 To a solution of E5-6 (830 mg, crude) in DMF (N, N-Dimethylformamide) (10 mL) was added K 2 CO 3 (1.06 g, 7.68 mmol) and D1 (627.20 mg, 2.56 mmol) . The mixture was stirred at 60 °C overnight. The reaction mixture was quenched by water (100 ml) and extracted with EtOAc (50 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E5-7 (340.00 mg, 0.62 mmol, yield: two steps 29.95%) as a yellow solid. LC-MS (ESI) : 552 [M+H] + .
  • Step 7 To a solution of E5-7 (340.00 mg, 0.62 mmol) in TFA (3.06 mL) was added TfOH (0.17 mL) , TES (0.09 mL) and H 2 O (0.17 mL) . The reaction mixture was stirred at r.t. for 2 h. The mixture was sedimentation with Diethyl ether. The solid obtained by filtration to give crude, which was dissolved in DCM (5 mL) , followed by addition of di-tert-butyl dicarbonate (0.21 mL, 0.93 mmol) and TEA (0.26 mL, 1.86 mmol) . The mixture was stirred at r.t. overnight.
  • Step 8 To a solution of E5-8 (88 mg, 0.18 mmol) in DMF (2 mL) under nitrogen was added D2 (41.58 mg, 0.22 mmol) , HATU (102.60 mg, 0.27 mmol) and DIEA (0.09 mL, 0.54 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (15 mL) and extracted with EtOAc (15 mL ⁇ 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E5-9 (35.00 mg, 0.05 mmol, yield: 29.20%) as a yellow solid. LC-MS (ESI) : 667 [M+H] + .
  • Step 9 To a solution of E5-9 (35.00 mg, 0.05 mmol) in ACN (acetonitrile) (3 mL) was added TsOH (4-methylbenzenesulfonic acid) (25.80 mg, 0.15 mmol) , and the reaction mixture was stirred at 60 °C for 2 h. The mixture was then evaporated under reduced pressure to give crude, which was dissolved in DMF (2 mL) , followed by addition of DOTA-PNP (26.25 mg, 0.05 mmol) and DIEA (0.07 mL, 0.40 mmol) . The reaction mixture was stirred at r.t.
  • 177 Lu label 177 Lu-cpmd was prepared in sodium acetate buffer (1M, pH 4.75) after incubation of 30 ⁇ g of precursor with 5mCi 177 LuCl 3 (ITG) at 70°C for 30 min. Quality control was performed by iTLC (Eckert&Ziegler) . The hot compound was diluted with 0.9%NaCl solution for further utility.
  • 68 Ga label 68 GaCl 3 solution (1.0 mL, 370 MBq) , was eluted from the 68 Ge/ 68 Ga generator (Isotope Technologies Garching) with 0.05M HCl.
  • 68 Ga-cpmd was prepared in sodium acetate buffer (1M, pH 4.2) after incubation of 20 ⁇ g of precursor with 20mCi 68 GaCl 3 at 95°C for 20 min.
  • Quality standard RCP>98% (iTLC) , specific activity >0.75mCi/ug, and activity >1mCi/ml.
  • the biological activities of the compounds provided herein can be determined by using any suitable assay for determining the in vitro binding affinity of a compound as a FAP or PREP competitive inhibitor.
  • the cell-based assay is conducted to determine the cell internalization capability of a compound over time, including the efflux property.
  • Recombinant FAP (SinoBio, Cat. #10464-H07H ) , was diluted in FAP enzymatic buffer (50mM Tris pH7.5, 140mM NaCl) into 1ng/ul. Compounds were diluted with the same buffer into varying concentrations.
  • Z-GP-AMC Biochem partner, Cat#. 68542-93-8-8 was regenerated into 8.3mM/mL with FAP enzymatic buffer. 50 ⁇ l of compound and 20 ⁇ l of diluted FAP were mixed and incubated at RT for 15 min, followed with addition of 30 ⁇ l of diluted Z-GPAMC. The mixture was incubated at 37°C for 30minutes. Reaction was terminated with glacial acid. The released AMC was detected with flurorescence reader (Perkin Elmer Victor Nivo Plate reader) with excitation and emission wavelength at 360nm and 460nm, respectively.
  • PREP R&D System, Cat. #4308-SE
  • cmpd and Z-GP-AMC were diluted with PREP enzymatic buffer (100mM Tris pH7.5, 1mM EDTA, 3mM DTT) .
  • the procedure remained the same as FAP enzymatic assay.
  • HEK-FAP cells were cultured in 24-well plates. 20nCi of 177 Lu-labeled compound was added into each well, and then incubated in 37°C, 5%CO 2 incubator for varying durations. At each time point, the supernatant, cell membrane fraction and intracellular fraction were collected. The cell membrane fraction was recovered by incubating cells with buffer containing 50mM glycine and 100mM NaCl, pH 2.7 for 10minutes at 37°C, 5%CO 2 , while the intracellular fraction was collected by harvesting the cell pellets following trypsin digestion. 177 Lu-compound in each component was detected by gamma counter.
  • Efflux 20nCi of 177 Lu-labeled compound was incubated with cells for 2 hours, and then cells was washed and replaced with fresh medium. At each time point, the supernatant, cell membrane fraction and intracellular fraction were collected. The cell membrane fraction was recovered by incubating cells with buffer containing 50mM glycine and 100mM NaCl, pH 2.7 for 10minutes at 37°C, 5%CO 2 , while the intracellular fraction was collected by harvesting the cell pellets following trypsin digestion. 177 Lu-compound in each component was detected by gamma counter.
  • Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction. J Mol Cell Cardiol. 2015 Oct; 87: 194-203.

Abstract

Provided herein are a compound of Formula (I), a pharmaceutical composition comprising said compound, and method of use of the compound or pharmaceutical composition in the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein (FAP).

Description

FAP INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to International Patent Application No. PCT/CN2022/107957, filed on July 26, 2022, the entirety of which is incorporated herein by reference.
FIELD
Provided herein are certain compounds which demonstrate potent FAP enzymatic inhibition, great tumor uptake and/or retention, pharmaceutical compositions comprising said compounds, and method of use of the compounds or pharmaceutical compositions in the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) .
BACKGROUND
Fibroblast activation protein alpha (FAP, also named seprase, EC 3.4.21. B28) , encoded by the FAP gene, also known as prolyl endopeptidase FAP, is a 760 amino acid type II transmembrane glycoprotein. It contains a short intracellular domain of 6 amino acids at the N-terminal, a transmembrane section of 22 amino acids and a large extracellular region at the C-terminal. The extracellular domain consists of a beta propeller domain, which functions as a substrate selectivity gatekeeper, and an alpha/beta hydrolase domain. FAP is not enzymatic active until it forms homodimer or heterodimer with DPP4.
FAP is a serine protease. It belongs to the propyl dipeptidyl peptidase family, which also includes DPP4, DPP7, DPP8, DPP9, prolyl carboxypeptidase, and prolyl endopeptidase (PREP) . It mostly resembles DDP4, with which shares 84%amnio acid homology and 51%identity. In addition to a post-proline exopeptidase, which is similar to DPP4, FAP is also an endopeptidase. It degrades denatured collagen I and III, α2-antiplasmin, FGF-21, LOX-L1, CXCL-5, CSF-1 and C1qT6 et al (Zhang et al, 2019) and regulates proteins that associated with ECM, ECM-cell interaction, coagulation, metabolism, tissue remodeling and would healing.
FAP, albeit having a dozen of nature substrates, is rarely expressed in healthy tissues and has little impact on the normal physical activity. FAP knockout mice are normal, fertile and healthy (Niedermeyer et al 2000) , suggesting that its function could be fully  compensated by proteins with similar activity. Echoing with what is observed with FAP knockout mice, loss of function SNP variant in a Turkish family was not associated with any phenotype (Osborne et al 2014) .
On the contrary, FAP is found upregulated in 90%of carcinoma. It promotes cancer cell proliferation, migration and invasion (An et al 2022) . FAP is profoundly known as a marker of cancer associated fibroblast (CAF) , which plays a pro-tumorigenic role in a broad spectrum of cancers, breast cancer, colorectal, pancreatic, lung, bladder, ovarian, head and neck, glioblastoma et al, just to name a few (Kratochwil et al 2019, Windisch et al 2020) . As such, targeting FAP is a promising strategy for cancer therapy. Multiple approaches targeting FAP have been intensively exploited and developed as noted. Those could be clustered into: 1) FAP enzymatic inhibition and functional block by small molecular inhibitors, vaccination, antibody against FAP; 2) FAP protein depletion by PROTACs and oligonucleotide drugs of miRNA, shRNA, siRNA; 3) FAP (+) cell depletion, such as CAR-T and CAR-NK; 4) FAP directed prodrug and micelle (Chai et al 2018, Teng et al 2020) ; 5) FAP ligand mediated therapy, such as FAP ligand mediated radiotherapy or chemotoxicity and antibody-conjugated chemotherapy.
Besides cancers, FAP is involved in varying diseases, including but not limited to cardiovascular, infection, arthritis, inflammation, fibrosis, metabolic and autoimmune diseases (Tillmanns et al 2015, Croft et al 2019, Lay et al 2019, Schmidkonz et al 2020, Hoffmann et al 2021, Windisch et al 2021) . FAP imaging is being exploited in delineating tumor volume, diagnosis and staging of FAP-associated diseases (Dendl et al 2021, Kratochwil et al 2019, Luo et al 2021) .
FAP mediates tumor growth and FAP associated diseases in both enzymatic activity dependent and independent way. Breast cancer cell line that expressed enzymatic inactive FAP is more invasive and produces tumor that grow rapidly (Huang et al 2011) , which is likely through activating PI3K and MMP2/9 pathways (Lv et al 2016) .
Given the broad spectrum of FAP in oncology and multiple diseases, ligands binding/targeting FAP provides great potential of clinical value in therapy or diagnosis.
SUMMARY
In one embodiment, provided herein are some chemical entities which demonstrate potent FAP enzymatic inhibition, great tumor uptake and/or retention. In one embodiment, without being limited by a particular theory, small animal PET/CT delineate the  tumor volume with great tumor-to-blood, tumor-to-kidney ratio, and long-term tumor retention, and resulting in completely tumor inhibition in the in vivo efficacy study.
In one embodiment, provided herein is a compound of Formula (I) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein Q1 to Q7, Ring C, R2, n, X1, G1, X, Ring B, G, s, X2, L, Ring A, R3, m, R4, p, and Z are as defined herein or elsewhere.
Also provided herein is a complex formed by a compound provided herein and a divalent or trivalent metal cation.
Also provided herein is a liposome comprising the compound provided herein. Also provided herein is a virus-like particle (VLP) comprising the compound provided herein.
Also provided herein is a pharmaceutical composition comprising a compound provided herein, a liposome provided herein, or a virus-like particle (VLP) provided herein, and a pharmaceutically acceptable excipient.
Also provided herein is a method for the diagnosis of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a diagnostically effective amount of a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein.
Also provided herein is a method for the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein.
Also provided herein is a kit comprising a compound provided herein, a complex provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein, and instructions for the diagnosis or treatment of a disease.
DETAILED DESCRIPTION
It is to be understood that the invention provided herein is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention provided herein. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions etc. ) , whether supra or infra, is hereby incorporated by reference in its entirety. In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence.
DEFINITIONS
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In one embodiment, unless otherwise specified, the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations) ” , Leuenberger, H.G. W, Nagel, B. and Klbl, H. eds. (1995) , Helvetica Chimica Acta, CH-4010 Basel, Switzerland.
As used herein, and in the specification and the accompanying claims, the indefinite articles “a” and “an” and the definite article “the” include plural as well as single referents, unless the context clearly indicates otherwise.
As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of” . Consequently, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.
As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C” . An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.
As used herein, the phrase “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone) ; and B (alone) . Likewise, the phrase “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .
As used herein, and unless otherwise specified, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated. In one embodiment, the alkyl group has, for example, from one to twenty-four carbon atoms (C1-C24 alkyl) , four to twenty carbon atoms (C4-C20 alkyl) , six to sixteen carbon atoms (C6-C16 alkyl) , six to nine carbon atoms (C6-C9 alkyl) , one to fifteen carbon atoms (C1-C15 alkyl) , one to twelve carbon atoms (C1-C12 alkyl) , one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl) and which is attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl) , n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) , 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specified, an alkyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “alkenyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds. The term “alkenyl” also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations, as appreciated by those of ordinary skill in the art. In one embodiment, the alkenyl group has, for example, from two to twenty-four carbon atoms (C2-C24 alkenyl) , four to twenty carbon atoms (C4-C20 alkenyl) , six to sixteen carbon atoms (C6-C16 alkenyl) , six to nine carbon atoms (C6-C9 alkenyl) , two to fifteen carbon atoms (C2-C15 alkenyl) , two to twelve carbon atoms (C2-C12 alkenyl) , two to eight carbon atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl) and which is attached to the rest of the molecule by a single bond. Examples of alkenyl groups include, but are not limited to, ethenyl, prop-1-enyl, but- 1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like. Unless otherwise specified, an alkenyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “alkynyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon triple bonds. In one embodiment, the alkynyl group has, for example, from two to twenty-four carbon atoms (C2-C24 alkynyl) , four to twenty carbon atoms (C4-C20 alkynyl) , six to sixteen carbon atoms (C6-C16 alkynyl) , six to nine carbon atoms (C6-C9 alkynyl) , two to fifteen carbon atoms (C2-C15 alkynyl) , two to twelve carbon atoms (C2-C12 alkynyl) , two to eight carbon atoms (C2-C8 alkynyl) or two to six carbon atoms (C2-C6 alkynyl) and which is attached to the rest of the molecule by a single bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specified, an alkynyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “cycloalkyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which is saturated. Cycloalkyl group may include fused, bridged, or spiro ring systems. In one embodiment, the cycloalkyl has, for example, from 3 to 15 ring carbon atoms (C3-C15 cycloalkyl) , from 3 to 10 ring carbon atoms (C3-C10 cycloalkyl) , or from 3 to 8 ring carbon atoms (C3-C8 cycloalkyl) . The cycloalkyl is attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include, but are not limited to, adamantyl, norbornyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, spiro [3, 3] heptyl, spiro [3, 4] octyl, spiro [4, 3] octyl, spiro [3, 5] nonyl, spiro [5, 3] nonyl, spiro [3, 6] decyl, spiro [6, 3] decyl, spiro [4, 5] decyl, spiro [5, 4] decyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and the like. Unless otherwise specified, a cycloalkyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “heteroalkyl” refers to a saturated straight or branched carbon chain that is interrupted one or more times with the same or different heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. Examples of heteroalkyl include, but are not limited to, -O-CH3, -S-CH3, -CH2-O-CH3, -CH2-O-C2H5, -CH2-S-CH3, -CH2-S-C2H5, -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-S-CH3, -C2H4-S-C2H5, and the like. Unless otherwise specified, a heteroalkyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “heterocyclyl” refers to a non-aromatic radical monocyclic or polycyclic moiety that contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other polycyclic ring system, wherein the polycyclic ring systems can be a fused, bridged or spiro ring system. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or more rings. A heterocyclyl group can be saturated or partially unsaturated. Saturated heterocycloalkyl groups can be termed “heterocycloalkyl” . Partially unsaturated heterocycloalkyl groups can be termed “heterocycloalkenyl” if the heterocyclyl contains at least one double bond, or “heterocycloalkynyl” if the heterocyclyl contains at least one triple bond. In one embodiment, the heterocyclyl has, for example, 3 to 18 ring atoms (3-to 18-membered heterocyclyl) , 4 to 18 ring atoms (4-to 18-membered heterocyclyl) , 5 to 18 ring atoms (3-to 18-membered heterocyclyl) , 4 to 8 ring atoms (4-to 8-membered heterocyclyl) , or 5 to 8 ring atoms (5-to 8-membered heterocyclyl) . Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heterocyclyl group can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to and including 18 ring atoms. Examples of heterocyclyl groups include, but are not limited to, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and piperidinyl. Examples of heterocyclyl groups also include, but are not limited to, 1- (1, 2, 5, 6-tetrahydropyridyl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1, 8 diazo-spiro- [4, 5] decyl, 1, 7 diazo-spiro- [4, 5] decyl, 1, 6 diazo-spiro- [4, 5] decyl, 2, 8 diazo-spiro [4, 5] decyl, 2, 7 diazo-spiro [4, 5] decyl, 2, 6 diazo-spiro [4, 5] decyl, 1, 8 diazo-spiro- [5, 4] decyl, 1, 7 diazo-spiro- [5, 4] decyl, 2, 8 diazo-spiro-[5, 4] decyl, 2, 7 diazo-spiro [5, 4] decyl, 3, 8 diazo-spiro [5, 4] decyl, 3, 7 diazo-spiro [5, 4] decyl, 1-azo-7, 11-dioxo-spiro [5, 5] undecyl, 1, 4-diazabicyclo [2.2.2] oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. Unless otherwise specified, a heterocyclyl group is optionally substituted.
As used herein, and unless otherwise specified, the term “aryl” refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 18 ring  carbon atoms (C6-C18 aryl) , from 6 to 14 ring carbon atoms (C6-C14 aryl) , or from 6 to 10 ring carbon atoms (C6-C10 aryl) . Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The term “aryl” also refers to bicyclic, tricyclic, or other multicyclic hydrocarbon rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) . Unless otherwise specified, an aryl group is optionally substituted.
As used herein, and unless otherwise specified, the term “heteroaryl” refers to a monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from O, S, and N. The heteroaryl may be attached to the main structure at any heteroatom or carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. The term “heteroaryl” also refers to bicyclic, tricyclic, or other multicyclic rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. Unless otherwise specified, a heteroaryl group is optionally substituted.
As used herein, and unless otherwise specified, the term “alkylene” or “alkylene chain” refers to a straight or branched multivalent (e.g., divalent or trivalent) hydrocarbon chain linking the rest of the molecule to a radical group (or groups) , consisting solely of carbon and hydrogen, which is saturated. In one embodiment, the alkylene has, for example, from one to twenty-four carbon atoms (C1-C24 alkylene) , one to fifteen carbon  atoms (C1-C15 alkylene) , one to twelve carbon atoms (C1-C12 alkylene) , one to eight carbon atoms (C1-C8 alkylene) , one to six carbon atoms (C1-C6 alkylene) , two to four carbon atoms (C2-C4 alkylene) , one to two carbon atoms (C1-C2 alkylene) . Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group (s) can be through one carbon or any two (or more) carbons within the chain. Unless otherwise specified, an alkylene chain is optionally substituted.
As used herein, and unless otherwise specified, the term “alkynylene” is a multivalent (e.g., divalent or trivalent) alkynyl group; the term “cycloalkylene” is a multivalent (e.g., divalent or trivalent) cycloalkyl group; the term “heterocyclylene” is a multivalent (e.g., divalent or trivalent) heterocyclyl group; the term “arylene” is a multivalent (e.g., divalent or trivalent) aryl group; and the term “heteroarylene” is a multivalent (e.g., divalent or trivalent) heteroaryl group. Other “ylene” terms can be constructed similarly from the corresponding “yl” terms.
It is to be understood that a “yl” term as used herein includes and can be replaced by the corresponding “ylene” term, if proper based on the valence of the group. For example, when a ring moiety of a compound provided herein is described as heterocyclyl, the ring moiety is also heterocyclylene if it is multivalent (e.g., divalent or trivalent) , i.e., it is connected to multiple parts of the compound.
As used herein, and unless otherwise specified, the term “aralkyl refers to an alkyl moiety, which is substituted by aryl. An example is the benzyl radical. As used herein, and unless otherwise specified, the term “heteroaralkyl” refers to an alkyl moiety, which is substituted by heteroaryl. Unless otherwise specified, the terms for other similar composite moieties can be constructed similarly.
When the groups described herein are said to be “substituted, ” they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents include, but are not limited to, those found in the exemplary compounds and embodiments provided herein, as well as: a halogen atom such as F, CI, Br, or I; cyano; oxo (=O) ; hydroxyl (-OH) ; alkyl; alkenyl; alkynyl; cycloalkyl; aryl; - (C=O) OR’ ; -O (C=O) R’; -C (=O) R’; -OR’; -S (O) xR’; -S-SR’; -C (=O) SR’; -SC (=O) R’; -NR’R’; -NR’C (=O) R’; -C (=O) NR’R’; -NR’C (=O) NR’R’; -OC (=O) NR’R’; -NR’C (=O) OR’; -NR’S (O) xNR’R’; - NR’S (O) xR’; and -S (O) xNR’R’, wherein: R’ is, at each occurrence, independently H, C1-C15 alkyl or cycloalkyl, and x is 0, 1 or 2. In some embodiments the substituent is a C1-C12 alkyl group. In other embodiments, the substituent is a cycloalkyl group. In other embodiments, the substituent is a halo group, such as fluoro. In other embodiments, the substituent is an oxo group. In other embodiments, the substituent is a hydroxyl group. In other embodiments, the substituent is an alkoxy group (-OR’) . In other embodiments, the substituent is a carboxyl group. In other embodiments, the substituent is an amino group (-NR’R’) .
As used herein, and unless otherwise specified, the term “optional” or “optionally” (e.g., optionally substituted) means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means that the alkyl radical may or may not be substituted and that the description includes both substituted alkyl radicals and alkyl radicals having no substitution.
As used herein, and unless otherwise specified, the term “halo” or “halogen” refers to a halogen residue selected from the group consisting of F, Cl, Br, and I.
As used herein, and unless otherwise specified, the term “linker” refers to any chemically suitable linker. In one embodiment, a linker is not or only slowly cleaved under physiological conditions. In one embodiment, the linker does not comprise recognition sequences for proteases or recognition structures for other degrading enzymes. In one embodiment, when the compounds provided herein are administered systemically to allow broad access to all compartments of the body and subsequently enrichment of the compounds provided herein wherever in the body the tumor is located, the linker is chosen in such that it is not or only slowly cleaved in blood. In one embodiment, the cleavage is considered slowly, if less than 50%of the linkers are cleaved 2 h after administration of the compound to a human patient. Suitable linkers include, but are not limited to, optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aralkyl, heteroaralyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, sulfonyl, amines, ethers, thioethers phosphines, phosphoramidates, carboxamides, esters, imidoesters, amidines, thioesters, sulfonamides, 3-thiopyrrolidine-2, 5-dion, carbamates, ureas, guanidines, thioureas, disulfides, oximes, hydrazines, hydrazides, hydrazones, diaza bonds, triazoles, triazolines, tetrazines, platinum complexes and amino acids, or combinations thereof. In one embodiment, the linker comprises 1, 4-piperazine, 1, 3-propane and a phenolic ether or combinations thereof.
The linker can also be a cleavable linker such as a peptide motif that is cleaved by cathepsin. Any suitable linker that is cleavable by cathepsin can be used. Certain suitable cleavable peptide linkers are described in Peterson et al., Bioconjugate Chem., 1998. Suitable cleavable linkers, for example, comprises optionally substituted NO2Tyr-Gln-Gly-Val-Gln-Phe-Lys (Aminobenzoyl) , NO2Tyr-Asn-Gly-Thr-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ser-Val-Val-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Val-Gln-Ser-Ala-Phe, Multiple-Val-Gln-Phe-Val, NO2Tyr-Gly-Val-Phe-Gln-Phe, NO2Tyr-Gly-Thr-Val-Ala-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Thr-Ala-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Ser-Val-Gln-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Gly-Gln-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gln-Ser-Val-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Ser-Thr-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Thr-Val-Gln-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Ser-Thr-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Val-Ala-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Ser-Thr-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Ala-Gly-Thr-Phe-Lys (Aminobenzoyl) , NO2Tyr-Val-Ala-Gln-Phe, NO2Tyr-Gln-Gly-Val-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Val-Asn-Asn-Asn-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Ser-Ala-Asn-Phe-Lys (Aminobenzoyl) , NO2Tyr-Phe-Gln-Thr-Gln-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Ala-Ala-Ser-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gln-Tyr-Ser-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Ala-Thr-Ala-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Thr-Gln-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gln-Ser-Ala-Ser-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Thr-Ser-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Thr-Ala-Gly-Ala-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Thr-Thr-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Ser-Gly-Ser-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Thr-Thr-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Ala-Ala-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Thr-Gln-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Ala-Thr-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Thr-Gln-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gln-Thr-Val-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Thr-Gln-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Ser-Ala-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Gln-Ser-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Thr-Ser-Ala-Thr-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Thr-Val-Ala-Phe-Lys (Aminobenzoyl) , NO2Tyr-Thr-Ala-Gln-Ala-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Val-Ala-Ala-Phe-Lys (Aminobenzoyl) , NO2Tyr-Val-Ala-Ser-Ala-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gln-Gly-Ser-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Thr-Ala-Thr-Asn-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ala-Thr-Ser-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Thr-Gly-Val-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Thr-Ala-Phe-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gln-Val-Ala-Gly-Phe-Lys (Aminobenzoyl) , NO2Tyr-Gly-Ser-Ala-Gln-Phe-Lys (Aminobenzoyl) , NO2Tyr-Val-Ala-Ala-Gln-Phe- Lys (Aminobenzoyl) , NO2Tyr-Gln-Thr-Ala-Thr-Phe-Lys (Aminobenzoyl) , NO2Tyr-Thr-Gly-Tyr-Thr-Phe-Lys (Aminobenzoyl) , NO2Tyr-Ser-Ala-Gly-Thr-Phe-Lys (Aminobenzoyl) , NO2Tyr-Val-Tyr-Tyr-Val-Phe, NO2Tyr-Ala-Ser-Tyr-Gly-Phe, Z-Phe-Lys-PABC, Z-Phe-Lys, Z-Val-Lys-PABC, Z-Ala-Lys-PABC, Phe-Phe-Lys-PABC, D-Phe-Phe-Lys-PABC, D-Ala-Phe-Lys-PABC, Gly-Phe-Lys-PABC, Ac-Phe-Lys-PABC, HCO-Phe-Lys-PABC, Phe-Lys-PABC, Z-Lys-PABC, Z-Val-Cit-PABC, Z-Val-Cit, Z-Phe-Cit-PABC, Z-Leu-Cit-PABC, Z-Ile-Cit-PABC, Z-Trp-Cit-PABC, Z-Phe-Arg (NO2) -PABC, and Z-Phe-Arg (Ts) -PABC.
As used herein, and unless otherwise specified, the term “amino acid” refers to any organic acid containing one or more amino substituents, e.g., α-, β-or γ-amino, derivatives of aliphatic carboxylic acids. In the polypeptide notation used herein, e.g., Xaa1Xaa2Xaa3Xaa4Xaa5, wherein Xaa1 to Xaa5 are each and independently selected from amino acids as defined, the left hand direction is the amino terminal direction and the right hand direction is the carboxy terminal direction, in accordance with standard usage and convention.
As used herein, and unless otherwise specified, the term “conventional amino acid” refers to the twenty naturally occurring amino acids, and encompasses all stereomeric isoforms, i.e., D, L-, D-and L-amino acids thereof. These conventional amino acids can herein also be referred to by their conventional three-letter or one-letter abbreviations and their abbreviations follow conventional usage (see, for example, Immunology-ASynthesis, 2nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer Associates, Sunderland Mass. (1991) ) .
As used herein, and unless otherwise specified, the term “non-conventional amino acid” refers to unnatural amino acids or chemical amino acid analogues, e.g. α, α-disubstituted amino acids, N-alkyl amino acids, homo-amino acids, dehydroamino acids, aromatic amino acids (other than phenylalanine, tyrosine and tryptophan) , and ortho-, meta-or para-aminobenzoic acid. Non-conventional amino acids also include compounds which have an amine and carboxyl functional group separated in a 1, 3 or larger substitution pattern, such as β-alanine, γ-amino butyric acid, Freidinger lactam, the bicyclic dipeptide (BTD) , amino-methyl benzoic acid and others known in the art. Statine-like isosteres, hydroxyethylene isosteres, reduced amide bond isosteres, thioamide isosteres, urea isosteres, carbamate isosteres, thioether isosteres, vinyl isosteres and other amide bond isosteres known to the art may also be used. The use of analogues or non-conventional amino acids may improve the stability and biological half-life of the added peptide since they are more  resistant to breakdown under physiological conditions. The person skilled in the art will be aware of similar types of substitution which may be made. A non-limiting list of non-conventional amino acids which may be used as suitable building blocks for a peptide and their standard abbreviations (in brackets) is as follows: α-aminobutyric acid (Abu) , L-N-methylalanine (Nmala) , α-amino-α-methylbutyrate (Mgabu) , L-N-methylarginine (Nmarg) , aminocyclopropane (Cpro) , L-N-methylasparagine (Nmasn) , carboxylate L-N-methylaspartic acid (Nmasp) , aniinoisobutyric acid (Aib) , L-N-methylcysteine (Nmcys) , aminonorbornyl (Norb) , L-N-methylglutamine (Nmgln) , carboxylate L-N-methylglutamic acid (Nmglu) , cyclohexylalanine (Chexa) , L-N-methylhistidine (Nmhis) , cyclopentylalanine (Cpen) , L-N-methylisolleucine (Nmile) , L-N-methylleucine (Nmleu) , L-N-methyllysine (Nmlys) , L-N-methylmethionine (Nmmet) , L-N-methylnorleucine (Nmnle) , L-N-methylnorvaline (Nmnva) , L-N-methylornithine (Nmorn) , L-N-methylphenylalanine (Nmphe) , L-N-methylproline (Nmpro) , L-N-methylserine (Nmser) , L-N-methylthreonine (Nmthr) , L-N-methyltryptophan (Nmtrp) , D-ornithine (Dorn) , L-N-methyltyrosine (Nmtyr) , L-N-methylvaline (Nmval) , L-N-methylethylglycine (Nmetg) , L-N-methyl-t-butylglycine (Nmtbug) , L-norleucine (NIe) , L-norvaline (Nva) , α-methyl-aminoisobutyrate (Maib) , α-methyl-γ-aminobutyrate (Mgabu) , D-α-methylalanine (Dmala) , α-methylcyclohexylalanine (Mchexa) , D-α-methylarginine (Dmarg) , α-methylcylcopentylalanine (Mcpen) , D-α-methylasparagine (Dmasn) , α-methyl-α-napthylalanine (Manap) , D-α-methylaspartate (Dmasp) , α-methylpenicillamine (Mpen) , D-α-methylcysteine (Dmcys) , N- (4-aminobutyl) glycine (NgIu) , D-α-methylglutamine (Dmgln) , N- (2-aminoethyl) glycine (Naeg) , D-α-methylhistidine (Dmhis) , N- (3-aminopropyl) glycine (Norn) , D-α-methylisoleucine (Dmile) , N-amino-α-methylbutyrate (Nmaabu) , D-α-methylleucine (Dmleu) , α-napthylalanine (Anap) , D-α-methyllysine (Dmlys) , N-benzylglycine (Nphe) , D-α-methylmethionine (Dmmet) , N- (2-carbamylethyl) glycine (NgIn) , D-α-methylornithine (Dmorn) , N- (carbamylmethyl) glycine (Nasn) , D-α-methylphenylalanine (Dmphe) , N- (2-carboxyethyl) glycine (NgIu) , D-α-methylproline (Dmpro) , N- (carboxymethyl) glycine (Nasp) , D-α-methylserine (Dmser) , N-cyclobutylglycine (Ncbut) , D-α-methylthreonine (Dmthr) , N-cycloheptylglycine (Nchep) , D-α-methyltryptophan (Dmtrp) , N-cyclohexylglycine (Nchex) , D-α-methyltyrosine (Dmty) , N-cyclodecylglycine (Ncdec) , D-α-methylvaline (Dmval) , N-cylcododecylglycine (Ncdod) , D-N-methylalanine (Dnmala) , N-cyclooctylglycine (Ncoct) , D-N-methylarginine (Dnmarg) , N-cyclopropylglycine (Nepro) , D-N-methylasparagine (Dnmasn) , N-cycloundecylglycine (Ncund) , D-N-methylaspartate (Dnmasp) , N- (2, 2-diphenylethyl) glycine (Nbhm) , D-N-methylcysteine (Dnmcys) , N- (3, 3-diphenylpropyl) glycine (Nbhe) , D-N-methylglutamine (Dnmgln) , N- (3- guanidinopropyl) glycine (Narg) , D-N-methylglutamate (Dnmglu) , N- (1-hydroxyethyl) glycine (Ntbx) , D-N-methylhistidine (Dnmhis) , N- (hydroxyethyl) ) glycine (Nser) , D-N-methylisoleucine (Dnmile) , N- (imidazolylethyl) ) glycine (Nhis) , D-N-methylleucine (Dnmleu) , N- (3-indolylyethyl) glycine (Nhtrp) , D-N-methyllysine (Dnnilys) , N-methyl-γ-aminobutyrate (Nmgabu) , N-methylcyclohexylalanine (Nmchexa) , D-N-methylmethionine (Dnmmet) , D-N-methylornithine (Dnmorn) , N-methylcyclopentylalanine (Nmcpen) , N-methylglycine (Nala) , D-N-methylphenylalanine (Dnmphe) , N-methylaminoisobutyrate (Nmaib) , D-N-methylproline (Dnmpro) , N- (1-methylpropyl) glycine (Nile) , D-N-methylserine (Dnmser) , N- (2-methylpropyl) glycine (Nleu) , D-N-methylthreonine (Dnmthr) , D-N-methyltryptophan (Dnmtrp) , N- (1-methylethyl) glycine (Nval) , D-N-methyltyrosine (Dnmtyr) , N-methyla-napthylalanine (Nmanap) , D-N-methylvaline (Dnmval) , N-methylpenicillamine (Nmpen) , γ-aminobutyric acid (Gabu) , N- (p-hydroxyphenyl) glycine (Nhtyr) , L-/-butylglycine (Tbug) , N- (thiomethyl) glycine (Ncys) , L-ethylglycine (Etg) , penicillamine (Pen) , L-homophenylalanine (Hphe) , L-α-methylalanine (Mala) , L-α-methylarginine (Marg) , L-α-methylasparagine (Masn) , L-α-methylaspartate (Masp) , L-α-methyl-t-butylglycine (Mtbug) , L-α-methylcysteine (Mcys) , L-methylethylglycine (Metg) , L-α-methylglutamine (MgIn) , L-α-methylglutamate (MgIu) , L-α-methylhistidine (Mhis) , L-α-methylhomophenylalanine (Mhphe) , L-α-methylisoleucine (Mile) , N- (2-methylthioethyl) glycine (Nmet) , L-α-methylleucine (Mleu) , L-α-methyllysine (Mlys) , L-α-methylmethionine (Mmet) , L-α-methylnorleucine (MnIe) , L-α-methylnorvaline (Mnva) , L-α-methylornithine (Mom) , L-α-methylphenylalanine (Mphe) , L-α-methylproline (Mpro) , L-α-methylserine (Mser) , L-α-methylthreonine (Mthr) , L-α-methyltryptophan (Mtrp) , L-α-methyltyrosine (Mtyr) , L-α-methylvaline (Mval) , L-N-methylhomophenylalanine (Nmhphe) , N- (N- (2, 2-diphenylethyl) carbamylmethyl) glycine (Nnbhm) , N- (N- (3, 3-diphenylpropyl) -carbamylmethyl) glycine (Nnbhe) , 1-carboxy-1- (2, 2-diphenyl-ethylamino) cyclopropane (Nmbc) , L-O-methyl serine (Omser) , L-O-methyl homoserine (Omhser) .
As used herein, and unless otherwise specified, the term “radioactive moiety” refers to a molecular assembly which carries a radioactive nuclide. The nuclide is bound either by covalent or coordinate bonds which remain stable under physiological conditions. Examples are [113I] -3-iodobenzoic acid or 68Ga-DOTA.
As used herein, and unless otherwise specified, the term “fluorescent isotope” refers to an isotope that emits electromagnetic radiation after excitation by electromagnetic radiation of a shorter wavelength.
As used herein, and unless otherwise specified, the term “radioisotope” is a radioactive isotope of an element (included by the term "radionuclide" ) emitting α-, β-, and/or γ-radiation.
As used herein, and unless otherwise specified, the term “radioactive drug” refers to a biologic active compound which is modified by a radioisotope. Especially, intercalating substances can be used to deliver the radioactivity to direct proximity of DNA (e.g. a 131I-carrying derivative of Hoechst-33258) .
As used herein, and unless otherwise specified, the terms “chelating agent” or “chelator” are used interchangeably and refer to a molecule, often an organic one, and often a Lewis base, having two or more unshared electron pairs available for donation to a metal ion. The metal ion is usually coordinated by two or more electron pairs to the chelating agent. The terms “bidentate chelating agent” , “tridentate chelating agent” , and “tetradentate chelating agent” refer to chelating agents having, respectively, two, three, and four electron pairs readily available for simultaneous donation to a metal ion coordinated by the chelating agent. Usually, the electron pairs of a chelating agent forms coordinate bonds with a single metal ion; however, in certain examples, a chelating agent may form coordinate bonds with more than one metal ion, with a variety of binding modes being possible.
As used herein, and unless otherwise specified, the term “fluorescent dye” refers to a compound that emits visible or infrared light after excitation by electromagnetic radiation of a shorter and suitable wavelength. It is understood by the skilled person that each fluorescent dye has a predetermined excitation wavelength.
As used herein, and unless otherwise specified, the term “contrast agent” refers to a compound which increases the contrast of structures or fluids in medical imaging. The enhancement is achieved by absorbing electromagnetic radiation or altering electromagnetic fields.
As used herein, and unless otherwise specified, the term “paramagnetic” refers to paramagnetism induced by unpaired electrons in a medium. A paramagnetic substance induces a magnetic field if an external magnetic field is applied. Unlike diamagnetism the  direction of the induced field is the same as the external field and unlike ferromagnetism the field is not maintained in absence of an external field.
As used herein, and unless otherwise specified, the term “nanoparticle” as used herein refers to particles, such as particles of spheric shape, with diameters of sizes between 1 and 100 nanometers. Depending on the composition, nanoparticles can possess magnetical, optical or physico-chemical qualities that can be assessed. Additionally surface modification is achievable for many types of nanoparticles.
As used herein, and unless otherwise specified, a “pharmaceutically acceptable salt” includes both acid and base addition salts. Suitable pharmaceutically acceptable salts of the compound provided herein include acid addition salts which may, for example, be formed by mixing a solution of choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound provided herein carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts) ; alkaline earth metal salts (e.g., calcium or magnesium salts) ; and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counter anions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate) . Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphor sulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentane propionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate) , palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate,  valerate, and the like (see, for example, Berge, S. M., et al, “Pharmaceutical Salts” , Journal of Pharmaceutical Science, 1977, 66, 1-19) . Certain specific compounds provided herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes provided herein.
In addition to salt forms, also provided herein are compounds that are in a prodrug form. Prodrugs of a compound readily undergoes chemical changes under physiological conditions to provide the compound. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound provided herein following administration of the prodrug to a patient. Additionally, prodrugs can be converted to the compounds provided herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds provided herein when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 16.5 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985) . Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl) , cycloalkyl (for example, cyclohexyl) , aralkyl (for example, benzyl, p-methoxybenzyl) , and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl) . Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989) ) . Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985) ) . Hydroxyl groups have been masked as esters and ethers. EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Compounds provided herein can be synthesized according to one or more of the methods/examples provided herein. It should be noted that the general procedures may  be shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R) . In addition, the compounds having one stereochemistry (e.g., (R) ) can often be utilized to produce those having opposite stereochemistry (i.e., (S) ) using well-known methods, for example, by inversion.
Certain compounds provided herein possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are intended to be encompassed within the scope of this application.
The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H) , iodine-125 (125I) or carbon-14 (14C) . All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of this application.
As used herein, and unless otherwise specified, the term “pharmaceutical composition” refers to a substance and/or a combination of substances being used for the identification, prevention or treatment of a tissue status or disease. The pharmaceutical composition is formulated to be suitable for administration to a patient in order to prevent and/or treat disease. Further a pharmaceutical composition refers to the combination of an active agent with a carrier, inert or active, making the composition suitable for therapeutic use. Pharmaceutical compositions can be formulated for oral, parenteral, topical, inhalative, rectal, sublingual, transdermal, subcutaneous or vaginal application routes according to their chemical and physical properties. Pharmaceutical compositions comprise solid, semisolid, liquid, transdermal therapeutic systems (TTS) . Solid compositions are selected from the group consisting of tablets, coated tablets, powder, granulate, pellets, capsules, effervescent tablets or transdermal therapeutic systems. Also comprised are liquid compositions, selected from the group consisting of solutions, syrups, infusions, extracts, solutions for intravenous application, solutions for infusion or solutions of the carrier systems provided herein. Semisolid compositions provided herein comprise emulsion, suspension, creams, lotions, gels, globules, buccal tablets and suppositories.
As used herein, and unless otherwise specified, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
As used herein, and unless otherwise specified, the term “carrier” or “excipient” , as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A saline solution is a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include 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. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
As used herein, and unless otherwise specified, the term “cytotoxic effect” refers to the depletion, elimination and/or the killing of a target cell (s) . As used herein, and unless otherwise specified, the term “cytotoxic agent” refers to an agent that has a cytotoxic and/or cytostatic effect on a cell. The term is intended to include chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant, or animal origin, and fragments thereof. As used herein, and unless otherwise specified, the term “cytostatic effect” refers to the inhibition of cell proliferation. As used herein, and unless otherwise specified, the term “cytostatic agent” refers to an agent that has a cytostatic effect on a cell, thereby inhibiting the growth and/or expansion of a specific subset of cells.
As used herein, and unless otherwise specified, the term “cytokine” refers to small proteins (～5-20 kDa) that are involved in autocrine signaling, paracrine signaling and endocrine signaling as immunomodulating agents. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors but generally not hormones or growth factors.
As used herein, and unless otherwise specified, the term “immunomodulatory molecule” refers to substance that stimulates or suppresses the immune system and may help the body fight cancer, infection, or other diseases. Specific immunomodulating molecules can be monoclonal antibodies, cytokines, and vaccines, which affect specific parts of the immune system.
As used herein, and unless otherwise specified, the term “amphiphilic substance” refers to compounds with both hydrophilic and lipophilic properties. Common amphiphilic substances are phospholipids, cholesterol, glycolipids, fatty acids, bile acids, saponins, pediocins, local anesthetics, Ab proteins and antimicrobial peptides.
As used herein, and unless otherwise specified, the term “protein” and “polypeptide” are used interchangeably herein and refer to any peptide-bond-linked chain of amino acids, regardless of length or post-translational modification. In one embodiment, the amino acid is any of the amino acids provided herein. Proteins provided herein (including protein derivatives, protein variants, protein fragments, protein segments, protein epitopes and protein domains) can be further modified by chemical modification. This means such a chemically modified polypeptide comprises other chemical groups than the 20 naturally occurring amino acids. Examples of such other chemical groups include without limitation glycosylated amino acids and phosphorylated amino acids. Chemical modifications of a polypeptide may provide advantageous properties as compared to the parent polypeptide, e.g., one or more of enhanced stability, increased biological half-life, or increased water solubility.
As used herein, and unless otherwise specified, the terms “nucleic acid” and “polynucleotide” are used interchangeably herein and refer to polymeric or oligomeric macromolecules, or large biological molecules, essential for all known forms of life. Nucleic acids, which include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) , are made from monomers known as nucleotides. Most naturally occurring DNA molecules consist of two complementary biopolymer strands coiled around each other to form a double helix. The DNA strand is also known as polynucleotides consisting of nucleotides. Each nucleotide is composed of a nitrogen-containing nucleobase as well as a monosaccharide sugar called deoxyribose or ribose and a phosphate group. Naturally occurring nucleobases comprise guanine (G) , adenine (A) , thymine (T) , uracil (U) or cytosine (C) . The nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. If the sugar is  desoxyribose, the polymer is DNA. If the sugar is ribose, the polymer is RNA. Typically, a polynucleotide is formed through phosphodiester bonds between the individual nucleotide monomers. As used herein, and unless otherwise specified, the term “nucleic acid” includes but is not limited to ribonucleic acid (RNA) , deoxyribonucleic acid (DNA) , and mixtures thereof such as RNA-DNA hybrids (within one strand) , as well as cDNA, genomic DNA, recombinant DNA, cRNA and mRNA. A nucleic acid may consist of an entire gene, or a portion thereof, the nucleic acid may also be a miRNA, siRNA, piRNA or shRNA. miRNAs are short ribonucleic acid (RNA) molecules, which are on average 22 nucleotides long but may be longer and which are found in all eukaryotic cells, i.e., in plants, animals, and some viruses, which functions in transcriptional and post-transcriptional regulation of gene expression. miRNAs are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts (mRNAs) , usually resulting in translational repression and gene silencing. Small interfering RNAs (siRNAs) , sometimes known as short interfering RNA or silencing RNA, are short ribonucleic acid (RNA molecules) , between 20-25 nucleotides in length. They are involved in the RNA interference (RNAi) pathway, where they interfere with the expression of specific genes. A short hairpin RNA (shRNA) or small hairpin RNA (shRNA) is an artificial RNA molecule with a tight hairpin turn that can be used to silence target gene expression via RNA interference (RNAi) . Expression of shRNA in cells is typically accomplished by delivery of plasmids or through viral or bacterial vectors. piRNAs are also short RNAs which usually comprise 26-31 nucleotides and derive their name from so-called piwi proteins they are binding to. The nucleic acid can also be an artificial nucleic acid. Artificial nucleic acids include polyamide or peptide nucleic acid (PNA) , morpholino and locked nucleic acid (LNA) , as well as glycol nucleic acid (GNA) and threose nucleic acid (TNA) . Each of these is distinguished from naturally-occurring DNA or RNA by changes to the backbone of the molecule. The nucleic acids, can, e.g., be synthesized chemically, e.g., in accordance with the phosphotriester method (see, for example, Uhlmann, E. &Peyman, A. (1990) Chemical Reviews, 90, 543-584) .
As used herein, and unless otherwise specified, the term “viral structural protein” (VSP) refers to viral coat proteins (VCP) or viral envelope glycoproteins (VEG) . As used herein, and unless otherwise specified, the term “viral coat protein” (VCP) refers to a structural virus capsid protein of a virus. In one embodiment, the virus is a double-stranded DNA virus, single-stranded DNA virus, double-stranded RNA virus, single-stranded RNA virus, negative-sense single-stranded RNA virus, single-stranded RNA reverse transcribing  virus, double-stranded RNA reverse transcribing virus. The VCP can comprise major capsid proteins of adeno-associated virus (AAV) .
As used herein, and unless otherwise specified, the term “viral envelope glycoproteins” (VEG) refers to viral proteins that are part of the viral envelope. The viral envelope is typically derived from portions of the host cell membrane, e.g., comprises phospholipids, and additionally comprise viral glycoproteins that, e.g., help the virus to avoid the immune system. Enveloped viruses comprise DNA viruses, such as Herpesviruses, Poxviruses, and Hepadnaviruses; RNA viruses, such as Flavivirus, Togavirus, Coronavirus, Hepatitis D, Orthomyxovirus, Paramyxovirus, Rhabdovirus, Bunyavirus, Filovirus and Retroviruses. In one embodiment, the viral envelop glycoprotein is derived from any of these viruses.
As used herein, and unless otherwise specified, the term “liposome” refers to uni-or multilamellar (e.g., 2, 3, 4, 5, 6, 7, 8, 9, and 10 lamellar) lipid structures enclosing an aqueous interior, depending on the number of lipid membranes formed. Lipids, which are capable of forming a liposomes include all substances having fatty or fat-like properties. Such lipids comprise an extended apolar residue (X) and usually a water soluble, polar, hydrophilic residue (Y) , which can be characterized by the basic formula
X-Yn
wherein n equals or is greater than zero. Lipids with n = 0 are termed “apolar lipids” , while lipids with n > 1 are referred to as “polar lipids” . In one embodiment, lipids, which can make up the lipids in the liposomes provided herein are selected from the group consisting of glycerides, glycerophospholipids, sulfolipids, sphingolipids, phospholipids, isoprenolides, steroids, stearines, steroles and carbohydrate containing lipids.
A virus like particle (VLP) is a multimer of VSP, such as VCPs and/or VEPs that does not comprise polynucleotides but which otherwise has properties of a virus, e.g., binds to cell surface receptors, is internalized with the receptor, is stable in blood, and/or comprises glycoproteins etc. VLPs are typically assembled of multimers of VCPs and/or VEPs, in particular of VCPs. VLPs are known in the art and have been produced from a number of viruses including Parvoviridae (e.g., adeno-associated virus) , Retroviridae (e.g., HIV) , Flaviviridae (e.g., Hepatitis C virus) and bacteriophages (e.g., QP, AP205) .
As used herein, and unless otherwise specified, the term “fibroblast activation protein (FAP) ” as used herein is also known under the term “seprase” . Both terms can be  used interchangeably herein. Fibroblast activation protein is a homodimeric integral protein with dipeptidyl peptidase IV (DPPIV) -like fold, featuring an alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain.
It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.
COMPOUNDS
In one embodiment, provided herein is a compound of Formula (I) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein:
each of Q1 to Q7 is independently absent, O, C (R5) 2, NR5, C=O, C=S, or 3-to 10-membered N-containing heterocyclyl, provided that (i) two O are not directly adjacent to each other, and (ii) at least three of Q1 to Q7 are present;
Ring C is 1-naphthyl, 5-to 10-membered N-containing heteroaryl, or 5-to 10-membered N-containing heterocyclyl;
each instance of R2, R3, or R4 is independently -OH, halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , -N (R5) 2, or -S- (C1-C6 alkyl) , each of said C1-C6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo;
X1 is O, NR5, S, C=O, C=S, - (C=O) -NR5-*, - (C=S) -NR5-*, -O-aryl-*, -NR5-aryl-*, - (C=O) -NR5-aryl-*, - (C=S) -NR5-aryl-*, wherein *refers to the direction toward Ring C;
G1 is absent, C1-C5 alkylene, or C2-C5 alkynylene, wherein said C1-C5 alkylene and C2-C5 alkynylene are optionally substituted with one or more substituents independently selected from -OH, oxo, halo, C1-C3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
each instance of X is independently absent, O, NR5, C=O, C=S, - (C=O) -NR5-*, -NR5- (C=O) -*, - (C=S) -NR5-*, or -NR5- (C=S) -*, wherein *refers to the direction toward Ring C;
each instance of G is independently C1-C5 alkylene or C2-C5 alkynylene, wherein said C1-C5 alkylene and C2-C5 alkynylene are optionally substituted with one or more substituents  independently selected from -OH, oxo, halo, C1-C3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
each instance of Ring B is C3-C10 cycloalkyl, C6-C10 aryl, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
X2 is absent, O, NR5, C=O, C=S, - (C=O) -NR5-*, -NR5- (C=O) -*, - (C=S) -NR5-*, or -NR5- (C=S) -*, wherein *refers to the direction toward Ring C;
L is absent or a linker;
Ring A is 5 to 10-membered N-containing heteroaryl or 5 to 10-membered N-containing heterocyclyl;
n is 0, 1, 2, or 3;
m is 0, 1, 2, or 3;
p is 0, 1, 2, or 3;
s is 1, 2, or 3;
each instance of R5 is independently -H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from -OH, oxo, and halo; and
Z is a radioactive moiety, a chelating agent, a fluorescent dye, or a contrast agent.
In one embodiment, at least three of Q1 to Q7 are present. In one embodiment, exactly three of Q1 to Q7 are present. In one embodiment, at least four of Q1 to Q7 are present. In one embodiment, exactly four of Q1 to Q7 are present. In one embodiment, at least five of Q1 to Q7 are present. In one embodiment, exactly five of Q1 to Q7 are present. In one embodiment, at least six of Q1 to Q7 are present. In one embodiment, exactly six of Q1 to Q7 are present. In one embodiment, all of Q1 to Q7 are present.
In one embodiment, Q1 is absent. In one embodiment, Q1 is O. In one embodiment, Q1 is C (R5) 2. In one embodiment, Q1 is CH2. In one embodiment, Q1 is NR5. In one embodiment, Q1 is NH. In one embodiment, Q1 is C=O. In one embodiment, Q1 is C=S. In one embodiment, Q1 is 3-to 10-membered N-containing heterocyclyl. In one embodiment, Q1 is 5-to 6-membered N-containing heterocyclyl. In one embodiment, the heterocyclyl is heterocycloalkyl. In one embodiment, Q1 is azetidin-1-yl. In one embodiment, Q1 is pyrrolidin-1-yl. In one embodiment, Q1 is piperidin-1-yl. In one embodiment, Q1 is azepan-1-yl. In one embodiment, Q1 is azocan-1-yl. The point of  attachment for these groups is toward the direction of the terminal pyrrolidine ring (i.e., ) .
In one embodiment, Q2 is absent. In one embodiment, Q2 is O. In one embodiment, Q2 is C (R5) 2. In one embodiment, Q2 is CH2. In one embodiment, Q2 is NR5. In one embodiment, Q2 is NH. In one embodiment, Q2 is C=O. In one embodiment, Q2 is C=S. In one embodiment, Q2 is 3-to 10-membered N-containing heterocyclyl. In one embodiment, Q2 is 5-to 6-membered N-containing heterocyclyl. In one embodiment, the heterocyclyl is heterocycloalkyl. In one embodiment, Q2 is azetidin-1-yl. In one embodiment, Q2 is pyrrolidin-1-yl. In one embodiment, Q2 is piperidin-1-yl. In one embodiment, Q2 is azepan-1-yl. In one embodiment, Q2 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
In one embodiment, Q3 is absent. In one embodiment, Q3 is O. In one embodiment, Q3 is C (R5) 2. In one embodiment, Q3 is CH2. In one embodiment, Q3 is NR5. In one embodiment, Q3 is NH. In one embodiment, Q3 is C=O. In one embodiment, Q3 is C=S. In one embodiment, Q3 is 3-to 10-membered N-containing heterocyclyl. In one embodiment, Q3 is 5-to 6-membered N-containing heterocyclyl. In one embodiment, the heterocyclyl is heterocycloalkyl. In one embodiment, Q3 is azetidin-1-yl. In one embodiment, Q3 is pyrrolidin-1-yl. In one embodiment, Q3 is piperidin-1-yl. In one embodiment, Q3 is azepan-1-yl. In one embodiment, Q3 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
In one embodiment, Q4 is absent. In one embodiment, Q4 is O. In one embodiment, Q4 is C (R5) 2. In one embodiment, Q4 is CH2. In one embodiment, Q4 is NR5. In one embodiment, Q4 is NH. In one embodiment, Q4 is C=O. In one embodiment, Q4 is C=S. In one embodiment, Q4 is 3-to 10-membered N-containing heterocyclyl. In one embodiment, Q4 is 5-to 6-membered N-containing heterocyclyl. In one embodiment, the heterocyclyl is heterocycloalkyl. In one embodiment, Q4 is azetidin-1-yl. In one embodiment, Q4 is pyrrolidin-1-yl. In one embodiment, Q4 is piperidin-1-yl. In one embodiment, Q4 is azepan-1-yl. In one embodiment, Q4 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
In one embodiment, Q5 is absent. In one embodiment, Q5 is O. In one embodiment, Q5 is C (R5) 2. In one embodiment, Q5 is CH2. In one embodiment, Q5 is NR5. In one embodiment, Q5 is NH. In one embodiment, Q5 is C=O. In one embodiment, Q5 is C=S. In one embodiment, Q5 is 3-to 10-membered N-containing heterocyclyl. In one embodiment, Q5 is 5-to 6-membered N-containing heterocyclyl. In one embodiment, the heterocyclyl is heterocycloalkyl. In one embodiment, Q5 is azetidin-1-yl. In one embodiment, Q5 is pyrrolidin-1-yl. In one embodiment, Q5 is piperidin-1-yl. In one embodiment, Q5 is azepan-1-yl. In one embodiment, Q5 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
In one embodiment, Q6 is absent. In one embodiment, Q6 is O. In one embodiment, Q6 is C (R5) 2. In one embodiment, Q6 is CH2. In one embodiment, Q6 is NR5. In one embodiment, Q6 is NH. In one embodiment, Q6 is C=O. In one embodiment, Q6 is C=S. In one embodiment, Q6 is 3-to 10-membered N-containing heterocyclyl. In one embodiment, Q6 is 5-to 6-membered N-containing heterocyclyl. In one embodiment, the heterocyclyl is heterocycloalkyl. In one embodiment, Q6 is azetidin-1-yl. In one embodiment, Q6 is pyrrolidin-1-yl. In one embodiment, Q6 is piperidin-1-yl. In one embodiment, Q6 is azepan-1-yl. In one embodiment, Q6 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
In one embodiment, Q7 is absent. In one embodiment, Q7 is O. In one embodiment, Q7 is C (R5) 2. In one embodiment, Q7 is CH2. In one embodiment, Q7 is NR5. In one embodiment, Q7 is NH. In one embodiment, Q7 is C=O. In one embodiment, Q7 is C=S. In one embodiment, Q7 is 3-to 10-membered N-containing heterocyclyl. In one embodiment, Q7 is 5-to 6-membered N-containing heterocyclyl. In one embodiment, the heterocyclyl is heterocycloalkyl. In one embodiment, Q7 is azetidin-1-yl. In one embodiment, Q7 is pyrrolidin-1-yl. In one embodiment, Q7 is piperidin-1-yl. In one embodiment, Q7 is azepan-1-yl. In one embodiment, Q7 is azocan-1-yl. The point of attachment for these groups is toward the direction of the terminal pyrrolidine ring.
In one embodiment, at least four of Q1 to Q7 are present, wherein two are C=O, one is CH2 and one is NH. In one embodiment, exactly four of Q1 to Q7 are present, wherein two are C=O, one is CH2, and one is NH. In one embodiment, Q4 to Q7 are present, wherein Q4 and Q7 are C=O, and Q5 and Q6 are independently CH2 or NH.
In one embodiment, Q1, Q2, and Q3 are each independently absent or CH2; Q4 is CH2, C=O, or C=S; Q5 is NR5; Q6 is CHR5; and Q7 is C=O, or C=S. In one embodiment, -Q4-Q5-Q6-Q7- (in the same direction) is - (C=O) -NH-CH2- (C=O) -. In one embodiment, -Q1-Q2-Q3-Q4-Q5-Q6-Q7- (in the same direction) is - (C=O) -NH-CH2- (C=O) -.
In one embodiment, Q1, Q2, Q3, and Q4 are each independently absent or CH2; Q5 is 5-to 6-membered N-containing heterocyclyl; Q6 is CHR5; and Q7 is C=O or C=S. In one embodiment, Q1 is O or NR5 , and -Q2-Q3-Q4-Q5-Q6-Q7-is wherein *refers to the direction toward Ring C. In one embodiment, Q1 is O, and -Q2-Q3-Q4-Q5-Q6-Q7-isIn one embodiment, Q1 is O, and -Q2-Q3-Q4-Q5-Q6-Q7-isIn one embodiment, Q1 is NH, and -Q2-Q3-Q4-Q5-Q6-Q7-isIn one embodiment, Q1 is NH, and -Q2-Q3-Q4-Q5-Q6-Q7-is
In one embodiment, Ring C is 1-naphthyl.
In one embodiment, Ring C is 5-to 10-membered N-containing heteroaryl. In one embodiment, Ring C is 5-membered N-containing heteroaryl. In one embodiment, Ring C is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, 1, 2, 3-triazolyl, or 1, 2, 4-triazolyl. In one embodiment, Ring C is 6-membered N-containing heteroaryl. In one embodiment, Ring C is pyridyl, pyrimidinyl, pyridazinyl, or triazinyl. In one embodiment, the 5-or 6-membered N-containing heteroaryl is fused to a phenyl or another 5-or 6-membered N-containing heteroaryl. In one embodiment, Ring C is quinolinyl, 1, 8-naphthyridinyl, pyrido [2, 3-b] pyrazinyl, or quinazolinyl. In one embodiment, Ring C is quinolinyl.
In one embodiment, Ring C is 5-to 10-membered N-containing heterocyclyl. In one embodiment, Ring C is 5-membered N-containing heterocyclyl. In one embodiment, Ring C is pyrrolidinyl. In one embodiment, Ring C is 6-membered N-containing heterocyclyl. In one embodiment, Ring C is piperidinyl. In one embodiment, the 5-or 6-membered N-containing heterocyclyl is fused to a phenyl or another 5-or 6-membered N-containing heteroaryl. In one embodiment, Ring C is 1, 2, 3, 4-tetrahydroquinolinyl.
In one embodiment, there are two ring atoms between the ring atom of Ring C two which Q1 is attached and a nitrogen atom of Ring C.
In one embodiment, Ring C is
In one embodiment, Ring C is
wherein the shown point of attachment is toward Q1.
In one embodiment, Ring C iswherein the shown point of attachment is toward Q1.
In one embodiment, X1 is O, NR5, S, C=O, C=S, - (C=O) -NR5-*, - (C=S) -NR5-*, -O-aryl-*, -NR5-aryl-*, - (C=O) -NR5-aryl-*, - (C=S) -NR5-aryl-*, wherein *refers to the direction toward Ring C. In one embodiment, X1 is O. In one embodiment, X1 is NR5. In one embodiment, X1 is NH. In one embodiment, X1 is N (CH3) . In one embodiment, X1 is - (C=O) NR5-*. In one embodiment, X1 is - (C=O) NH-*.
In one embodiment, G1 is absent. In one embodiment, G1 is C1-C5 alkylene. In one embodiment, G1 is C2-C5 alkylene. In one embodiment, G1 is C1 alkylene. In one embodiment, G1 is C2 alkylene. In one embodiment, G1 is C3 alkylene. In one embodiment, G1 is C4 alkylene. In one embodiment, G1 is C5 alkylene. In one embodiment, G1 is C2-C5 alkynylene. In one embodiment, G1 is C2 alkynylene. In one embodiment, G1 is C3 alkynylene. In one embodiment, G1 is C4 alkynylene. In one embodiment, G1 is C5 alkynylene. In one embodiment, G1 is unsubstituted. In one embodiment, G1 is substituted with one or more substituents independently selected from -OH, oxo, halo, C1-C3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl. In one embodiment, G1 is substituted with one or more halo (e.g., one or more fluoro) .
In one embodiment, s is 1. In one embodiment, s is 2. In one embodiment, s is 3.
In one embodiment, X2 is absent, O, NR5, C=O, C=S, - (C=O) -NR5-*, -NR5-(C=O) -*, - (C=S) -NR5-*, or -NR5- (C=S) -*, wherein *refers to the direction toward Ring C. In one embodiment, X2 is absent. In one embodiment, X2 is O. In one embodiment, X2 is NR5. In one embodiment, X2 is NH. In one embodiment, X2 is N (CH3) . In one embodiment, X2 is - (C=O) NR5-*. In one embodiment, X2 is - (C=O) NH-*.
In one embodiment, each instance of X is independently absent, O, NR5, C=O, C=S, - (C=O) -NR5-*, -NR5- (C=O) -*, - (C=S) -NR5-*, or -NR5- (C=S) -*, wherein *refers to the direction toward Ring C. In one embodiment, each instance of X is independently absent, O, NH, N (CH3) , C=O, - (C=O) -NH-*, or -NH- (C=O) -*. In one embodiment, each instance of X is independently absent.
In one embodiment, each instance of G is independently C1-C5 alkylene. In one embodiment, each instance of G is independently C1-C3 alkylene. In one embodiment, each instance of G is independently C1 alkylene. In one embodiment, each instance of G is independently C2 alkylene. In one embodiment, each instance of G is independently  C3 alkylene. In one embodiment, each instance of G is independently C4 alkylene. In one embodiment, each instance of G is independently C5 alkylene. In one embodiment, each instance of G is independently C2-C5 alkynylene. In one embodiment, each instance of G is independently C2 alkynylene. In one embodiment, each instance of G is independently C3 alkynylene. In one embodiment, each instance of G is independently C4 alkynylene. In one embodiment, each instance of G is independently C5 alkynylene. In one embodiment, G is unsubstituted. In one embodiment, G is substituted with one or more substituents independently selected from -OH, oxo, halo, C1-C3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl. In one embodiment, G is substituted with one or more halo (e.g., one or more fluoro) .
In one embodiment, -X2- [G-X- (Ring B) -X] s-G1-X1-is -G- (Ring B) -G1-X1-, wherein G is C1-C2 alkylene, G1 is C1-C2 alkylene, and X1 is O, NR5, or - (C=O) NR5-*. In one embodiment, G is C1-C2 alkylene, G1 is C1-C2 alkylene, and X1 is O. In one embodiment, G is C1-C2 alkylene, G1 is C1-C2 alkylene, and X1 is NH. In one embodiment, G is C1-C2 alkylene, G1 is C1-C2 alkylene, and X1 is N (CH3) .
In one embodiment, -X2- [G-X- (Ring B) -X] s-G1-X1-is -G- (Ring B) -X1-, wherein G is C1-C2 alkylene, and X1 is O, NR5, or - (C=O) NR5-*. In one embodiment, G is C1-C2 alkylene, and X1 is O. In one embodiment, G is C1-C2 alkylene, and X1 is - (C=O) NH-*.
In one embodiment, -X2- [G-X- (Ring B) -X] s-G1-X1-is -G-X- (Ring B) -X1-, wherein G is C1-C2 alkylene, X is C=O, and X1 is O, NR5, or - (C=O) NR5-*. In one embodiment, G is C1-C2 alkylene, X is C=O, and X1 is N (CH3) .
In one embodiment, L is absent. In one embodiment, L is a linker. In one embodiment, the linker is a peptide comprising 2 to 5 amino acids.
In one embodiment, the compound is a compound of Formula (II-A) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula (II-A) , n is 1. In one embodiment, the one R2 is attached to 5-position of quinolinyl. In one embodiment, the one R2 is attached to 7-position of quinolinyl. In one embodiment, the one R2 is attached to 8-position of quinolinyl.
In one embodiment, the compound is a compound of Formula (III-A) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is a compound of Formula (IV-A) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is a compound of Formula (II-B) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula (II-B) , n is 1. In one embodiment, the one R2 is attached to 5-position of quinolinyl. In one embodiment, the one R2 is attached to 6-position of quinolinyl. In one embodiment, the one R2 is attached to 7-position of quinolinyl.
In one embodiment, the compound is a compound of Formula (III-B) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is a compound of Formula (IV-B) :
or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is a compound of Formula (II-A) (including sub-formulas such as (III-A) and (IV-A) ) , except that X1 is attached to the 5-position of quinolinyl. In one embodiment, the compound is a compound of Formula (II-A) (including sub-formulas such as (III-A) and (IV-A) ) , except that X1 is attached to the 7-position of quinolinyl.
In one embodiment, each instance of Ring B is C3-C10 cycloalkyl, C6-C10 aryl, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl.
In one embodiment, Ring B is C3-C10 cycloalkyl. In one embodiment, Ring B is C3-C8 cycloalkyl. In one embodiment, the cycloalkyl is a monocyclic cycloalkyl. In one embodiment, the cycloalkyl is a bridged cycloalkyl. In one embodiment, the cycloalkyl is a spiro cycloalkyl. In one embodiment, the cycloalkyl is cyclopropyl. In one embodiment, the cycloalkyl is cyclobutyl. In one embodiment, the cycloalkyl is cyclopentyl. In one embodiment, the cycloalkyl is cyclohexyl. In one embodiment, the cycloalkyl is In one embodiment, the cycloalkyl isIn one embodiment, the cycloalkyl isIn one embodiment, the cycloalkyl isIn one embodiment, the cycloalkyl isIn one embodiment, the cycloalkyl is
In one embodiment, Ring B is C6-C10 aryl. In one embodiment, the aryl is
In one embodiment, Ring B is 5 to 10-membered heteroaryl. In one embodiment, Ring B is 5 to 6-membered heteroaryl. In one embodiment, the heteroaryl is pyridyl. In one embodiment, the heteroaryl isIn one embodiment, the right side point of attachment of these groups (as shown here) is toward Ring C.
In one embodiment, Ring B is 5 to 10-membered heterocyclyl. In one embodiment, Ring B is 3 to 8-membered heterocyclyl. In one embodiment, the heterocyclyl is a monocyclic heterocyclyl. In one embodiment, the heterocyclyl is a bridged heterocyclyl. In one embodiment, the heterocyclyl is a spiro heterocyclyl. In one embodiment, the heterocyclyl is azetidinyl. In one embodiment, the heterocyclyl is pyrrolidinyl. In one embodiment, the heterocyclyl is piperidinyl. In one embodiment, the heterocyclyl isIn one embodiment, the heterocyclyl isIn one embodiment, the heterocyclyl isIn one embodiment, the heterocyclyl isIn one embodiment, the right side point of attachment of these groups (as shown here) is toward Ring C.
In one embodiment, Ring Ais absent. In one embodiment, Ring A is 5 to 10-membered N-containing heteroaryl. In one embodiment, Ring A is 5 to 6-membered N-containing heteroaryl.
In one embodiment, Ring A is 5 to 10-membered N-containing heterocyclyl. In one embodiment, Ring A is 5 to 8-membered N-containing heterocyclyl. In one  embodiment, the heterocyclyl is a monocyclic heterocyclyl. In one embodiment, the heterocyclyl is a bridged heterocyclyl. In one embodiment, the heterocyclyl is a spiro heterocyclyl. In one embodiment, the heterocyclyl is a fused heterocyclyl. In one embodiment, the heterocyclyl is azetidinyl. In one embodiment, the heterocyclyl is pyrrolidinyl. In one embodiment, the heterocyclyl is piperidinyl. In one embodiment, the heterocyclyl is azepanyl. In one embodiment, the heterocyclyl is azocanyl. In one embodiment, the heterocyclyl is piperazinyl. In one embodiment, the heterocyclyl isIn one embodiment, the heterocyclyl isIn one embodiment, the heterocyclyl isIn one embodiment, the heterocyclyl isIn one embodiment, the heterocyclyl isIn one embodiment, the heterocyclyl is In one embodiment, the right point of attachment of these groups (as shown here) is toward Ring B.
In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.
In one embodiment, each instance of R2 is independently -OH, halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , -N (R5) 2, or -S- (C1-C6 alkyl) , each of said C1-C6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo. In one embodiment, each instance of R2 is independently halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , or -N (R5) 2.
In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
In one embodiment, each instance of R3 is independently -OH, halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , -N (R5) 2, or -S- (C1-C6 alkyl) , each of said C1-C6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo. In one embodiment, each instance of R3 is independently halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , or -N (R5) 2.
In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, p is 3.
In one embodiment, each instance of R4 is independently -OH, halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , -N (R5) 2, or -S- (C1-C6 alkyl) , each of said C1-C6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo. In one embodiment, each instance of R4 is independently halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , or -N (R5) 2.
In one embodiment, isIn one embodiment, is a mixture of enantiomers (e.g., a racemic) or a mixture of diastereomers.
In In one embodiment, Z is a radioactive moiety. In one embodiment, the radioactive moiety is a fluorescent isotope, a radioisotope, or a radioactive drug. In one embodiment, the radioactive moiety is selected from the group consisting of alpha radiation emitting isotopes, beta radiation emitting isotopes, gamma radiation emitting isotopes, Auger electron emitting isotopes, X-ray emitting isotopes, and fluorescence emitting isotopes.
In one embodiment, the radioactive moiety is 177Lu-DOTA, 177Lu-DOTAGA, 68Ga-DOTA, 90Y-DOTA, Al18F-NOTA. 203Pb-TCMC, 212Pb-TCMC, 64Cu-DOTA, or 225Ac-DOTA. In one embodiment, the radioactive moiety is 177Lu-DOTA. In one embodiment, the radioactive moiety is 177Lu-DOTAGA. In one embodiment, the radioactive moiety is 68Ga-DOTA.
In one embodiment, the radioactive moiety is 11C, 18F, 72As, 72Se, 123I, 124I, 131I, or 211At.
In one embodiment, Z is a fluorescent dye. In one embodiment, the fluorescent dye is an Xanthene, an Acridine, an Oxazine, an Cyanine, a Styryl dye, a Coumarin, a Porphine, a Metal-Ligand-Complex, a Fluorescent protein, a Nanocrystals, a Perylene, a Boron-dipyrromethene, or a Phthalocyanine, or a conjugate or combination thereof.
In one embodiment, Z is a chelating agent. In one embodiment, the chelating agent is a chelating agent that forms a complex with a divalent or trivalent metal cation. In one embodiment, the chelating agent is 1, 4, 7, 10-tetraazacyclododecane-N, N', N, N'-tetra acetic acid (DOTA) , ethylenediaminetetraacetic acid (EDTA) , 1, 4, 7-triazacyclononane-l, 4, 7-triacetic acid (NOTA) , 1, 4, 7, 10-tetraazacyclododecane-1- (glutaric acid) -4, 7, 10-triacetic acid  (DOTAGA) , 2- [4, 7, 10-tris (2-amino-2-oxoethyl) -1, 4, 7, 10-tetrazacyclododec-1-yl] acetamide (TCMC) , triethylenetetramine (TETA) , iminodiacetic acid, diethylenetriamine-N, N, N', N', N"-penta acetic acid (DTPA) , bis- (carboxymethyl imidazole) glycine, or 6-hydrazinopyridine-3-carboxylic acid (HYNIC) .
In one embodiment, the chelating agent is a chelating agent in Table 1.
Table 1.

In one embodiment, Z is a contrast agent. In one embodiment, the contrast agent comprises a paramagnetic agent. In one embodiment, the paramagnetic agent comprises paramagnetic nanoparticles.
In one embodiment, Z is a cytostatic and/or cytotoxic agent. In one embodiment, the cytostatic and/or cytotoxic agent is selected from the group consisting of alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs) , inhibitors of cyclooxygenases and/or lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, such as acediasulfone, aclarubicine, a-amanitin, ambazone, aminoglutethimide, L-asparaginase, monomethyl auristatin E, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, capecitabine, carmustine, celecoxib, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, dolastatin 10 and 15, doxorubicin, enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon a, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, rapamycin, rofecoxib, rosiglitazone, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, UCN-01, vinblastine,  vincristine, vindesine, vinblastine, vinorelbine, zorubicin, or their respective derivatives or analogs thereof and combinations thereof.
In one embodiment, the cytostatic and/or cytotoxic agent is selected from the group consisting of doxorubicin, α-amanitin and monomethyl auristatin E. In one embodiment, Z is doxorubicin.
In one embodiment, Z is a cytokine. In one embodiment, the cytokine is a chemokine molecule. In one embodiment, the chemokine molecule is selected from the group consisting of CXCL9, CXCL10 and CX3CL1. In one embodiment, Z is CXCL9. In one embodiment, Z is CXCL10. In one embodiment, Z is CX3CL1.
In one embodiment, Z is an immunomodulatory molecule. In one embodiment, the immunomodulatory molecule is selected from the group consisting of CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, interleukin-2, interferon alpha and interferon gamma. In one embodiment, the immunomodulatory molecule is selected from the group consisting of CXCL3, interleukin-2 and CCL8. In one embodiment, Z is interleukin-2.
In one embodiment, Z is an amphiphilic substance. In one embodiment, the amphiphilic substance is selected from the group consisting of a lipid, a phospholipid and other highly lipophilic moiety conjugated to a polar group such as an ammonium ion or inositol triphosphate. In one embodiment, the lipid is selected from the group consisting of saccharolipids, prenol lipids, sterol lipids, glycerolipids, polyketides and fatty acids and the phospholipid is selected from the group consisting of plasmalogens, sphingo lipids, phophatidates and phosphoinositides. In one embodiment, the amphiphilic substance is a lipid or a phospholipid. In one embodiment, the amphiphilic substance is N-PEGylated l, 2-disteaorylglycero-3-phosphoethanolamine. In one embodiment, Z is a lipid. In one embodiment, Z is a phospholipid. In one embodiment, Z is N-PEGylatcd l, 2-disteaorylglycero-3-phosphoethanolamine.
In one embodiment, Z is a nucleic acid. In one embodiment, the nucleic acid is selected from the group consisting of DNA, RNA, siRNA, mRNA, PNA and cDNA. In  one embodiment, the nucleic acid encodes a cytokine and/or an immunomodulatory molecule provided herein. In one embodiment, the nucleic acid is a siRNA or PNA.
In one embodiment, Z is a viral structural protein. In one embodiment, the viral structural protein is of a virus selected from the group consisting of
(i) double-stranded DNA virus, such as Myoviridae, Siphoviridae, Podoviridae, Herpesviridae, Adenoviridae, Baculoviridae, Papillomaviridae, Polydnaviridae, Polyomaviridae, Poxviridae;
(ii) single-stranded DNA virus, such as Anelloviridae, Inoviridae, Parvoviridae;
(iii) double-stranded RNA virus, such as Reoviridae;
(iv) single-stranded RNA virus, such as Coronaviridae, Picomaviridae, Caliciviridae, Togaviridae, Flaviviridae, Astroviridae, Arteriviridae, Hepeviridae;
(v) negative-sense single-stranded RNA virus, such as Arenaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Bunyaviridae, Orthomyxoviridae, Bomaviridae;
(vi) single-stranded RNA reverse transcribing virus, such as Retroviridae;
(vii) double-stranded DNA reverse transcribing virus, such as Caulimoviridae, Hepadnaviridae.
In one embodiment, the viral structural protein, such as VCP is derived from a virus selected from the group consisting of double-stranded DNA virus, such as Myoviridae, Siphoviridae, Podoviridae, Herpesviridae, Adenoviridae, Baculoviridae, Papillomaviridae, Polydnaviridae, Polyomaviridae, Poxviridae; single-stranded DNA virus, such as Anelloviridae, Inoviridae, Parvoviridae; double-stranded RNA virus, such as Reoviridae; single-stranded RNA virus, such as Coronaviridae, Picomaviridae, Caliciviridae, Togaviridae, Flaviviridae, Astroviridae, Arteriviridae, Hepeviridae; negative-sense single-stranded RNA vims, such as Arenaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Bunyaviridae, Orthomyxoviridae, Bomaviridae; single-stranded RNA reverse transcribing vims, such as Retroviridae; double-stranded DNA reverse transcribing vims, such as Caulimoviridae, Hepadnaviridae. In one embodiment, the VCP is from a family of the Parvoviridae, such as from adeno-associated vims. In one embodiment, the VCP is human AAV, bovine AAV, caprine AAV, avian AAV, canine parvovirus (CPV) , mouse parvovirus; minute vims of mice (MVM) ; parvovirus B19 (B19) ; parvovirus Hl (Hl) ; human bocavims (HBoV) ; feline panleukopenia vims (FPV) ; or goose parvovirus (GPV) . In one embodiment,  the VCP is from a certain AAV-serotype, such as AAV-l, AAV-2, AAV-2-AAV-3 hybrid, AAV-3a, AAV-3b, AAV-4, AAV-5, AAV-6, AAV-6.2, AAV-7, AAV-8, AAV-9, AAV-10, AAVrh. 10, AAV-11, AAV-12, AAV-13 or AAVrh32.33. In one embodiment, the VCP is from AAV-2 or a variant thereof that is capable of assembling into a VLP.
In one embodiment, Z is protein. In one embodiment, the protein is selected from the group consisting of a membrane bound protein and unbound protein. Examples of the protein include but are not limited to CEA, CA19-9, Macrophage Migration Inhibition Factor (MIF) , IL-8 (interleukin 8) , AXL, MER and c-MET.
In one embodiment, Z is biotin. In one embodiment, provided herein is a liposome comprising a compound provided herein, wherein Z is an amphiphilic substance.
The liposomes provided herein can be various types of liposomes, for example, as described in Alavi et al., Adv Pharm Bull, 2017. In one embodiment, the liposomes provided herein is a stealth liposome. Stealth liposomes are known in the art and are for example reviewed by Immordino et al., Int J Nanomedicine, 2006.
The liposome provided herein can be positively charged, negatively charged or neutral liposomes. The charge of a liposome is determined by the lipid composition and is the average of all charges of the lipids comprised in the liposome. For example, a mixture of a negatively charged phospholipid and cholesterol will yield a negatively charged liposome.
In one embodiment, lipids/phospholipids to be used in liposomes include but are not limited to glycerides, glycerophospholipides, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, phospholipids, isoprenolides, steroids, stearines, steroles and carbohydrate containing lipids.
In one embodiment, the negatively charged lipid/phospholipid is selected from the group consisting of phosphatidylserine (PS) , phosphatidylglycerol (PG) and phosphatidic acid (PA) . PS and PG are collective terms for lipids sharing a similar phosphatidylserine and phosphatidylglycerol, respectively, head group. However, many different apolar residues can be attached to these head groups. Thus, PSs and PGs isolated from different natural sources vary substantially in the length, composition and/or chemical structure of the attached apolar residues and naturally occurring PS and PG usually is a mixture of PSs and PGs with different apolar residues.
In one embodiment, the PS employed in the liposomes provided herein is selected from the group consisting of palmitoyloleoylphosphatidylserine, palmitoyllinoeoyl- phosphatidylserine, palmitoylarachidonoylphosphatidylserine, palmitoyldocosahexaenoyl-phosphatidylserine, stearoyloleoylphosphatidylserine, stearoyllinoleoylphosphatidylserine, stearoyl-arachidonoylphosphatidylserine, stearoyldocosahexaenoylphosphatidylserine, dicaprylphosphatidylserine, dilauroylphosphatidylserine, dimyristoylphosphatidylserine, diphytanoylphosphatidylserine, diheptadecanoylphosphatidylserine, dioleoylphosphatidyl-serine, dipalmitoylphosphatidylserine, distearoylphosphatidylserine, dilinoleoy-lphosphatidylserine dierucoylphosphatidylserine, didocosahexaenoyl-phospahtidylserine, PS from brain, and PS from soy bean; in one embodiment, dioleoylphosphatidylserine.
In one embodiment, the PG employed in the liposome provided herein is selected from the group consisting of palmitoyloleoylphosphatidylglycerol, palmitoyl-linoleoylphosphatidylglycerol, palmitoylarachidonoylphosphatidylglycerol, palmitoyl-docosahexaenoylphosphatidylglycerol, stearoyloleoylphosphatidylglycerol, stearoyl-linoleoylphosphatidylglycerol, stearoylarachidonoylphosphatidylglycerol, stearoyldocosa-hexaenoylphosphatidylglycerol, dicaprylphosphatidylglycerol dilauroylphosphatidylglycerol, diheptadecanoylphosphatidylglycerol, diphytanoyl-phosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, dielaidoylphosphatidyl-glycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, dilinoeoyl-phosphatidylglycerol, diarachidonoylphosphatidylglycerol, docosahexaenoylphosphatidyl-glycerol, and PG from egg; in one embodiment, dioleoylphosphatidylglycerol.
Similar to PS and PG, PE is also a generic term for lipids sharing a phosphatidylethanolamine head group. In one embodiment, the PE is selected from the group consisting of palmitoyloleoylphosphatidylethanolamine, palmitoyllinoleoylphosphatidylethanolamine, palmitoylarachidonoylphosphatidylethanolamine, palmitoyldocosahexaenoylphosphatidyl-ethanolamine, stearoyloleoylphosphatidylethanolamine, stearoyllinoleoylphosphatidyl-ethanolamine, stearoylarachidonoylphosphatidylethanolamine, stearoyldocosahexaenoyl-phosphatidylethanolamine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidyl-ethanolamine, diphytanoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, diheptadecanoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, dielaidoyl-phosphatidylethanolamine, diarachidonoylphosphatidylethanolamine, docosahexaenoyl-phosphatidylethanolamine, PE from bacteria, PE from heart, PE from brain, PE from liver, PE from egg, and PE from soybean., in one embodiment, l, 2-diacyl-sn-glycero-3-PE, l-acyl-2-acyl-sn-glycero-3-PE, 1 , 2-dipalmitoyl-PE and/or l, 2-dilauroyl-sn-glycero-3-PE (DLPE) .
The liposome provided herein can comprise at least one further component selected from the group consisting of an adjuvant, additive, and auxiliary substance. In one embodiment, adjuvants are selected from the group consisting of unmethylated DNA, such as unmethylated DNA comprising CpG dinucleotides (CpG motif) , such as CpG ODN with phosphorothioate (PTO) backbone (CpG PTO ODN) or phosphodiester (PO) backbone (CpG PO ODN) ; bacterial products from the outer membrane of Gram-negative bacteria, such as monophosphoryl lipid A (MPLA) , lipopolysaccharides (LPS) , muramyl dipeptides and derivatives thereof; synthetic lipopeptide derivatives, such as ParmCys; lipoarabinomannan; peptidoglycan; zymosan; heat shock proteins (HSP) , such as HSP 70; dsRNA and synthetic derivatives thereof, such as Poly Epoly C; polycationic peptides, such as poly-L-arginine; taxol; fibronectin; flagellin; imidazoquinoline; cytokines with adjuvant activity, such as GM-CSF, interleukin- (IL-) 2, IL-6, IL-7, IL-18, type I and II, interferons, such as interferon-gamma, TNF-alpha; 25-dihydroxyvitamin D3 (calcitriol) ; synthetic oligopeptides, such as MHCII-presented peptides; gel-like precipitates of aluminum hydroxide (alum) . In one embodiment, adjuvants, which can be comprised in the liposome provided herein are selected from the group unmethylated DNA, such as unmethylated DNA comprising CpG dinucleotides (CpG motif) , such as CpG ODN with phosphorothioate (PTO) backbone (CpG PTO ODN) or phosphodiester (PO) backbone (CpG PO ODN) , bacterial products from the outer membrane of Gram-negative bacteria, such as monophosphoryl lipid A (MPLA) and synthetic lipopeptide derivatives, such as ParmCys.
As used herein, and unless otherwise specified, the term “additive” comprises substances, which stabilize any component of the liposome or of the liquid medium like, for example, antioxidants, radical scavengers or the like. In one embodiment, stabilizers are selected from the group consisting of a-tocopherol or carbohydrates, such as glucose, sorbitol, sucrose, maltose, trehalose, lactose, cellubiose, raffmose, maltotriose, or dextran. The stabilizers can be comprised in the lipid membranes of the liposomes, the interior of the liposomes and/or within the liquid medium surrounding the liposomes.
Liposomes provided herein can have a diameter between 10 and 1000 nm. In one embodiment, they have a diameter of between 30 and 800 nm, between 40 and 500 nm, between 50 and 300 nm, or between 100 and 200 nm. The diameter of the liposomes can be affected, for example, by extrusion of the liposomal composition through sieves or meshes with a known pore size. This and further methods of controlling the size of liposomes are  known in the art and are described, for example, in Mayhew et al. (1984) Biochim. Biophys. Acta 775: 169-174 or Olson et al. (1979) Biochim. Biophys. Acta 557: 9-23.
In one embodiment, the liposome or the mixture of liposomes provided herein are comprised in a liquid medium. As used herein, and unless otherwise specified, the term “liquid medium” comprises all biocompatible, physiological acceptable liquids and liquid compositions such as FLO, aqueous salt solutions, and buffer solutions like, for example, PBS, Ringer solution and the like.
In one embodiment, the liposome is loaded with a substance selected from the group consisting of an agent and a nucleic acid.
In one embodiment, the agent that the liposome is loaded with is a cytostatic and/or cytotoxic agent provided herein. In one embodiment, the nucleic acid that the liposome is loaded with is a nucleic acid provided herein. A variety of methods are available in the art to “load” a liposome with a given therapeutic agent. In one embodiment, the therapeutic agent (s) is (are) admixed with the lipid components during formation of the liposomes. Other passive loading methods include dehydration-rehydration (Kirby & Gregoriadis (1984) Biotechnology 2: 979) , reverse-phase evaporation (Szoka & Papahadjopoulos (1978) Proc. Natl. Acad. Sci. USA 75: 4194) , or detergent-depletion (Milsmann et al. (1978) Biochim. Biophys. Acta 512: 147-155) . Other methodologies for encapsulating therapeutic agents include so called “remote loading” or “active loading” in which due to a gradient, for example, a pH or salt gradient between the exterior and the interior of a preformed liposome the therapeutic agent is transported into the liposome along the gradient (see, for example, Cheung et al. (1998) Biochim. Biophys. Acta 1414: 205-216; Cullis et al. (1991) Trends Biotechnol. 9: 268-272; Mayer et al. (1986) Chem. Phys. Lipids 40: 333-345) .
In one embodiment, the compound is a compound in Table 2, or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
Table 2.

In one embodiment, provided herein is a complex formed by a compound provided herein and a divalent or trivalent metal cation. In one embodiment, the complex is formed when Z is a chelating agent.
In one embodiment, the metal cation is a cation of Cr, Ga, In, Tc, Re, La, Yb, Sm, Ho, Y, Pm, Dy, Er, Lu, Sc, Pr, Gd, Bi, Ru, Pd, Rh, Sb, Ba, Hg, Eu, Tl, Pb, Cu, Re, Au, Ac, Th, or Ag. In one embodiment, the metal cation is a cation of Ga. In one embodiment, the metal cation is a cation of Lu.
In one embodiment, the metal cation is a cation of 51Cr, 67Ga, 68Ga, 111In, 99mTc, 186Re, 188Re, 139La, 140La, 175Yb, 153Sm, 166Ho, 88Y, 90Y, 149Pm, 165Dy, 169Er, 177Lu, 47Sc, 142Pr, 159Gd, 212Bi, 213Bi, 97Ru, 109Pd, 105Rh, 101mRh, 119Sb, 128Ba, 197Hg, 151Eu, 153Eu, 169Eu, 201Tl, 203Pb, 212Pb, 64Cu, 67Cu, 188Re, 186Re, 198Au, 225Ac, 227Th, or 199Ag. In one embodiment, the metal cation is a cation of 68Ga. In one embodiment, the metal cation is a cation of 177Lu.
In one embodiment, without being limited by a particular theory, a compound or complex provided herein exhibit suitable cellular uptake in FAP transfected cells, as well as tumor uptake in FAP-positive tumors.
PHARMACEUTICAL COMPOSITION AND METHOD OF USE
In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein or a complex provided herein and a pharmaceutically acceptable excipient.
In one embodiment, provided herein is a virus-like particle (VLP) comprising a compound provided herein, wherein Z is a viral structural protein. In one embodiment, the virus-like particle is loaded with a substance selected from the group consisting of an agent and a nucleic acid. In one embodiment, the agent that the virus-like particle is loaded with is a cytostatic and/or cytotoxic agent provided herein. In one embodiment, the nucleic acid that the virus-like particle is loaded with is a nucleic acid provided herein.
In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein, a liposome provided herein, or a virus-like particle provided herein, and a pharmaceutically acceptable excipient.
In one embodiment, provided herein is a method for the diagnosis of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a diagnostically effective amount of a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein. In one embodiment, a compound provided herein, a complex provided herein, or a  pharmaceutical composition provided herein is for use in the diagnosis of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.
In one embodiment, provided herein is a method for the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein. In one embodiment, a compound provided herein or a pharmaceutical composition provided herein is for use in the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.
In one embodiment, provided herein is a method for the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein. In one embodiment, a compound provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein is for use in the treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.
In one embodiment, the disease characterized by overexpression of fibroblast activation protein (FAP) is cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling, or keloid disorder.
In one embodiment, the disease is cancer. In one embodiment, the cancer is breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocellular carcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary) , thymus carcinoma, desmoid tumors, glioma, astrocytoma, cervix carcinoma, or prostate cancer. In one embodiment, the cancer is glioma, breast cancer, colon cancer, lung cancer, head and neck cancer, liver cancer, or pancreatic cancer. In one embodiment, the cancer is glioma. In one embodiment, the cancer is colon cancer.
In one embodiment, the disease is chronic inflammation. In one embodiment, the chronic inflammation is rheumatoid arthritis, osteoarthritis, or Crohn's disease. In one embodiment, the chronic inflammation is rheumatoid arthritis.
In one embodiment, the disease is fibrosis. In one embodiment, the fibrosis is pulmonary fibrosis, such as idiopathic pulmonary fibrosis, or liver cirrhosis.
In one embodiment, the disease is tissue remodeling. In one embodiment, the tissue remodeling occurs after myocardial infarction.
In one embodiment, the disease is a keloid disorder. In one embodiment, the keloid disorder is scar formation, keloid tumors, or keloid scar.
In one embodiment, the subject is an animal. In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.
In one embodiment, provided herein is a kit comprising a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein and instructions for the diagnosis or treatment of a disease provided herein. In one embodiment, provided herein is a kit comprising a compound provided herein, a complex provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein, and instructions for the treatment of a disease.
It is understood that any embodiment of the compounds provided herein, as set forth above, and any specific substituent and/or variable in the compounds provided herein, as set forth above, may be independently combined with other embodiments and/or substituents and/or variables of the compounds to form embodiments not specifically set forth above. In addition, in the event that a list of substituents and/or variables is listed for any particular group or variable, it is understood that each individual substituent and/or variable may be deleted from the particular embodiment and/or claim and that the remaining list of substituents and/or variables will be considered to be within the scope of embodiments provided herein.
It is understood that in the present description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.
EXAMPLES
Certain embodiments of the invention are illustrated by the following non-limiting examples.
Methods of Purification
Prep-HPLC Purification Method 1: The compound was purified on Shimadzu LC-20AP and UV detector. The column used was Shim-pack GIS C18 (250*20) mm, 10 μm. Column flow was 20 ml/min. Mobile phase were used (A) 0.1%TFA in water and (B) acetonitrile. Purification were carried out employing a linear gradient from 5%to 30%of (B) acetonitrile for 20 min. The UV spectra were recorded at 202 nm&254 nm.
Prep-HPLC Purification Method 2: The compound was purified on Shimadzu LC-20AP and UV detector. The column used was Shim-pack GIS C18 (250*20) mm, 10 μm. Column flow was 20 ml/min. Mobile phase were used (A) 0.1%NH3 in water and (B) acetonitrile. Purification were carried out employing a linear gradient from 5%to 35%of (B) acetonitrile for 20 min. The UV spectra were recorded at 202 nm&254 nm.
Methods of Preparation
Compounds provided herein may be prepared using reactions and techniques known in the art and those described herein.
Preparation of Intermediate compounds:
D1: Tert-butyl-6-hydroxyquinoline-4-carboxylate
Step 1: To a solution of D1-1 (20.00 g, 79.34 mmol) in t-BuOH (2-methylpropan-2-ol) (200 mL) was added di-tert-butyl dicarbonate (20.75 g, 95.21 mmol) and DMAP (N, N-dimethylpyridin-4-amine) (96.51 mg, 0.79 mmol) . The mixture was stirred at 30 ℃ overnight. The reaction mixture was quenched by water (100 ml) and extracted with EtOAc (ethyl acetate) (100 mL × 3) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound D1-2 (23.00 g, 74.63 mmol, yield: 94.06%) as a white solid. LC-MS (ESI) : 308 [M+H] +.
Step 2: To a solution of D1-2 (23.00 g, 74.63 mmol) in 1, 4-dioxane (230 mL) was added 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2- dioxaborolane (22.74 g, 89.56 mmol) , potassium acetate (21.97 g, 223.89 mmol) and Pd(dppf) Cl2 (6.05 g, 7.46 mmol ) at r.t., and the reaction mixture was stirred at 100 ℃ under nitrogen overnight. The resulting suspension was filtered through a celite and the filter cake was washed with EtOAc (100 mL × 3) . The combined organic layer was concentrated to give crude product, which was purified by flash chromatography to afford the compound D1-3 (25.00 g, 70.37 mol, yield: 94.30%) as white solid. LC-MS (ESI) : 356 [M+H] +.
Step 3: To a solution of D1-3 (25.00 g, 70.37 mmol) in DMSO (50 mL) and EtOH (200 mL) was added 2.0 mol/L NaOH in water (106 mL) at 0 ℃ under nitrogen. The reaction mixture was stirred at 0 ℃ for 0.5 h, then 30%H2O2 (23.93 mL, 211.11 mmol) was added dropwise at 0 ℃. The solution was stirred at r.t. for 2 h. The reaction was quenched by addition of water (100 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the title compound D1 (14.00 g, 57.08 mmol, yield: 81.11%) as a white solid. LC-MS (ESI) : 246 [M+H] +.
D2: (S) -1- (2-aminoacetyl) -4, 4-difluoropyrrolidine-2-carbonitrile
Step 1: To a stirred solution of D2-1 (19.00 g, 78.19 mmol) in DCM (150 mL) was added DAST (26.83 mL, 203.29 mmol) dropwise at 0 ℃ over a period of 30 min, and the reaction mixture was stirred at r.t. overnight. The reaction was quenched by water (500 mL) . The resulting solution was extracted with DCM (500 mL × 3) . The combined organic layer was washed with saturated sodium bicarbonate solution (800 mL) and brine (800 mL) , then dried over Na2SO4 and concentrated to afford the title compound D2-2 (12.00 g, 45.28 mmol, yield: 57.91%) as a red oil. LC-MS (ESI) : 266 [M+H] +.
Step 2: To a stirred solution of D2-2 (12.00 g, 45.28 mmol) in MeOH (60 mL) was added a solution of NH3 in methanol (300 mL, 7.0 M) dropwise at 0 ℃. The  mixture was allowed to stir at 60 ℃ for 12 h. After completion of reaction, the solvent was concentrated to give a crude, which was recrystallized from hexane: pentane (1: 1, 200 mL) to afford the title compound D2-3 (10.00 g, 40.00 mmol, yield: 88.34%) as an off-white solid. LC-MS (ESI) : 251 [M+H] +.
Step 3: To a stirred solution of D2-3 (10.00 g, 40.00 mmol) in DCM (100 mL) was added DIPEA (26.39 mL, 160.00 mmol) dropwise at 0 ℃. The reaction mixture was allowed to stir for 15 min at 0 ℃. Trifluoroacetic anhydride (11.12 mL, 80.00 mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at r.t. for 5 h. The resulting mixture was quenched by water (500 mL) , extracted with DCM (300 mL × 3) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the title compound D2-4 (6.2 g, 26.72 mmol, yield: 66.80%) as a white solid. LC-MS (ESI) : 233 [M+H] +.
Step 4: To a stirred solution of D2-4 (6.2 g, 26.72 mmol) in acetonitrile (60 mL) was added TsOH (13.79 g, 80.16 mmol) . The resulting reaction mixture was allowed to stir at r.t. for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude, which was triturated with ethyl acetate (20 mL) to afford the title compound D2-5 (4.2 g, crude) as a colorless oil. LC-MS (ESI) : 133 [M+H] +.
Step 5: To a stirred solution of (tert-butoxycarbonyl) glycine (7.01 g, 40.08 mmol) and HATU (20.31 g, 53.44 mmol) in DMF (10 mL) was added D2-5 (4.2 g, crude) and stirred for 10 min, followed by addition of DIPEA (17.63 mL, 106.88 mmol) and the reaction mixture was allowed to stir at r.t. for 16 h. The reaction mixture was quenched by cold water (500 mL) and extracted with ethyl acetate (500 mL × 3) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound D2-7 (4.80 g, 16.61 mmol, yield: two steps 62.16%) as a yellow solid. LC-MS (ESI) : 290 [M+H] +.
Step 6: To a stirred solution of D2-7 (100 mg, 0.35 mmol) in DCM (2 mL) was added TFA (0.5 mL) dropwise at 0 ℃. The mixture was allowed to stir at r.t. for 1 h. The solvent was concentrated under reduced pressure to obtain residue which was triturated with ethyl acetate (10 mL) to afford the compound D2 (80 mg, crude) as a colorless oil. LC-MS (ESI) : 190 [M+H] +.
D3: Methyl-6-hydroxyquinoline-4-carboxylate
Step 1: To a solution of D3-1 (30.00 g, 119.01 mmol) in MeOH (300 mL) was added thionyl chloride (25.90 mL, 357.04 mmol) . The mixture was stirred at 60 ℃ for 24 h and then concentrated to give a residue, to which was added DCM (300 mL) . Adjust the reaction solution to alkaline with saturated sodium bicarbonate aqueous solution, extracted with DCM (50 mL × 2) and washed with brine (300 mL) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound D3-2 (37.80 g, crude) as a white solid. LC-MS (ESI) : 266 [M+H] +.
Step 2: To a solution of D3-2 (37.8 g, crude) in 1, 4-dioxane (400 mL) was added 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (36.27 g, 142.81 mmol) , potassium acetate (34.99 g, 357.03 mmol) and Pd(dppf) Cl2 (9.67 g, 11.90 mmol) at r.t. and the reaction mixture was stirred at 100 ℃ for 16 h. The reaction mixture was quenched by water (150 mL) and extracted with EtOAc (200 mL × 2) . The organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound D3-3 (40.10 g, crude) as white solid. LC-MS (ESI) : 314 [M+H] +.
Step 3: To a solution of D3-3 (40.10 g, crude) in EtOH: DMSO = 4: 1 (400 mL) was added aq. NaOH (2 N, 179 mL) at 0 ℃ and the reaction mixture was stirred at 0 ℃ for 0.5 h, then 30%H2O2 (40.46 mL, 357.03 mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 h. Then, the reaction was quenched by addition of saturated aqueous NH4Cl and extracted with EtOAc (200 mL × 3) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound D3 (20.10 g, 98.92 mmol, yield: three steps 83.12%) as a white solid. LC-MS (ESI) m/z: 204 [M+H] +.
Example 1 (Method A) : E1: (S) -2, 2', 2” - (10- (2- (3- (2- (3- ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) (methyl) amino) azetidin-1-yl) ethyl) azetidin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
Step 1: To a solution of D3-2 (4.00 g, 15.09 mmol) in dioxane (40 mL) was added tert-butyl 3- (methylamino) azetidine-1-carboxylate (2.95 g, 15.84 mmol) , Cs2CO3 (14.76 g, 45.27 mmol) , Pd2 (dba) 3 (1.38 g, 1.51 mmol) and Xantphos (4, 5-Bis (diphenylphosphino) -9, 9-dimethylxanthene) (1.74 g, 3.02 mmol) . The reaction mixture was stirred at 100 ℃ overnight. The suspension was then filtered through a celite and the filter cake was washed with DCM (40 mL × 2) , to which was added water (20 mL) and separated. The organic layer was dried over and concentrated to give a residue, which was purified by flash chromatography to afford the compound E1-1 (4.20 g, 11.32 mmol, yield: 75.02%) as a yellow solid. LC-MS (ESI) : 372 [M+H] +.
Step 2: To a solution of E1-1 (2.00 g, 5.39 mmol) in DCM (16 mL) was added TFA (4 mL) . The reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E1-2 (2.30 g, crude) as a yellow oil. LC-MS (ESI) : 272 [M+H] +.
Step 3: To a solution of E1-2 (271.00 mg, 1.00 mmol) in DMF (N, N-Dimethylformamide) (4 mL) was added Cs2CO3 (977.46 mg, 3.00 mmol) and tert-butyl 3- (2-bromoethyl) azetidine-1-carboxylate (289.30 mg, 1.10 mmol) . The mixture was stirred at 60 ℃ overnight. The reaction mixture was quenched by water (25 ml) and extracted with EtOAc (25 mL × 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E1-3 (145.00 mg, 0.32 mmol, yield: 31.94%) as a yellow solid. LC-MS (ESI) : 455 [M+H] +.
Step 4: To a solution of E1-3 (145.00 mg, 0.32 mmol) in THF (2 mL) was added MeOH (0.50 mL) , H2O (1 mL) . Then the mixture was cooled to 0 ℃, slowly add aq. NaOH (0.48 mL, 2N) dropwise at this temperature. Then the reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E1-4 (150.00 mg, 0.34 mmol, yield: 106.25%) as a yellow solid. LC-MS (ESI) : 441 [M+H] +.
Step 5: To a solution of E1-4 (150.00 mg, 0.34 mmol) in DMF (2 mL) under nitrogen was added D2 (70.69 mg, 0.37 mmol) , HATU (258.40 mg, 0.68 mmol) and DIEA (0.28 mL, 1.70 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (15 mL) and extracted with EtOAc (15 mL × 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E1-5 (110.00 mg, 0.18 mmol, yield: 52.94%) as a yellow oil. LC-MS (ESI) : 612 [M+H] +.
Step 6: To a solution of E1-5 (110.00 mg, 0.18 mmol) in ACN (acetonitrile) (3 mL) was added TsOH (4-methylbenzenesulfonic acid) (92.88 mg, 0.54 mmol) , and the reaction mixture was stirred at 60 ℃ for 2 h. The mixture was then evaporated under reduced pressure to give crude, which was dissolved in DMF (2 mL) , followed by addition of DOTA-PNP (94.50 mg, 0.18 mmol) and DIEA (0.21 mL, 1.26 mmol) . The reaction mixture was stirred at r.t. for 2 h and concentrated to give a crude product, which was purified by prep-HPLC (Method 1) to afford the title compound E1 (30.00 mg, 0.03 mmol, yield: 18.56%) as a yellow solid. LC-MS (ESI) : 898.4 [M+H] +.
1H NMR (400 MHz, D2O) δ 8.81 –8.74 (m, 1H) , 8.12 –8.04 (m, 1H) , 7.91 (d, J = 5.2 Hz, 1H) , 7.89 –7.80 (m, 1H) , 7.17 (s, 1H) , 5.15 –5.08 (m, 1H) , 4.63 (s, 1H) , 4.42 –4.16 (m, 6H) , 4.17 –3.98 (m, 3H) , 3.86 –3.53 (m, 10H) , 3.47 –3.00 (m, 20H) , 2.95 –2.81 (m, 3H) , 2.76 –2.57 (m, 2H) , 1.93 –1.79 (m, 2H) .
Example 2 (Method B) : E2: (S) -2, 2', 2” - (10- (2- (4- ( (3- ( ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) methyl) oxetan-3-yl) methyl) piperazin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
Step 1: To a solution of D1 (1.50 g, 6.12 mmol) in DMF (N, N-Dimethylformamide) (20 mL) was added Cs2CO3 (5.99 g, 18.36 mmol) and 3, 3-bis (bromomethyl) oxetane (1.04 g, 4.28 mmol) . The mixture was stirred at 60 ℃ overnight. The reaction mixture was quenched by water (100 ml) and extracted with EtOAc (50 mL × 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E2-1 (2.20 g, 5.41 mmol, yield: 88.40%) as a yellow oil. LC-MS (ESI) : 408 [M+H] +.
Step 2: To a solution of E2-1 (2.20 g, 5.41 mmol) in DMF (25 mL) was added Cs2CO3 (5.29 g, 16.23 mmol) and tert-butyl piperazine-1-carboxylate (1.11 g, 5.95 mmol) . The reaction mixture was stirred at 60 ℃ overnight. The reaction mixture was quenched by water (150 ml) and extracted with EtOAc (100 mL × 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E2-2 (1.40 g, 2.73 mmol, yield: 50.46%) as a white solid. LC-MS (ESI) : 514 [M+H] +.
Step 3: To a solution of E2-2 (1.40 g, 2.73 mmol) in TFA (Trifluoroacetic acid) (12.60 mL) was added TfOH (Trifluoromethanesulfonic acid) (0.70 mL) , TES (Triethylsilane) (0.35 mL) and H2O (0.70 mL) . The mixture was stirred at r.t. for 2 h. The resulting mixture was evaporated under reduced pressure to give crude, which was dissolved in DCM (10 mL) , followed by addition of di-tert-butyl dicarbonate (0.81 mL, 3.55 mmol) and TEA (1.14 mL, 8.19 mmol) . The mixture was stirred at r.t. for 24 h. The reaction mixture was quenched by water (50 mL) and extracted with DCM (50 mL × 3) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E2-3 (450.00 mg, 0.98 mmol, yield: 36.07%) as a white solid. LC-MS (ESI) : 458 [M+H] +.
Step 4: To a solution of E2-3 (450.00 mg, 0.98 mmol) in DMF (5 mL) under nitrogen was added D2 (204.12 mg, 1.08 mmol) , HATU (744.80 mg, 1.96 mmol) and DIEA (0.81 mL, 4.90 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (50 mL) and extracted with EtOAc (25 mL × 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E2-4 (360.00 mg, 0.57 mmol, yield: 58.16%) as a colorless oil. LC-MS (ESI) : 629 [M+H] +.
Step 5: To a solution of E2-4 (360.00 mg, 0.57 mmol) in ACN (acetonitrile) (4 mL) was added TsOH (4-methylbenzenesulfonic acid) (294.12 mg, 1.71 mmol) , and the reaction mixture was stirred at 60 ℃ for 2 h. The mixture was then evaporated under reduced pressure to give crude, which was dissolved in DMF (3 mL) , followed by addition of DOTA-PNP (299.25 mg, 0.57 mmol) and DIEA (0.56 mL, 3.42 mmol) . The reaction mixture was stirred at r.t. for 2 h and concentrated to give a crude product, which was purified by prep-HPLC (Method 2) to afford the title compound E2 (50.00 mg, 0.05 mmol, yield: 9.60%) as a yellow solid. LC-MS (ESI) : 915.4 [M+H] +.
1H NMR (400 MHz, D2O) δ 8.72 –8.65 (m, 1H) , 7.97 –7.90 (m, 1H) , 7.66 –7.60 (m, 1H) , 7.57 –7.50 (m, 1H) , 7.48 –7.40 (m, 1H) , 5.10 –5.02 (m, 1H) , 4.69 –4.59 (m, 2H) , 4.55 (s, 2H) , 4.32 –3.98 (m, 5H) , 3.76 –3.18 (m, 23H) , 3.12 –2.75 (m, 14H) .
Example 3 (Method C) : E3: (S) -2, 2', 2” - (10- (2- (4- ( (6- ( ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) methyl) pyridin-3-yl) methyl) piperazin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
Step 1: To a solution of D1 (2.00 g, 8.16 mmol) in DMF (N, N-Dimethylformamide) (20 mL) was added K2CO3 (3.38 g, 24.48 mmol) and methyl 6- (bromomethyl) nicotinate (2.06 g, 8.98 mmol) . The mixture was stirred at 60 ℃ overnight. The reaction mixture was quenched by water (100 ml) and extracted with EtOAc (50 mL × 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E3-1 (400.00 mg, 5.41 mmol, yield: 88.40%) as a yellow oil. LC-MS (ESI) : 408 [M+H] +.
Step 2: To a solution of E3-1 (400.00 mg, 1.02 mmol) in THF: H2O: MeOH (2.80 mL: 1.40 mL: 0.70 mL) was added aq. LiOH (5.10 mL, 1N, 5.10 mmol) at 0℃, and the reaction mixture was stirred at r.t. for 2 h. Then the reaction mixture was concentrated, quenched by addition of water (15 mL) , adjust the pH to 4 with 2N aqueous hydrochloride, extracted with EtOAc (20 mL × 2) . The combined organic layer was dried and concentrated to give compound E3-2 (260.00 mg, 0.68 mmol, yield: 67.08%) as a white solid. LC-MS (ESI) : 381 [M+H] +.
Step 3: To a solution of E3-2 (260.00 mg, 0.68 mmol) in DMF (3 mL) under nitrogen was added tert-butyl 1-piperazinecarboxylate (126.48 mg, 0.68 mmol) , HATU (387.60 mg, 1.02 mmol) and DIEA (0.67 mL, 4.08 mmol) . The reaction mixture was stirred at r.t. 12 h. The resulting mixture was quenched by water (25 mL) and extracted with EtOAc (25 mL × 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E3-3 (80.00 mg, 0.15 mmol, yield: 21.34%) as a white solid. LC-MS (ESI) : 549 [M+H] +.
Step 4: To a mixture E3-3 (80.00 mg, 0.15 mmol) in anhydrous tetrahydrofuran (2 mL) was added a tetrahydrofuran solution of borane-tetrahydrofuran complex (1 M, 1.50 mL, 1.50 mmol) under nitrogen at 0 ℃. The reaction mixture was stirred at room temperature for 3 h. The mixture was quenched by MeOH (10 mL) slowly at 0 ℃. The resulting mixture was evaporated under reduced pressure to afford the compound, which was purified by flash chromatography to afford the title compound E3-4 (70.00 mg, 0.13 mmol, yield: 87.39%) as a white solid. LC-MS (ESI) : 535 [M+H] +.
Step 5: To a solution of E3-4 (70.00 mg, 0.13 mmol) in TFA (0.63 mL) was added TfOH (0.04 mL) , TES (0.02 mL) and H2O (0.04 mL) . The reaction mixture was stirred at r.t. for 2 h. The resulting mixture was evaporated under reduced pressure to give crude residue, which was dissolved in DCM (10 mL) , followed by addition of di-tert-butyl  dicarbonate (0.05 mL, 0.20 mmol) and TEA (0.05 mL, 0.39 mmol) . The mixture was stirred at r.t. for 24 h. The reaction mixture was quenched by water (10 mL) and extracted with DCM (10 mL × 3) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E3-5 (40.00 mg, 0.08 mmol, yield: 64.37%) as a colorless oil. LC-MS (ESI) : 479 [M+H] +.
Step 6: To a solution of E3-5 (40.00 mg, 0.08 mmol) in DMF (1 mL) under nitrogen was added D2 (18.14 mg, 0.10 mmol) , HATU (45.60 mg, 0.12 mmol) and DIEA (0.08 mL, 0.48 mmol) . The reaction mixture was stirred at r.t. 12 h. The resulting mixture was quenched by water (10 mL) and extracted with EtOAc (10 mL × 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E3-6 (20.00 mg, 0.03 mmol, yield: 36.83%) as a yellow solid. LC-MS (ESI) : 650 [M+H] +.
Step 7: To a solution of E3-6 (20.00 mg, 0.03 mmol) in ACN (1 mL) was added TsOH (15.48 mg, 0.09 mmol) and the reaction mixture was stirred at 60 ℃ for 2 h. The solution was evaporated under reduced pressure to give crude, which was dissolved in DMF (1 mL) , followed by addition of DOTA-PNP (15.75 mg, 0.03 mmol) and DIEA (0.03 mL, 0.18 mmol) . The reaction mixture was stirred at r.t. for 2 h. Then, the reaction mixture was concentrated to give a crude, which was purified by prep-HPLC (Method 1) to afford the title compound E3 (13.00 mg, 0.01 mmol, yield: 46.35%) as a white solid. LC-MS (ESI) : 936.4 [M+H] +.
1H NMR (400 MHz, D2O) δ 8.99 (d, J = 5.6 Hz, 1H) , 8.67 (s, 1H) , 8.21 (d, J = 9.2Hz, 1H) , 8.12 (d, J = 8.0 Hz, 1H) , 8.04 (d, J = 5.6 Hz, 1H) , 7.92 –7.87 (m, 1H) , 7.86 –7.78 (m, 2H) , 5.54 (s, 1H) , 5.19 –5.09 (m, 1H) , 4.62 –4.55 (m, 1H) , 4.47 (s, 2H) , 4.34 (d, J = 8.4 Hz, 2H) , 4.28 –4.17 (m, 1H) , 4.18 –4.04 (m, 2H) , 4.03 –3.91 (m, 2H) , 3.89 –3.58 (m, 9H) , 3.57 –3.48 (m, 2H) , 3.45 –3.23 (m, 9H) , 3.19 –2.74 (m, 11H) .
Example 4 (Method D) : E4: (S) -2, 2', 2” - (10- (2- (4- (2- (3- ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) azetidin-1-yl) ethyl) piperidin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
Step 1: To a solution of D3 (1.00 g, 4.93 mmol) in ACN (Acetonitrile) (10 mL) was added K2CO3 (2.04 g, 14.79 mmol) and tert-butyl 3-bromoazetidine-1-carboxylate (1.28 g, 5.42 mmol) . The mixture was stirred at 60 ℃ overnight. The reaction mixture was filtered with diatomite and evaporated to dryness to give a crude product, which was purified by flash chromatography to afford the compound E4-1 (623.00 mg, 1.74 mmol, yield: 35.30%) as a yellow solid. LC-MS (ESI) : 359 [M+H] +.
Step 2: To a solution of E4-1 (623.00 mg, 1.74 mmol) in DCM (4 mL) was added TFA (1 mL) . The reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E4-2 (570.00 mg, 2.21 mmol, yield: 126.97%) as a yellow oil. LC-MS (ESI) : 259 [M+H] +.
Step 3: To a solution of E4-2 (570.00 mg, 2.21 mmol) in DMF (N, N-dimethylformamide) (10 mL) was added Cs2CO3 (2.16 g, 6.63 mmol) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (707.13 mg, 2.43 mmol) . The mixture was stirred at 60 ℃ overnight. The reaction mixture was quenched by water (60 ml) and extracted with EtOAc (60 mL × 2) . The combined organic layer was dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E4-3 (400.00 mg, 0.85 mmol, yield: 38.59%) as a yellow solid. LC-MS (ESI) : 470 [M+H] +.
Step 4: To a solution of E4-3 (400.00 mg, 0.85 mmol) in THF (4 mL) was added MeOH (1 mL) , H2O (2 mL) . Then the mixture was cooled to 0 ℃, slowly add aq. NaOH (1.28 mL, 2N, 2.55 mmol) dropwise at this temperature. Then the reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E4-4 (345.00 mg, 0.76 mmol, yield: 89.20%) as a yellow solid. LC-MS (ESI) : 456 [M+H] +.
Step 5: To a solution of E4-4 (345.00 mg, 0.76 mmol) in DMF (3 mL) under nitrogen was added D2 (171.99 mg, 0.91 mmol) , HATU (433.20 mg, 1.14 mmol) and DIEA  (0.50 mL, 3.04 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (15 mL) and extracted with EtOAc (15 mL × 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E4-5 (230.00 mg, 0.37 mmol, yield: 48.34%) as a yellow solid. LC-MS (ESI) : 627 [M+H] +.
Step 6: To a solution of E4-5 (230.00 mg, 0.37 mmol) in ACN (acetonitrile) (3 mL) was added TsOH (4-methylbenzenesulfonic acid) (190.92 mg, 1.11 mmol) , and the reaction mixture was stirred at 60 ℃ for 2 h. The mixture was then evaporated under reduced pressure to give crude residue, which was dissolved in DMF (2 mL) , followed by addition of DOTA-PNP (194.25 mg, 0.37 mmol) and DIEA (0.37 mL, 2.22 mmol) . The reaction mixture was stirred at r.t. for 2 h and concentrated to give a crude product, which was purified by prep-HPLC (Method 1) to afford the title compound E4 (15.00 mg, 0.02 mmol, yield: 4.44%) as a yellow solid. LC-MS (ESI) : 913.4 [M+H] +.
1H NMR (400 MHz, D2O) δ 8.98 –8.92 (m, 1H) , 8.19 –8.11 (m, 1H) , 8.02 –7.96 (m, 1H) , 7.82 –7.71 (m, 1H) , 7.59 –7.47 (m, 1H) , 5.36 –5.26 (m, 1H) , 5.11 –5.04 (m, 1H) , 4.93 –4.80 (m, 1H) , 4.61 –4.47 (m, 1H) , 4.44 –4.33 (m, 1H) , 4.32 –4.23 (m, 2H) , 4.23 –4.11 (m, 1H) , 4.09 –3.69 (m, 1H) , 3.62 –3.17 (m, 15H) , 3.10 –2.75 (m, 11H) , 2.67 –2.54 (m, 1H) , 1.72 –1.37 (m, 5H) , 1.11 –1.00 (m, 2H) .
Example 5 (Method E) : E5: (S) -2, 2', 2” - (10- (2- (4- ( (6- ( ( (4- ( (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) methyl) spiro [3.3] heptan-2-yl) methyl) piperazin-1-yl) -2-oxoethyl) -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl) triacetic acid
Step 1: To a solution of E5-1 (2.00 g, 10.87 mmol) in MeOH (30 mL) was added SOCl2 (2.37 mL, 32.61 mmol) at 0 ℃. Then the mixture was stirred at r.t. overnight.  The reaction mixture was concentrated to afford the compound d E5-2 (2.10 g, crude) as a brown solid. LC-MS (ESI) : 213 [M+H] +.
Step 2: To a solution of E5-2 (2.10 g, crude) in THF (12 mL) was added MeOH (3 mL) , H2O (6 mL) . Then the mixture was cooled to 0 ℃, slowly add aq. NaOH (16.31 mL, 2N, 32.61 mmol) dropwise at this temperature. Then the reaction mixture was stirred at r.t. for 2 h. The resulting mixture was concentrated to afford the compound E5-3 (1.30 g, 6.57 mmol, yield: two steps 60.44%) as a yellow solid. LC-MS (ESI) : 199 [M+H] +.
Step 3: To a solution of E5-3 (1.30 g, 6.57 mmol) in DMF (13 mL) under nitrogen was added tert-butyl piperazine-1-carboxylate (1.47 g, 7.88 mmol) , HATU (3.75 g, 9.86 mmol) and DIEA (6.50 mL, 39.42 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (80 mL) and extracted with EtOAc (80 mL × 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E5-4 (1.40 g, 3.83 mmol, yield: 57.59%) as a yellow solid. LC-MS (ESI) : 367 [M+H] +.
Step 4: To a solution of E5-4 (1.40 g, 3.83 mmol) in THF (20 mL) under nitrogen was added LiAlH4 (436.62 mg, 11.49 mmol) at 0 ℃. The reaction mixture was stirred at r.t. for 2 h. The resulting mixture was quenched by Sodium sulfate decahydrate. The suspension was then filtered through a celite and the filter cake was washed with DCM (40 mL × 2) , to which was added water (20 mL) and separated. The organic layer was dried over and concentrated to give a residue, which was purified by flash chromatography to afford the compound E5-5 (830.00 mg, 2.56 mmol, yield: 66.89%) as a yellow oil. LC-MS (ESI) : 325 [M+H] +.
Step 5: To a solution of E5-5 (830.00 mg, 2.56 mmol) in DCM (10 mL) was added triethylamine (1.42 mL, 10.24 mmol) . Then the mixture was cooled to 0 ℃, slowly add MsCl (0.39 mL, 5.12 mmol) dropwise at this temperature. Then the mixture was stirred at r.t. for 2 h. The reaction mixture was quenched by water (30 mL) and extracted with DCM (30 mL × 2) . The combined organic layer was dried and concentrated to afford the compound d E5-6 (830.00 mg, crude) as a yellow oil. LC-MS (ESI) : 403 [M+H] +.
Step 6: To a solution of E5-6 (830 mg, crude) in DMF (N, N-Dimethylformamide) (10 mL) was added K2CO3 (1.06 g, 7.68 mmol) and D1 (627.20 mg, 2.56 mmol) . The mixture was stirred at 60 ℃ overnight. The reaction mixture was quenched by water (100 ml) and extracted with EtOAc (50 mL × 2) . The combined organic layer was  dried and concentrated to give a crude product, which was purified by flash chromatography to afford the compound E5-7 (340.00 mg, 0.62 mmol, yield: two steps 29.95%) as a yellow solid. LC-MS (ESI) : 552 [M+H] +.
Step 7: To a solution of E5-7 (340.00 mg, 0.62 mmol) in TFA (3.06 mL) was added TfOH (0.17 mL) , TES (0.09 mL) and H2O (0.17 mL) . The reaction mixture was stirred at r.t. for 2 h. The mixture was sedimentation with Diethyl ether. The solid obtained by filtration to give crude, which was dissolved in DCM (5 mL) , followed by addition of di-tert-butyl dicarbonate (0.21 mL, 0.93 mmol) and TEA (0.26 mL, 1.86 mmol) . The mixture was stirred at r.t. overnight. The reaction mixture was quenched by water (10 mL) and extracted with DCM (10 mL × 3) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E5-8 (88.00 mg, 0.18 mmol, yield: 28.67%) as a colorless oil. LC-MS (ESI) : 496 [M+H] +.
Step 8: To a solution of E5-8 (88 mg, 0.18 mmol) in DMF (2 mL) under nitrogen was added D2 (41.58 mg, 0.22 mmol) , HATU (102.60 mg, 0.27 mmol) and DIEA (0.09 mL, 0.54 mmol) . The reaction mixture was stirred at r.t. overnight. The resulting mixture was quenched by water (15 mL) and extracted with EtOAc (15 mL × 2) . The combined organic layer was dried and concentrated to give a residue, which was purified by flash chromatography to afford the compound E5-9 (35.00 mg, 0.05 mmol, yield: 29.20%) as a yellow solid. LC-MS (ESI) : 667 [M+H] +.
Step 9: To a solution of E5-9 (35.00 mg, 0.05 mmol) in ACN (acetonitrile) (3 mL) was added TsOH (4-methylbenzenesulfonic acid) (25.80 mg, 0.15 mmol) , and the reaction mixture was stirred at 60 ℃ for 2 h. The mixture was then evaporated under reduced pressure to give crude, which was dissolved in DMF (2 mL) , followed by addition of DOTA-PNP (26.25 mg, 0.05 mmol) and DIEA (0.07 mL, 0.40 mmol) . The reaction mixture was stirred at r.t. for 2 h and concentrated to give a crude product, which was purified by prep-HPLC (Method 2) to afford the title compound E5 (7.00 mg, 0.01 mmol, yield: 14.69%) as a yellow solid. LC-MS (ESI) : 953.5 [M+H] +.
1H NMR (400 MHz, D2O) δ 8.65 –8.56 (m, 1H) , 7.79 (d, J = 9.6 Hz, 1H) , 7.49 –7.45 (m, 1H) , 7.41 (s, 1H) , 7.28 (d, J = 9.2 Hz, 1H) , 5.12 –5.02 (m, 1H) , 4.28 –4.15 (m, 3H) , 4.13 –3.92 (m, 4H) , 3.80 –3.57 (m, 7H) , 3.49 –3.04 (m, 20H) , 2.98 –2.83 (m, 4H) , 2.70 –2.44 (m, 4H) , 2.27 –1.97 (m, 6H) , 1.87 –1.68 (m, 4H) .
The following compounds were prepared using procedures analogous to those described in Examples above. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions. In the table, the M1 (Synthetic Method) and M2 (Purification Method) columns indicate preparatory methods and purification methods described above used in the preparation of the compounds.


Radiochemistry
177Lu label: 177Lu-cpmd was prepared in sodium acetate buffer (1M, pH 4.75) after incubation of 30μg of precursor with 5mCi 177LuCl3 (ITG) at 70℃ for 30 min. Quality control was performed by iTLC (Eckert&Ziegler) . The hot compound was diluted with 0.9%NaCl solution for further utility.
68Ga label: 68GaCl3 solution (1.0 mL, 370 MBq) , was eluted from the 68Ge/68Ga generator (Isotope Technologies Garching) with 0.05M HCl. 68Ga-cpmd was prepared in sodium acetate buffer (1M, pH 4.2) after incubation of 20μg of precursor with 20mCi 68GaCl3 at 95℃ for 20 min. Quality standard: RCP>98% (iTLC) , specific activity >0.75mCi/ug, and activity >1mCi/ml.
Biological Assays and Data
The biological activities of the compounds provided herein can be determined by using any suitable assay for determining the in vitro binding affinity of a compound as a FAP or PREP competitive inhibitor.
The cell-based assay is conducted to determine the cell internalization capability of a compound over time, including the efflux property.
The biological activity data for each compound was either reported in at least one experiment or the average of multiple experiments. It is understood that the data described herein may have reasonable variations depending on the specific conditions and procedures used by the person conducting the experiments.
FAP and PREP enzymatic assay
Recombinant FAP (SinoBio, Cat. #10464-H07H ) , was diluted in FAP enzymatic buffer (50mM Tris pH7.5, 140mM NaCl) into 1ng/ul. Compounds were diluted with the same buffer into varying concentrations. Z-GP-AMC (Biochem partner, Cat#. 68542-93-8) was regenerated into 8.3mM/mL with FAP enzymatic buffer. 50μl of compound and 20μl of diluted FAP were mixed and incubated at RT for 15 min, followed with addition of 30μl of diluted Z-GPAMC. The mixture was incubated at 37℃ for 30minutes. Reaction was terminated with glacial acid. The released AMC was detected with flurorescence reader (Perkin Elmer Victor Nivo Plate reader) with excitation and emission wavelength at 360nm and 460nm, respectively.
For PREP enzymatic assay, PREP (R&D System, Cat. #4308-SE) , cmpd and Z-GP-AMC were diluted with PREP enzymatic buffer (100mM Tris pH7.5, 1mM EDTA, 3mM DTT) . The procedure remained the same as FAP enzymatic assay.
Curve fitting, IC50 calculation and QC analysis was conducted by Prism 6.0.

Cell based assay
Cell uptake: HEK-FAP cells were cultured in 24-well plates. 20nCi of 177Lu-labeled compound was added into each well, and then incubated in 37℃, 5%CO2 incubator for varying durations. At each time point, the supernatant, cell membrane fraction and intracellular fraction were collected. The cell membrane fraction was recovered by incubating cells with buffer containing 50mM glycine and 100mM NaCl, pH 2.7 for 10minutes at 37℃, 5%CO2, while the intracellular fraction was collected by harvesting the cell pellets following trypsin digestion. 177Lu-compound in each component was detected by gamma counter.
Efflux: 20nCi of 177Lu-labeled compound was incubated with cells for 2 hours, and then cells was washed and replaced with fresh medium. At each time point, the supernatant, cell membrane fraction and intracellular fraction were collected. The cell membrane fraction was recovered by incubating cells with buffer containing 50mM glycine and 100mM NaCl, pH 2.7 for 10minutes at 37℃, 5%CO2, while the intracellular fraction was collected by harvesting the cell pellets following trypsin digestion. 177Lu-compound in each component was detected by gamma counter.

*The percentage of intracellular fraction is presented.
**The cells were washed and replaced with fresh medium after 2-hour incubation with 177Lu labeled compounds.
***Reference compound from WO2019154886A1
Compare to literature compound FAPI-04 (WO2019154886A1) some of the presented examples demonstrated improved cell internalization capability and lower efflux profile in the assay.
The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.
Reference
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Claims (68)

  1. A compound of Formula (I) :
    or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein:
    each of Q1 to Q7 is independently absent, O, C (R5) 2, NR5, C=O, C=S, or 3-to 10-membered N-containing heterocyclyl, provided that (i) two O are not directly adjacent to each other, and (ii) at least three of Q1 to Q7 are present;
    Ring C is 1-naphthyl, 5-to 10-membered N-containing heteroaryl, or 5-to 10-membered N-containing heterocyclyl;
    each instance of R2, R3, or R4 is independently -OH, halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , -N (R5) 2, or -S- (C1-C6 alkyl) , each of said C1-C6 alkyl being independently and optionally substituted with one or more substituents independently selected from -OH, oxo, and halo;
    X1 is O, NR5, S, C=O, C=S, - (C=O) -NR5-*, - (C=S) -NR5-*, -O-aryl-*, -NR5-aryl-*, - (C=O) -NR5-aryl-*, - (C=S) -NR5-aryl-*, wherein *refers to the direction toward Ring C;
    G1 is absent, C1-C5 alkylene, or C2-C5 alkynylene, wherein said C1-C5 alkylene and C2-C5 alkynylene are optionally substituted with one or more substituents independently selected from -OH, oxo, halo, C1-C3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
    each instance of X is independently absent, O, NR5, C=O, C=S, - (C=O) -NR5-*, -NR5- (C=O) -*, - (C=S) -NR5-*, or -NR5- (C=S) -*, wherein *refers to the direction toward Ring C;
    each instance of G is independently C1-C5 alkylene or C2-C5 alkynylene, wherein said C1-C5 alkylene and C2-C5 alkynylene are optionally substituted with one or more substituents independently selected from -OH, oxo, halo, C1-C3 alkyl optionally substituted with one or more halo, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
    each instance of Ring B is C3-C10 cycloalkyl, C6-C10 aryl, 5-to 10-membered heteroaryl, or 3-to 10-membered heterocyclyl;
    X2 is absent, O, NR5, C=O, C=S, - (C=O) -NR5-*, -NR5- (C=O) -*, - (C=S) -NR5-*, or -NR5- (C=S) -*, wherein *refers to the direction toward Ring C;
    L is absent or a linker;
    Ring A is 5 to 10-membered N-containing heteroaryl or 5 to 10-membered N-containing heterocyclyl;
    n is 0, 1, 2, or 3;
    m is 0, 1, 2, or 3;
    p is 0, 1, 2, or 3;
    s is 1, 2, or 3;
    each instance of R5 is independently -H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from -OH, oxo, and halo; and
    Z is a radioactive moiety, a chelating agent, a fluorescent dye, or a contrast agent.
  2. The compound of claim 1, wherein Q1, Q2, and Q3 are each independently absent or CH2; Q4 is CH2, C=O, or C=S; Q5 is NR5; Q6 is CHR5; and Q7 is C=O, or C=S.
  3. The compound of claim 2, wherein -Q1-Q2-Q3-Q4-Q5-Q6-Q7-is - (C=O) -NH-CH2- (C=O) -.
  4. The compound of claim 1, wherein Q1, Q2, Q3, and Q4 are each independently absent or CH2; Q5 is 5-to 6-membered N-containing heterocyclyl; Q6 is CHR5; and Q7 is C=O or C=S.
  5. The compound of claim 4, wherein Q1 is O or NR5 , and -Q2-Q3-Q4-Q5-Q6-Q7-is wherein *refers to the direction toward Ring C.
  6. The compound of any one of claims 1 to 5, wherein Ring C is 5 to 10-membered N-containing heteroaryl.
  7. The compound of any one of claims 1 to 5, wherein Ring C is
  8. The compound of claim 7, wherein Ring C iswherein the shown point of attachment is toward Q1.
  9. The compound of any one of claims 1 to 8, wherein X1 is O, NR5, or - (C=O) NR5-*.
  10. The compound of any one of claims 1 to 9, wherein G1 is absent or C1 alkylene.
  11. The compound of any one of claims 1 to 10, wherein s is 1.
  12. The compound of any one of claims 1 to 11, wherein X2 is absent, O, or NH.
  13. The compound of any one of claims 1 to 12, wherein each instance of X is independently absent.
  14. The compound of any one of claims 1 to 13, wherein each instance of G is independently C1-C3 alkylene.
  15. The compound of any one of claims 1 to 8, wherein -X2- [G-X- (Ring B) -X] s-G1-X1-is -G- (Ring B) -G1-X1-, wherein G is C1-C2 alkylene, G1 is C1-C2 alkylene, and X1 is O, NR5, or - (C=O) NR5-*.
  16. The compound of any one of claims 1 to 8, wherein -X2- [G-X- (Ring B) -X] s-G1-X1-is -G- (Ring B) -X1-, wherein G is C1-C2 alkylene, and X1 is O, NR5, or - (C=O) NR5-*.
  17. The compound of any one of claims 1 to 8, wherein -X2- [G-X- (Ring B) -X] s-G1-X1-is -G-X- (Ring B) -X1-, wherein G is C1-C2 alkylene, X is C=O, and X1 is O, NR5, or - (C=O) NR5-*.
  18. The compound of any one of claims 1 to 17, wherein L is absent.
  19. The compound of any one of claims 1 to 17, wherein L is a linker.
  20. The compound of claim 19, wherein the linker is a peptide comprising 2 to 5 amino acids.
  21. The compound of any one of claims 1 to 20, which is a compound of Formula (II-A) :
    or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  22. The compound of claim 21, which is a compound of Formula (III-A) :
    or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  23. The compound of claim 21, which is a compound of Formula (IV-A) :
    or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  24. The compound of any one of claims 1 to 20, which is a compound of Formula (II-B) :
    or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  25. The compound of claim 24, which is a compound of Formula (III-B) :
    or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  26. The compound of claim 25, which is a compound of Formula (IV-B) :
    or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  27. The compound of any one of claims 1 to 26, wherein Ring B is C3-C10 cycloalkyl.
  28. The compound of claim 27, wherein the cycloalkyl is a monocyclic cycloalkyl, a bridged cycloalkyl, or a spiro cycloalkyl.
  29. The compound of claim 28, wherein the cycloalkyl is
  30. The compound of any one of claims 1 to 26, wherein Ring B is C6-C10 aryl.
  31. The compound of claim 30, wherein the aryl is
  32. The compound of any one of claims 1 to 26, wherein Ring B is 5 to 10-membered heteroaryl.
  33. The compound of claim 32, wherein the heteroaryl is
  34. The compound of any one of claims 1 to 26, wherein Ring B is 5 to 10-membered heterocyclyl.
  35. The compound of claim 34, wherein the heterocyclyl is
  36. The compound of any one of claims 1 to 35, wherein Ring A is 5 to 10-membered N-containing heterocyclyl.
  37. The compound of claim 36, wherein the heterocyclyl is a monocyclic heterocyclyl.
  38. The compound of claim 37, wherein the heterocyclyl is
  39. The compound of claim 36, wherein the heterocyclyl is a bridged heterocyclyl, a spiro heterocyclyl, or a fused heterocyclyl.
  40. The compound of claim 39, wherein the heterocyclyl is
  41. The compound of any one of claims 1 to 40, wherein n is 1.
  42. The compound of any one of claims 1 to 41, wherein each instance of R2 is independently halo, C1-C6 alkyl, -O- (C1-C6 alkyl) , or -N (R5) 2.
  43. The compound of any one of claims 1 to 40, wherein n is 0.
  44. The compound of any one of claims 1 to 43, wherein m is 0.
  45. The compound of any one of claims 1 to 44, wherein p is 0.
  46. The compound of any one of claims 1 to 45, whereinis
  47. The compound of any one of claims 1 to 46, wherein Z is a radioactive moiety.
  48. The compound of claim 47, wherein the radioactive moiety is a fluorescent isotope, a radioisotope, or a radioactive drug.
  49. The compound of claim 47, wherein the radioactive moiety is selected from the group consisting of alpha radiation emitting isotopes, beta radiation emitting isotopes, gamma radiation emitting isotopes, Auger electron emitting isotopes, X-ray emitting isotopes, and fluorescence emitting isotopes.
  50. The compound of claim 47, wherein the radioactive moiety is 177Lu-DOTA, 177Lu-DOTAGA, 68Ga-DOTA, 90Y-DOTA, Al18F-NOTA. 203Pb-TCMC, 212Pb-TCMC, 64Cu-DOTA, or 225Ac-DOTA.
  51. The compound of claim 47, wherein the radioactive moiety is 11C, 18F, 72As, 72Se, 123I, 124I, 131I, or 211At.
  52. The compound of any one of claims 1 to 46, wherein Z is a fluorescent dye.
  53. The compound of claim 52, wherein the fluorescent dye is an Xanthene, an Acridine, an Oxazine, an Cyanine, a Styryl dye, a Coumarin, a Porphine, a Metal-Ligand-Complex, a Fluorescent protein, a Nanocrystals, a Perylene, a Boron-dipyrromethene, or a Phthalocyanine, or a conjugate or combination thereof.
  54. The compound of any one of claims 1 to 46, wherein Z is a chelating agent.
  55. The compound of claim 54, wherein the chelating agent is a chelating agent that forms a complex with a divalent or trivalent metal cation.
  56. The compound of claim 54, wherein the chelating agent is 1, 4, 7, 10-tetraazacyclododecane-N, N', N, N'-tetra acetic acid (DOTA) , ethylenediaminetetraacetic acid (EDTA) , 1, 4, 7-triazacyclononane-l, 4, 7-triacetic acid (NOTA) , 1, 4, 7, 10-tetraazacyclododecane-1- (glutaric acid) -4, 7, 10-triacetic acid (DOTAGA) , 2- [4, 7, 10-tris (2-amino-2-oxoethyl) -1, 4, 7, 10-tetrazacyclododec-1-yl] acetamide (TCMC) , triethylenetetramine (TETA) , iminodiacetic acid, diethylenetriamine-N, N, N', N', N"-penta acetic acid (DTPA) , bis- (carboxymethyl imidazole) glycine, or 6-hydrazinopyridine-3-carboxylic acid (HYNIC) .
  57. The compound of claim 54, wherein the chelating agent is a chelating agent in Table 1.
  58. The compound of any one of claims 1 to 46, wherein Z is a contrast agent.
  59. The compound of claim 58, wherein the contrast agent comprises a paramagnetic agent.
  60. A compound in Table 2, or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  61. A complex formed by a compound of any one of claims 1 to 60 and a divalent or trivalent metal cation.
  62. The complex of claim 61, wherein the metal cation is a cation of Cr, Ga, In, Tc, Re, La, Yb, Sm, Ho, Y, Pm, Dy, Er, Lu, Sc, Pr, Gd, Bi, Ru, Pd, Rh, Sb, Ba, Hg, Eu, Tl, Pb, Cu, Re, Au, Ac, Th, or Ag.
  63. The complex of claim 61, wherein the metal cation is a cation of 51Cr, 67Ga, 68Ga, 111In, 99mTc, 186Re, 188Re, 139La, 140La, 175Yb, 153Sm, 166Ho, 88Y, 90Y, 149Pm, 165Dy, 169Er, 177Lu, 47Sc, 142Pr, 159Gd, 212Bi, 213Bi, 97Ru, 109Pd, 105Rh, 101mRh, 119Sb, 128Ba, 197Hg, 151Eu, 153Eu, 169Eu, 201Tl, 203Pb, 212Pb, 64Cu, 67Cu, 188Re, 186Re, 198Au, 225Ac, 227Th, or 199Ag.
  64. A pharmaceutical composition comprising a compound of any one of claims 1 to 60 or a complex of any one of claims 61 to 63, and a pharmaceutically acceptable excipient.
  65. A method for the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, comprising administering to the subject a diagnostically or therapeutically effective amount of a compound of any one of claims 1 to 60, a complex of any one of claims 61 to 63, or a pharmaceutical composition of claim 64.
  66. The method of claim 65, wherein the disease is cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling, or keloid disorder.
  67. The method of claim 66, wherein the disease is cancer, and the cancer is breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocellular carcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (carcinoma of unknown primary) , thymus carcinoma, desmoid tumors, glioma, astrocytoma, cervix carcinoma, or prostate cancer.
  68. A kit comprising a compound of any one of claims 1 to 60, a complex of any one of claims 61 to 63, or a pharmaceutical composition of claim 64, and instructions for the diagnosis or treatment of a disease.
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