WO2024078592A1 - 靶向成纤维细胞活化蛋白的药物及其应用 - Google Patents

靶向成纤维细胞活化蛋白的药物及其应用 Download PDF

Info

Publication number
WO2024078592A1
WO2024078592A1 PCT/CN2023/124323 CN2023124323W WO2024078592A1 WO 2024078592 A1 WO2024078592 A1 WO 2024078592A1 CN 2023124323 W CN2023124323 W CN 2023124323W WO 2024078592 A1 WO2024078592 A1 WO 2024078592A1
Authority
WO
WIPO (PCT)
Prior art keywords
nrc
cancer
compound
substituted
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2023/124323
Other languages
English (en)
French (fr)
Inventor
颜成龙
方鹏
虞善友
伍维思
杨思
于德峰
Original Assignee
无锡诺宇医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 无锡诺宇医药科技有限公司 filed Critical 无锡诺宇医药科技有限公司
Publication of WO2024078592A1 publication Critical patent/WO2024078592A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins

Definitions

  • the present invention relates to the field of biomedicine, and in particular to a drug targeting fibroblast activation protein and an application thereof.
  • Fibroblast activation protein (FAP, also known as fibroblast activation protein ⁇ , FAP ⁇ ) is highly overexpressed on cancer-associated fibroblasts (CAFs) in solid tumors, but is generally not expressed in normal tissues and benign tumors.
  • CAFs cancer-associated fibroblasts
  • Tumor stroma CAFs can promote the growth and infiltration of tumor cells and have become an important target for tumor intervention.
  • Overexpression of the tumor biomarker molecule FAP is a significant feature of CAFs.
  • FAP is a potential target for CAF targeting for tumor diagnosis and treatment.
  • FAP is a type II transmembrane serine protease on tumor fibroblasts. It exists on the cell surface in the form of homodimers and belongs to the proline oligopeptidase family. Its enzymatic activity plays an important role in tumor growth and tissue remodeling.
  • CAF surface-specific FAP can promote tumor progression by promoting matrix reconstruction, participating in signal transduction pathways such as VEGF/AKT/ERK to enhance the ability of tumor cells to invade along fibers, participating in tumor angiogenesis, etc. to form a tumor biological barrier and inhibit the function of effector T cells.
  • the induced high expression of FAP in the tumor stroma also depends on the malignant transformation of tumor tissue. The high expression of FAP is positively correlated with the poor prognosis of tumors.
  • Non-inhibitory FAP monoclonal antibodies themselves have no tumor therapeutic effect, and ADCs with antibodies as carriers are not conducive to clinical development due to their poor permeability, long half-life, long non-target organ uptake and retention time, and greater toxicity.
  • Small molecule FAP selective (targeted) inhibitors that have undergone structural modification and optimized screening have great advantages and development value for the diagnosis and treatment of cancer.
  • the present invention aims to solve one of the technical problems in the related art at least to a certain extent.
  • one object of the present invention is to propose some compounds that have the ability to bind to fibroblast activation protein- ⁇ (FAP), which have good clinical application prospects.
  • FAP fibroblast activation protein- ⁇
  • the compounds of the present invention have better pharmacodynamic activity.
  • the compounds provided by the present invention also have excellent physicochemical properties and pharmacokinetic properties, and have lower toxic and side effects.
  • Fibroblast activation protein-alpha is a type II transmembrane serine protease of the prolyl oligopeptidase family, characterized by its ability to cleave the Pro-AA peptide bond (wherein AA represents any amino acid). It has been shown to play a role in cancer by modifying multiple biologically active signal peptides through the enzymatic activity (Kelly et al., 2005; Edosada et al., 2006).
  • Fibroblast activation protein-alpha expression has been detected on the surface of multiple fibroblasts in the stroma surrounding more than 90% of the multiple epithelial cancers, including but not limited to: malignant breast cancer, colorectal cancer, skin cancer, prostate cancer, pancreatic cancer, etc., and inflammation, including but not limited to: arthritis, fibrosis, etc., while there is almost no expression in multiple healthy tissues. Therefore, treatment and imaging specifically targeting fibroblast activation protein-alpha are of clinical importance.
  • the present invention provides a class of compounds that bind to fibroblast activation protein- ⁇ (FAP), which can be used to prepare drugs for diagnosing and/or treating and/or preventing diseases that express fibroblast activation protein, such as fibrosarcoma, osteosarcoma and other sarcoma malignant tumors, pancreatic cancer, ovarian cancer, melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, and neuroendocrine tumors.
  • FAP fibroblast activation protein- ⁇
  • the present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds or compositions to treat the above diseases in mammals, especially humans.
  • the compound of the present invention can be well combined with fibroblast activation protein- ⁇ , and thus has better efficacy, pharmacokinetic properties and/or toxicological characteristics, such as good bioavailability, low toxic side effects and high safety.
  • the compound or pharmaceutical composition of the present invention can be well combined with fibroblast activation protein- ⁇ , and can be used for diagnosing and/or treating and/or preventing diseases related to the expression of fibroblast activation protein.
  • the present invention provides a compound, which is a compound represented by formula (X) or a stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (X),
  • Y is selected from a ligand that binds to fibroblast activation protein- ⁇ ;
  • L is selected from a linker
  • At least one of X and Z is present, X and Z are independently selected from albumin-binding ligands, cytotoxic drugs or chelating agents, and at least one of X and Z is a cytotoxic drug or a chelating agent.
  • X and Z are different.
  • Y has a structure represented by formula (I'), a stereoisomer of the structure represented by formula (I'), or a pharmaceutically acceptable salt thereof.
  • each y is independently selected from 0, 1 or 2;
  • R 1x , R 2x and R 3x' are each independently selected from H, -OH, halogen, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • connection point in It represents the connection point between the ligand binding to fibroblast activation protein- ⁇ and the linker, wherein the connection point can be connected to the linker through any one of the 5th, 6th, 7th or 8th carbon atoms of the quinoline ring of the fibroblast activation protein- ⁇ binding ligand.
  • the Y structure is selected from the following:
  • the Y structure is selected from the following:
  • Y has a structure represented by formula (I), a stereoisomer of the structure represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • each y is independently selected from 0, 1 or 2;
  • R 1x , R 2x and R 3x' are each independently selected from H, -OH, halogen, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • connection point in It represents the connection point between the ligand binding to fibroblast activation protein- ⁇ and the linker, wherein the connection point can be connected to the linker through any one of the 5th, 6th, 7th or 8th carbon atoms of the quinoline ring of the fibroblast activation protein- ⁇ binding ligand.
  • the Y structure is selected from the following:
  • the Y structure is selected from the following:
  • L is selected from one or more of (a), (b) and (c),
  • V 1 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 1 is at least one selected from -NR-, -RC( ⁇ O)-, -NRC(S)NR′-, -NRC(O)O-, -C(O)NR-, or -NR-C(O)-;
  • n 1 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • V2 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • n2 and m3 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • V3 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • n4 and m5 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R, R' and R" in formula (a), (b) or (c) are independently selected from H, alkyl, substituted alkyl, cyclo at least one of alkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the remaining variables are as defined in the present invention.
  • L is selected from one or more of (a-1), (a-2), (b) and (c),
  • V 1 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 1 is at least one selected from -NR-, -RC(O)-, -RCH 2 C(O)-, -NRC(S)NR'-, -NRC(O)O-, -C(O)NR- or -NR-C(O)-;
  • n 1 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • V 1 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 4 is at least one selected from -NR-, -R-, -RC(O)-, -C(O)NR- or -NR-C(O)-;
  • M is at least one selected from -NR-, -O-, -OC(O)-, -C(O)NR-, -C(O)-, or -RC(O)-;
  • n6 and m7 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • V2 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 2 is at least one selected from -NR-, -RC(O)-, -RCH 2 C(O)-, -NRC(S)NR'-, -NRC(O)O-, -C(O)NR- or -NR-C(O)-;
  • n2 and m3 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • V3 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 3 is at least one selected from -R-, -NR-, -RC(O)-, -RCH 2 C(O)-, -NRC(S)NR'-, -NRC(O)O-, -C(O)NR- or -NR-C(O)-;
  • n4 and m5 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R, R' and R" in formula (a-1), (a-2), (b) or (c) are independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the remaining variables are as defined in the present invention.
  • R, R' and R" are independently selected from at least one of H, C1-6 alkyl, substituted C1-6 alkyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, piperazine, lactone, cyclic anhydride, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, dihydroindole, quinuclidine, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydrofuranyl, substituted heterocycloalkyl, phenyl, naphthyl, substituted aryl, pyrimidine, pyridine, pyrazine, furan, thiophene or substituted heteroaryl, and the remaining variables are as defined in the present invention.
  • R, R' and R" are independently selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, The remaining variables are as defined in the present invention.
  • L has one of the following structures: the remaining The variables are as defined herein.
  • L has one of the following structures: The remaining variables are as defined in the present invention.
  • the albumin-binding ligand has one of the following structures:
  • the cytotoxic drug is selected from camptothecins or their derivatives, tubulin inhibitors or their derivatives, RNA or DNA synthesis inhibitors or their derivatives.
  • camptothecins or their derivatives include irinotecan, SN38, and DXd;
  • the tubulin inhibitors or their derivatives include maytansinoids, auristatins and their derivatives, especially DM1 and MMAE;
  • the RNA or DNA synthesis inhibitors or their derivatives include doxorubicin and its derivatives, and the remaining variables are as defined in the present invention.
  • the cytotoxic drug is selected from one of the following structures and derivatives thereof: The remaining variables are as defined in the present invention.
  • the cytotoxic drug is derived from one of the following structures or a derivative of one of the following structures: The remaining variables are as defined in the present invention.
  • the derivatives include but are not limited to amino derivatives, sulfide derivatives, nitrogen derivatives Derivatives, carbonyl derivatives, alkyl derivatives.
  • the chelating agent is derived from 1,4,7,10-tetraazacyclododecane-N,N ⁇ ,N ⁇ ,N ⁇ ,-tetraacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazononan-1-yl)pentanedioic acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid, 1,4,7-triazacyclononane phosphinic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-carboxymethyl)phosphinic acid], N'- ⁇ 5-[acetyl(hydroxy)amino]- [0063]
  • the invention is derived from 1,4,
  • the above-mentioned compound The structure is selected from one of the following (a), (b) and (c):
  • V 1 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 1 is at least one selected from -NR-, -RC( ⁇ O)-, -NRC(S)NR′-, -NRC(O)O-, -C(O)NR-, or -NR-C(O)-;
  • n 1 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Z is a cytotoxic drug
  • V2 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • n2 and m3 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • Z is a cytotoxic drug
  • X is a ligand that binds to albumin
  • V3 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • n4 and m5 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • Z and X are independently selected from albumin-binding ligands, cytotoxic drugs or chelating agents;
  • R, R' and R" in formula (a), (b) or (c) are independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the remaining variables are as defined in the present invention.
  • the above-mentioned compound The structure is selected from one of the following (d-1), (d-2), (d-3) and (d-4):
  • V 1 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 1 is at least one selected from -NR-, -RC(O)-, -RCH 2 C(O)-, -NRC(S)NR'-, -NRC(O)O-, -C(O)NR- or -NR-C(O)-;
  • n 1 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • Z is a cytotoxic drug
  • V 1 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 4 is at least one selected from -NR-, -R-, -RC(O)-, -C(O)NR- or -NR-C(O)-;
  • M is at least one selected from -NR-, -O-, -OC(O)-, -C(O)NR-, -C(O)-, or -RC(O)-;
  • n6 and m7 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • Z is a cytotoxic drug
  • V2 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 2 is at least one selected from -NR-, -RC(O)-, -RCH 2 C(O)-, -NRC(S)NR'-, -NRC(O)O-, -C(O)NR- or -NR-C(O)-;
  • n2 and m3 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • Z is a cytotoxic drug or a chelating agent
  • X is a ligand that binds to albumin
  • V3 is at least one selected from -NR-, -O-, -C(O)-, -OC(O)-, -NRC(O)- or -NRC(S)-;
  • W 3 is at least one selected from -R-, -NR-, -RC(O)-, -RCH 2 C(O)-, -NRC(S)NR'-, -NRC(O)O-, -C(O)NR- or -NR-C(O)-;
  • n4 and m5 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • Z and X are independently selected from albumin-binding ligands, cytotoxic drugs or chelating agents;
  • Z is selected from a cytotoxic drug or a chelating agent
  • X is selected from a ligand that binds to albumin
  • R, R' and R" in formula (d-1), (d-2), (d-3) or (d-4) are independently selected from at least one of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the remaining variables are as defined in the present invention.
  • the present invention proposes a compound.
  • the compound is the aforementioned compound or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and its structure is selected from the following:
  • the present invention relates to a complex.
  • the complex is formed by the above-mentioned compound or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof and a radioactive nuclide or non-radioactive element A', and its structure is shown in formula (II),
  • Z is a chelating agent
  • X is a ligand that binds to albumin, a cytotoxic drug or is absent, and the remaining variables are as defined in the present invention.
  • the present invention relates to a complex.
  • the complex is formed by the above-mentioned compound or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof and a radioactive nuclide or non-radioactive element A', and its structure is shown in formula (III),
  • X is a chelating agent
  • Z is an albumin-binding ligand
  • a cytotoxic drug or is absent and the remaining variables are as defined in the present invention.
  • the present invention relates to a compound.
  • the compound is the compound described in the first aspect or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, characterized in that its structure is selected from the following:
  • the present invention relates to a complex.
  • the complex is formed by the compound described in the fifth aspect or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof and a radioactive nuclide or non-radioactive element B'.
  • the radioactive nuclide or non-radioactive element A' is the same as or different from the radioactive nuclide or non-radioactive element B'.
  • the radionuclide A' or B' is independently selected from: at least one of 68 Ga, 18 F, 99 mTc, 89 Zr, 111 In, 45 Ti, 59 Fe, 64 Cu, 94 mTc, 67 Ga, 71/72/74 As, 43/44 Sc, 82 mRb, 52 Mn, 86 Y, 76 Br, 177 Lu, 90 Y, 153 Sm, 67 Cu, 89 Sr, 137 Cs, 166 Ho, 177 Yb, 105 Rh, 186/188 Re, 47 Sc, 212/213 Bi, 225 Ac, 212 Pb, 149 Pm and 227 Th, and the remaining variables are as defined in the present invention.
  • the non-radioactive element A' or B' is independently selected from at least one of Ga, Fe and Gd, and the remaining variables are as defined in the present invention.
  • the radionuclide is selected from 18 F, and the remaining variables are as defined in the present invention.
  • the radionuclide 18 F complex is formed by radioactive isotope aluminum fluoride, and the remaining variables are as defined in the present invention.
  • the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises the compound described in the first, second or fifth aspect, or the complex described in the third, fourth or sixth aspect, or its stereoisomers, nitrogen oxides, solvates, metabolites, and pharmaceutically acceptable salts.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.
  • the present invention proposes the use of the compound described in the first, second or fifth aspect, or the complex described in the third, fourth or sixth aspect, or its stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition described in the seventh aspect in the preparation of one or more reagents and/or drugs for diagnosing and/or treating and/or preventing tumors, cancers or cells expressing FAP.
  • the tumor or cancer expressing FAP is selected from at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, fibrosarcoma, osteosarcoma and other sarcoma malignant tumors, pancreatic cancer, ovarian cancer, head and neck cancer, and neuroendocrine tumors.
  • the tumor or cancer expressing FAP is selected from at least one of sarcoma-like malignant tumors such as fibrosarcoma, osteosarcoma, pancreatic cancer and ovarian cancer.
  • the present invention proposes the use of the compound described in the first, second or fifth aspect, or the complex described in the third, fourth or sixth aspect, or its stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition described in the seventh aspect for diagnosis and/or treatment and/or prevention of diseases associated with high expression of FAP.
  • the present invention proposes the use of the compound described in the first, second or fifth aspect, or the complex described in the third, fourth or sixth aspect, or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition described in the seventh aspect in the preparation of one or more reagents and/or drugs for inhibiting FAP expression.
  • the present invention provides a method for imaging a tissue expressing FAP.
  • the method comprises: applying the complex or its stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug described in the third, fourth or sixth aspect, or the pharmaceutical composition described in the seventh aspect to the tissue; and imaging the tissue using PET.
  • the present invention proposes the use of the compound described in the first, second or fifth aspect, or the complex described in the third, fourth or sixth aspect, or its stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition described in the seventh aspect, in the diagnosis and/or treatment and/or prevention of diseases associated with the expression of FAP.
  • the present invention provides the compound described in the first, second or fifth aspect, or the complex described in the third, fourth or sixth aspect, or its stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutical
  • the present invention relates to a pharmaceutical composition according to the seventh aspect, wherein the pharmaceutical composition comprises an acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition according to the seventh aspect, for use in diagnosing and/or treating and/or preventing tumors or cancers expressing FAP.
  • the present invention also proposes a method for diagnosing and/or treating and/or preventing tumors and cancers expressing FAP, characterized in that a pharmaceutically acceptable dose of the compound described in the first, second or fifth aspect, or the complex described in the third, fourth or sixth aspect, or its stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition described in the seventh aspect is administered to the patient.
  • the tumor or cancer expressing FAP is selected from at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, and neuroendocrine tumors.
  • the tumor or cancer expressing FAP is selected from at least one of fibrosarcoma, osteosarcoma, pancreatic cancer and ovarian cancer.
  • a component refers to one or more components, ie, there may be more than one component contemplated for use or use in practicing the embodiments.
  • Stereoisomers refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.
  • Chiral refers to a molecule that is non-superimposable on its mirror image; “achiral” refers to a molecule that is superimposable on its mirror image.
  • Enantiomers refer to two non-superimposable isomers of a compound that are mirror images of each other.
  • Diastereoisomers refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.
  • the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms).
  • Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
  • racemate of the resulting final product or intermediate can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the obtained diastereomeric salts thereof.
  • the racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible across a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol and imine-enamine isomerizations.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the above general formula compounds, or as the specific examples, subclasses, and classes of compounds included in the embodiments.
  • substituted generally means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted by one or more substituents selected from a specified group, then the substituents may be the same or different at each substitutable position.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as The general formula compounds, or the specific examples, subclasses, and classes of compounds included in the embodiments.
  • substituents such as The general formula compounds, or the specific examples, subclasses, and classes of compounds included in the embodiments.
  • substituents such as The general formula compounds, or the specific examples, subclasses, and classes of compounds included in the embodiments.
  • substituents such as The general formula compounds, or the specific examples, subclasses, and classes of compounds included in the embodiments.
  • substituents such as The general formula compounds, or the specific examples, subclasses, and classes of compounds included in the embodiments.
  • the term “optionally substituted” can be used interchangeably with the term “substituted or unsubstituted”.
  • the term “optionally”, whether or not it is preceded by the term “substituted” indicates that one or more hydrogen atoms in the given structure are replaced by a specific substituent.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2. As used herein, Indicates the attachment site of a group.
  • C 1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood as a linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is connected.
  • alkyl refers to a group having 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 ),
  • alkyl and its prefix “alkane” as used herein include both straight and branched saturated carbon chains.
  • alkylene refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms, such examples include, but are not limited to, methylene, ethylidene, isopropylidene, and the like.
  • alkylene means a saturated divalent hydrocarbon radical derived from a saturated straight or branched hydrocarbon radical by removing two hydrogen atoms. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group contains 1-3 carbon atoms; in yet another embodiment, an alkylene group contains 1-2 carbon atoms. Such examples include methylene ( -CH2- ), ethylene ( -CH2CH2- ), isopropylene (-CH( CH3 ) CH2- ) , and the like.
  • alkenyl refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon sp2 double bond, including “cis” and “trans” orientations, or “E” and “Z” orientations.
  • the alkenyl group may be optionally substituted with one or more substituents described herein.
  • the alkenyl group contains 2-12 carbon atoms; in another embodiment, the alkenyl group contains 3-12 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2-4 carbon atoms.
  • alkynyl refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one carbon-carbon sp triple bond exists, wherein the alkynyl group may be optionally substituted with one or more substituents described herein.
  • the alkynyl group contains 3 to 12 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms. atom; in yet another embodiment, the alkynyl group contains 2-4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ) and the like.
  • alkoxy means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2CH 3 ), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 2 ), 2-pentyloxy (-OCH(CH 3 ) 3
  • alkylamino includes “N-alkylamino” and "N,N-dialkylamino", wherein the amino groups are independently substituted by one or two alkyl groups; the alkyl group has the meaning described in the present invention.
  • the alkylamino group is a lower alkylamino group formed by one or two C 1-6 alkyl groups connected to the nitrogen atom.
  • the alkylamino group is an alkylamino group formed by one or two C 1-4 lower alkyl groups connected to the nitrogen atom.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.
  • hydroxyalkyl means an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group has the meaning as described herein. Such examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxypropyl, and the like.
  • aminoalkyl means that an alkyl group is substituted with one or more amino groups, wherein the alkyl group has the meaning as described herein. Such examples include, but are not limited to, aminomethyl, 2-aminoethyl, 3-amino-1-propyl, 4-amino-1-butyl, etc.
  • haloalkyl means that an alkyl, alkenyl, alkoxy or alkylamino group is substituted by one or more halogen atoms, wherein the alkyl, alkenyl, alkoxy or alkylamino group has the meaning as described in the present invention, such examples include, but are not limited to, trifluoromethyl, 2,2,3,3-tetrafluoropropyl, trifluoromethoxy, trifluoromethylamino and the like.
  • cycloalkyl refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms. In one embodiment, the cycloalkyl contains 7-12 ring carbon atoms; in another embodiment, the cycloalkyl contains 3-8 ring carbon atoms; in another embodiment, the cycloalkyl contains 3-6 ring carbon atoms.
  • the cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
  • Carbocyclyl or “carbocycle” refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms.
  • Carbobicyclic groups include spirocarbobicyclic groups and fused carbobicyclic groups.
  • Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. In one embodiment, the carbocyclyl contains 3-8 ring carbon atoms; in another embodiment, the carbocyclyl contains 3-6 ring carbon atoms.
  • carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • the carbocyclyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
  • heteroalkyl by itself or in combination with another term refers to a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom O, N, P, S and Si may be located at any interior position of the heteroalkyl group, or at the position where the alkyl group is attached to the rest of the molecule.
  • heteroalkyl groups used in this specification include those groups connected to the rest of the molecule through a heteroatom, for example: C(O)NR', NR'R", OR', SR, S(O)R and/or -S(O 2 )R'.
  • heteroalkyl When “heteroalkyl” is listed and then a specific heteroalkyl group is listed, for example: -NR'R, etc., it should be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the multiple specific heteroalkyl groups are listed to increase clarity. Therefore, the term “heteroalkyl” should not be interpreted in this specification to exclude multiple specific heteroalkyl groups, for example: -NR'R", etc.
  • cycloheteroalkyl refers to a non-aromatic ring system, an unsaturated or partially unsaturated ring system, such as a 3- to 10-membered substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms which may be the same or different and are selected from nitrogen (N), oxygen (O), sulfur (S), phosphorus (P) and silicon (Si), and may optionally include one or more double bonds.
  • the cycloheteroalkyl ring may be optionally fused with other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings or otherwise Connected.
  • Multiple heterocyclic rings include those with one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the nitrogen and sulfur heteroatoms can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized.
  • heterocyclic ring refers to a non-aromatic 5-, 6- or 7-membered ring or polycyclic group, wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen atom and the sulfur heteroatom can be selectively oxidized), including but not limited to: a bicyclic or tricyclic group, which includes multiple fused six-membered rings with one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen atom and sulfur heteroatom can be selectively oxidized, (iii) the nitrogen heteroatom can be selectively quaternized, and (iv) any of the above heterocyclic rings can be fused with an aryl or heteroaryl ring.
  • cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydrofuranyl, and the like.
  • cycloalkyl and “heterocycloalkyl” by themselves or in combination with other terms refer to cyclic forms of “alkyl” and “heteroalkyl”, respectively.
  • a heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule.
  • Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • cycloalkenyl and “heterocycloalkenyl” refer to divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.
  • An unsaturated alkyl group is a group having one or more double or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologs and isomers.
  • Alkyl groups limited to hydrocarbon groups are referred to as "homoalkyl".
  • aryl refers to an aromatic hydrocarbon substituent which may be a single ring or a single or multiple rings (e.g., 1 to 3 rings) fused together or covalently linked.
  • heteroaryl refers to multiple aromatic groups (or multiple rings) containing one to four heteroatoms (in each single ring in the case of multiple rings) selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group may be attached to the rest of the molecule via a carbon atom or a heteroatom.
  • aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquino
  • arylene and heteroarylene refer to the divalent forms of aryl and heteroaryl, respectively.
  • aryl when the term “aryl” is used in combination with other terms (e.g., aryloxy, arylthio, arylalkyl), the term “aryl” includes aryl and heteroaryl rings as defined above.
  • arylalkyl and heteroarylalkyl are intended to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furanylmethyl, etc.), including those in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.).
  • haloaryl as used in this specification is intended to cover only aryl groups substituted by one or more halogens.
  • heteroaryl may be used alone or as a large part of “heteroarylalkyl” or “heteroarylalkoxy” to refer to monocyclic, bicyclic and tricyclic ring systems containing a total of 5-14 ring members, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meanings as described herein, wherein each ring system contains 3-7 ring members and has one or more points of attachment to the rest of the molecule.
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl),
  • heteroatom refers to O, S, N, P and Si, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is replaced, for example, N (such as 3,4-dihydro-2H- substituted pyrrolidinyl), NH (as NH in pyrrolidinyl) or NR (as NR in N-substituted pyrrolidinyl).
  • N such as 3,4-dihydro-2H- substituted pyrrolidinyl
  • NH as NH in pyrrolidinyl
  • NR as NR in N-substituted pyrrolidinyl
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66, 1-19, 1977.
  • salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates
  • organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionat
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed by compounds of any N-containing group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium/quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.
  • salts are generally known to those of ordinary skill in the art and include salts of active compounds prepared with relatively nontoxic acids or bases according to the specific substitution moieties present on the compounds described in this specification.
  • base addition salts can be obtained by contacting the neutral form of the compounds with a sufficient amount of the desired base under neat conditions or in a suitable inert solvent or by ion exchange (whereby one basic counterion (base) in an ionic complex is replaced by another).
  • base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral forms of the compounds with a sufficient amount of the desired acid, either directly under solvent-free conditions or in a suitable inert solvent or by ion exchange (whereby one acidic counterion (acid) in an ion complex is replaced by another).
  • Examples of pharmaceutically acceptable acid addition salts include acid addition salts derived from inorganic acids, For example, salts of hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydrofluoric acid or phosphorous acid, and salts derived from relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, and also include salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galactu
  • a variety of pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, citrate, edetate, edisylate, propionate dodecyl sulfate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, mucate, naphthylate, nitrate, pamoate (enbolate), pantothenate, phosphate/diphosphate, polygalact
  • prodrug used in the present invention refers to a compound that is converted into a compound represented by formula (X) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues.
  • the prodrug compound of the present invention can be an ester.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • phosphate esters such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • Metabolites refer to products obtained by metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be determined by the methods described in the present invention. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compound, including metabolites produced by contacting the compound of the present invention with a mammal for a sufficient period of time.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol.
  • hydrate refers to an association formed by a solvent molecule that is water.
  • the term "hydrate” may be used.
  • one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.
  • the compounds disclosed herein can be formulated for a variety of modes of administration, including systemic or local administration. Techniques and formulations generally can be found in Remington's Pharmaceutical Science and Practice (20th Edition) Lippincott, Williams & Wilkins Publishers (2000).
  • these agents can be formulated into liquid or solid dosage forms, and systemically or topically administered.
  • the multiple medicaments can be delivered in the form of timing or continuous slow release. Multiple technologies of preparation and administration can be found in "Remington: Pharmaceutical Science and Practice” (20th Edition) Lippincott, Williams and Wilkins Publishers (2000).
  • Multiple suitable approaches may include: via inhalation spray, transdermal, or transmucosal administration; intestinal delivery, including intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular injection or other delivery modes.
  • the various agents disclosed herein can be formulated and diluted in various aqueous solutions, for example, in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation, and such penetrants are generally known in the art.
  • compositions suitable for the present disclosure include: a plurality of compositions containing an effective amount of active ingredients to achieve their intended purpose.
  • the determination of the plurality of effective amounts is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided in this specification.
  • the plurality of compounds according to the present invention are effective over a wide dosage range.
  • multiple doses of 0.01 to 1000 milligrams (mg), 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of doses that can be used.
  • a non-limiting dose is 10 to 30 mg per day.
  • the exact dose will depend on the route of administration, the form of administration of the compound, the subject to be treated, and the dosage.
  • ADME bioavailability, adsorption, distribution, metabolism and
  • the multiple pharmaceutical compositions may also contain multiple suitable pharmaceutically acceptable carriers, including multiple auxiliary materials and adjuvants that help process the multiple active compounds into multiple pharmaceutically usable preparations.
  • the subject treated by the methods of the present disclosure is ideally a human subject, although it should be understood that the methods described herein are effective for all vertebrate species that are intended to be included in the term “subject.”
  • a “subject” can include a human subject for medical purposes, such as a prophylactic treatment for treating an existing condition or disease or for preventing the onset of a condition or disease, or an animal (non-human) subject for medical, veterinary, or developmental purposes.
  • a plurality of suitable animal subjects include: mammals, including but not limited to: primates, such as humans, monkeys, apes, etc.; bovines, such as cattle, oxen, etc.; ovines, such as sheep, etc.; caprines, such as goats, etc.; suines, such as pigs, hogs, etc.; equines, such as horses, donkeys, zebras, etc.; felines, including wild cats and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, etc.; and rodents, including mice, rats, etc.
  • An animal can be a transgenic animal.
  • the subject is a human, including but not limited to fetuses, newborns, infants, adolescents, and adult subjects.
  • a "subject” may include a patient suffering from or suspected of suffering from a condition or disease. Therefore, the terms “subject” and “patient” are used interchangeably herein.
  • the subject is a human. In other embodiments, the subject is a non-human.
  • treating may include reversing, alleviating, inhibiting the development of the disease, preventing or reducing the disease or condition to which the term applies or one or more symptoms or manifestations of the disease or condition.
  • Prevent means not causing a disease, condition, symptom or manifestation or worsening of severity.
  • the compounds disclosed herein can be administered prophylactically to prevent or reduce the occurrence or recurrence of the disease or condition.
  • treatment refers to all diseases or conditions that can be slowed down, interrupted, prevented, controlled or stopped, but does not necessarily mean that all symptoms of all diseases or conditions disappear, and it also includes preventive treatment of the symptoms, especially in patients who are prone to such diseases or disorders. In some embodiments, it refers to improving the disease or condition (i.e., slowing down or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treatment” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • treatment refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters) or both. In other embodiments, “treatment” refers to preventing or delaying the onset, occurrence or deterioration of a disease or condition.
  • therapeutically effective amount or “therapeutically effective dose” refers to an amount that can induce biological
  • therapeutically effective amount refers to an amount of the compound of the present invention that can produce a clinical or medical response (e.g., reduce or inhibit enzyme or protein activity, or improve symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease, etc.).
  • the term "therapeutically effective amount” refers to an amount that, when the compound of the present invention is administered to an individual, is effective for: (1) at least partially alleviating, inhibiting, preventing and/or improving (i) a condition or disease mediated by FAP, or (ii) associated with FAP activity, or (iii) characterized by abnormal activity of FAP; or (2) reducing or inhibiting the activity of FAP; or (3) reducing or inhibiting the expression of FAP.
  • the term "therapeutically effective amount” refers to an amount of an effective compound of the present invention that, when administered to a cell, or an organ, or a non-cellular biological substance, or a medium, can at least partially reduce or inhibit the activity of FAP; or at least partially reduce or inhibit the expression of FAP.
  • administering and “administering” a compound should be understood as providing a compound of the present invention or a prodrug of a compound of the present invention to an individual in need thereof. It should be recognized that one skilled in the art can treat a disease currently expressing FAP, such as fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, etc., by using an effective amount of a compound of the present invention.
  • a disease currently expressing FAP such as fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, etc.
  • composition refers to a product containing a specified amount of a specified component, and any product directly or indirectly produced by a combination of specified amounts of specified components.
  • the meaning of this term related to a pharmaceutical composition includes a product containing an active ingredient (single or multiple) and an inert ingredient (single or multiple) constituting a carrier, and any product directly or indirectly produced by mixing, compounding or aggregating any two or more ingredients, or by decomposing one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present invention includes any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier.
  • FIG. 1 is a nuclear magnetic resonance spectrum of NYM030 according to an embodiment of the present invention.
  • FIG2 is an LC-MS diagram of NYM030 according to an embodiment of the present invention.
  • Fig. 3 is a HPLC spectrogram of NYM030 according to an embodiment of the present invention.
  • FIG4 is a nuclear magnetic resonance spectrum of NYM031 according to an embodiment of the present invention.
  • FIG5 is an LC-MS diagram of NYM031 according to an embodiment of the present invention.
  • FIG6 is a HPLC spectrogram of NYM031 according to an embodiment of the present invention.
  • FIG. 7 is a test result of the in vitro anti-tumor activity of NYM030 according to an embodiment of the present invention.
  • FIG8 is a tumor volume trend diagram of a HT1080 tumor-bearing mouse model according to an embodiment of the present invention.
  • FIG9 is a weight trend chart of HT1080 tumor-bearing mice according to an embodiment of the present invention.
  • FIG10 is a diagram showing changes in tumor volume in SJSA-1 tumor-bearing mice according to an embodiment of the present invention.
  • FIG11 is a diagram showing changes in body weight of SJSA-1 tumor-bearing mice according to an embodiment of the present invention.
  • FIG12 is a diagram showing changes in body weight of ICR mice according to an embodiment of the present invention.
  • FIG. 13 is a graph showing a weight trend of ICR mice according to an embodiment of the present invention.
  • the compound (13) obtained in the above step was dissolved in 5 mL of DCM solvent, DMAP (398 mg, 3.26 mmol, 3.30 eq) and sodium sulfate (281 mg, 1.97 mmol, 2.00 eq) were added to the solution, and the mixture was stirred at 25°C for 1 hour.
  • Compound (11) (239 mg, 1.18 mmol, 1.20 eq) was dissolved in 2.0 mL of DCM solvent at 0°C, and then the solution was added to the above mixture. The mixed solution was stirred at 25°C for 11 hours. After removing the solvent under vacuum, a yellow solid compound (14) (720 mg) was obtained.
  • the affinity of NYM030 compound to FAP was determined using the Biacore 8K protein interaction system.
  • BR102910 was used as a positive control, which has a strong affinity for FAP.
  • FAP (purchased from ACROBiosystems Inc) was coupled to the surface of a CM5 chip.
  • the running buffer consisted of 50 mM Tris, 150 mM NaCl, 0.05% P20 (Tween 20), and 5% DMSO, pH 7.2-7.4.
  • a series of different concentrations of test samples BR102910 (a selective fibroblast activation protein (FAP) inhibitor, purchased from MedChemExpress LLC) and NYM030 molecules were prepared.
  • a series of different concentrations of test sample solutions were diluted in equal proportions (the highest concentration was 70 nM, and the dilution ratio was 2, 5 different concentrations). The samples were injected and the affinity of the test samples BR102910 and NYM030 to FAP was measured.
  • the affinity of the test samples BR102910 and NYM030 to FAP is represented by the equilibrium dissociation constant KD (Kd/Ka) value, wherein Kd is the dissociation constant and Ka is the binding constant.
  • Kd is the dissociation constant
  • Ka is the binding constant. The smaller the KD value, the higher the affinity of the compound to the protein.
  • ES-2 ovarian cancer
  • HS746T gastric cancer
  • SJSA-1 osteosarcoma
  • 5637 blade cancer
  • SHP-77 lung cancer
  • test sample storage solution DMSO solution of NYM030, concentration 6 mg/ml
  • DMSO DMSO at a ratio of 1:3. Then each solution was diluted 100 times with culture medium. Finally, 10 ⁇ l of the corresponding solution was added to each well of each cell line. The corresponding 100-fold dilutions were plated in triplicate for each drug concentration and cultured in a 37°C, 5% CO 2 incubator for 72 hours;
  • CTG CELL TITER-GLO
  • the in vitro antitumor activity test results and cell viability results of NYM030 are shown in Table 3 and Figure 7, respectively.
  • the results show that NYM030 has a strong in vitro antitumor effect on ES2, SJSA-1, and 5637 cells, and can significantly inhibit the proliferation of ES2, SJSA-1, and 5637 cells.
  • the inhibitory activity against ES-2 is the highest, while the antitumor activity against HS746T and SHP-77 cells is low, showing the specific antitumor activity of NYM030.
  • the experimental animal HT1080 model was provided by Suzhou Hengjia Biotechnology Co., Ltd. It is a HT1080 subcutaneous heterotopic transplant tumor model based on BALB/c nude mice. This model is a mouse model constructed with human fibrosarcoma cells. 20 female HT1080 heterotopic human fibrosarcoma model mice were randomly selected for the experiment. Before the experiment, the tumor size was measured and arranged in order according to the tumor size. 16 tumor mice with appropriate tumor volume were selected and divided into three groups: numbered G1, G2, and G3. Among them, there were six tumor mice in group G1 (treatment group), and each animal was injected with NYM030 saline solution through the tail vein, and the dosage was about 10 mg/kg.
  • the injection amount of the drug was calculated according to the weight of each tumor-bearing mouse.
  • Six tumor mice in group G2 positive control group
  • the dosage was about 5 mg/kg (NYM030 and irinotecan were administered in the same molar amount, that is, the dosage of cytotoxic drugs was the same).
  • the G3 group control group
  • four tumor-bearing mice were injected with physiological saline solution through the tail vein of each animal. The dosage was close to that of the G1 and G2 groups, and the injection time of each group was recorded.
  • the tumor volume (long and short diameter) and body weight of the G1, G2, and G3 groups were measured before administration and 2, 4, 6, 8, 10, 12, and 14 days after administration. The status of the mice was observed and accurately recorded. The long diameter and short diameter of the tumor measured during the efficacy evaluation were used to calculate the tumor volume.
  • the trend graph of tumor volume in each group is shown in Figure 8, and the trend graph of mouse weight change is shown in Figure 9. It can be seen that NYM030 inhibits tumor growth more significantly than irinotecan and saline, and there is no significant change in mouse weight, indicating that NYM030 has a good anti-tumor effect and good safety.
  • the experimental animal SJSA-1 model was provided by Sino-US Crown Biotechnology (Taicang) Co., Ltd. It is a female BALB/c nude mouse animal model of subcutaneous xenograft of humanized SJSA-1 cell line. BALB/c nude mice were subcutaneously inoculated with 2 ⁇ 10 6 SJSA-1 cells on the right back, and the tumors grew to an average volume of about 100 mm 3 .
  • the experiment was divided into a negative control and three doses of NYM030 (10 mg/kg, 3 mg/kg and 1 mg/kg, prepared as a dosing solution using 5% glucose solution), each with 8 animals in each group, administered by tail vein injection, with a dosing volume of 10 ⁇ L/g, for a total of two weeks, and the experiment ended on the 28th day.
  • Specific dosing information is shown in Table 4. Before the start of dosing, all animals were weighed and the tumor volume was measured with a vernier caliper.
  • TGI tumor inhibition rate
  • the tumor volume of mice in the negative control group exceeded 3000 mm 3 and they were euthanized.
  • the average tumor volume of the negative control group was 2997.74 mm 3 ; NYM030 (10 mg/kg, 3 mg/kg and 1 mg/kg) in each dose group could significantly inhibit tumor growth, with TGI of 60.69%, 46.59% and 44.46% respectively, among which the high dose group had better tumor inhibition effect, and there was no obvious weight loss in the negative control group and each dose group of NYM030, and no abnormal conditions occurred in the mice, indicating that NYM030 has good safety.
  • the mouse model was 6-8 week old female ICR mice purchased from Suzhou Hengjia Biotechnology Co., Ltd. Six ICR mice were randomly selected and given NYM030 drugs, with a single dose of 10 mg/kg for 7 consecutive days.
  • the general indicators of the animals (animal hair, activity, diet, etc.), animal deaths (death time, etc.) and weight changes of the animals were observed (before administration, during observation, and before killing at the end of the experiment).
  • the animals were killed on the last day of the experiment, and the tissue changes of the main organs such as the heart, liver, spleen, lung, and kidney were observed by dissection.
  • the weight change in Figure 12 is used to evaluate the change in weight at a certain time point compared with the weight before the start of the experiment.
  • the mouse model was 6-8 week old female ICR mice purchased from Suzhou Hengjia Biotechnology Co., Ltd. 9 ICR mice were randomly selected and divided into three groups, 3 mice in each group.
  • the experimental group was given 100 mg/kg NYM031, the positive control was given 50 mg/kg irinotecan, and the control group was given normal saline.
  • the general indicators of the animals (animal hair, activity, diet, etc.), animal deaths (death time, etc.) and animal weights were observed before and 2, 4, 6, and 8 days after administration. The animals were killed and dissected on the last day of the experiment to observe whether the main organs were abnormal.
  • mice did not die, had no abnormal reactions, and there were no abnormalities in the organs observed by dissection, and their weight increased after the experiment was completed; under the premise of the same amount of effective drugs (cytotoxic drugs), the weight loss of mice in the experimental group was less than that of the positive control group.
  • the weight of the mice in the experimental group increased compared with before administration, while the weight of the positive control group did not increase. It can be seen that the NYM031 molecule is safe.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

本发明涉及式(X)所示的靶向成纤维细胞活化蛋白的化合物及其应用，进一步涉及包含该类化合物的药物组合物和用途；其中，所述化合物或药物组合物可用于诊断和/或治疗和/或预防一种或多种表达FAP的肿瘤、癌症或细胞。

Description

靶向成纤维细胞活化蛋白的药物及其应用
优先权信息
本申请请求2022年10月14日向中国国家知识产权局提交的、专利申请号为202211260609.3的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及生物医药领域，具体地，本发明涉及靶向成纤维细胞活化蛋白的药物及其应用。
背景技术
成纤维细胞活化蛋白(FAP，又称为成纤维细胞活化蛋白α，FAPα)在实体肿瘤中与癌相关的成纤维细胞(CAFs)上高度过表达，而在正常组织和良性肿瘤中一般不表达。肿瘤基质CAFs能够促进肿瘤细胞的生长和浸润，已成为肿瘤干预的重要靶标。肿瘤生物标记分子FAP的过表达是CAFs的一个显著特征，FAP在CAF靶向用于肿瘤诊断和治疗方面，是一个具有潜力的靶点。
FAP是一种肿瘤成纤维细胞上的II型跨膜丝氨酸蛋白酶，以同源二聚体形式存在于细胞表面，属于脯氨酸寡肽酶家族，其本身酶活性对于肿瘤生长和组织重构有重要作用。CAF表面特异性FAP可通过促进基质重建、参与VEGF/AKT/ERK等信号转导途径增强肿瘤细胞沿纤维定向侵袭能力、参与肿瘤血管生成等以形成肿瘤生物屏障并抑制效应T细胞的功能，进而促进肿瘤进展。FAP在肿瘤间质中的诱导性高表达也依赖于肿瘤组织的恶性癌变。FAP的高表达程度与肿瘤的预后不良呈正相关性。
而非抑制性FAP单克隆抗体本身无肿瘤治疗作用，且以抗体为载体的ADC因其渗透性差、半衰期长、非靶器官摄取和持留时间长、毒性作用较大等原因，不利于临床开发。经过结构修饰和优化筛选的小分子FAP选择性(靶向性)抑制剂，对于癌症的诊断和治疗具有较大优势和开发价值。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提出了一些具有结合成纤维细胞活化蛋白-α(FAP)的化合物，其具备较好的临床应用前景。与已有的同类化合物相比，本发明的化合物具有更好的药效活性，此外，本发明提供的化合物还具有优良的理化性质和药代性质，并且具有较低的毒副作用。
以下仅概括说明本发明的一些方面，并不局限于此。这些方面和其他部分在后面有更完整的说明。本说明书中的所有参考文献通过整体引用于此。当本说明书的公开内容与引用文献有差异时，以本说明书的公开内容为准。
成纤维细胞活化蛋白-α是脯氨酰寡肽酶家族的第II型跨膜丝氨酸蛋白酶，其特征在于其裂解所述Pro-AA肽键的能力(其中AA代表任何氨基酸)。已表明它通过所述酶活性修饰多个生物活性信号肽而在癌症中起作用(Kelly等人，2005；Edosada等人，2006)。已在超过90％的所述多个上皮癌周围的所述基质中的多个成纤维细胞的表面检测到成纤维细胞活化蛋白-α的表达，包括但不限于：恶性乳腺癌、结肠直肠癌、皮肤癌、前列腺癌、胰腺癌等以及炎症，包括但不限于：关节炎、纤维化等，而在多个健康组织中几乎没有表达。因此，专门针对成纤维细胞活化蛋白-α的治疗及成像具有临床重要性。
本发明提供了一类具有结合成纤维细胞活化蛋白-α(FAP)的化合物，可以制备用于诊断和/或治疗和/或预防表达成纤维细胞活化蛋白的疾病，比如纤维肉瘤、骨肉瘤等肉瘤类恶性肿瘤、胰腺癌、卵巢癌、黑色素瘤、食管癌、乳腺癌、胆管癌、肺癌、肝癌、结直肠癌、头颈部癌、神经内分泌肿瘤的药物。
本发明也提供了这些化合物的制备方法和包含这些化合物的药物组合物以及使用这些化合物或组合物治疗哺乳动物，尤其是人类的上述疾病的方法。
本发明化合物能够与成纤维细胞活化蛋白-α较好的结合，因此具有更好的药效、药代性质和/或毒理特性，例如良好的生物利用度、低毒副作用和高安全性等。
本发明化合物或药物组合物能够很好地与成纤维细胞活化蛋白-α进行结合，可用于诊断和/或治疗和/或预防表达成纤维细胞活化蛋白的相关疾病。
在本发明的第一方面，本发明提出了一种化合物，其为式(X)所示的化合物或式(X)所示化合物的立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
其中，Y选自结合成纤维细胞活化蛋白-α的配体；
L选自连接子；
X和Z至少存在之一，X、Z分别独立地选自结合白蛋白的配体、细胞毒性药物或螯合剂，且X与Z至少之一为细胞毒性药物或螯合剂。
根据本发明的实施例，所述X和Z不同。
根据本发明的实施例，所述Y具有式(I’)所示结构、式(I’)所示结构的立体异构体或药学上可接受的盐，
其中每个y独立地选自0、1或2；
R1x、R2x及R3x’各自独立地选自H、-OH、卤素、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；
R3x选自H、-CN、-B(OH)2、-C(O)烷基、-C(O)芳基-、-C＝C-C(O)芳基、-C＝CS(O)2芳基-CO2H、-SO3H、-SO2NH2、-PO3H2或5-四唑基；
其中表示所述结合成纤维细胞活化蛋白-α的配体与所述连接子的连接点，其中所述连接点可通过所述成纤维细胞活化蛋白-α结合配体的所述喹啉环的第5、6、7或8个碳原子中的任何一个与所述连接子相连。
根据本发明的实施例，Y结构选自如下一种：
根据本发明的具体实施例中，Y结构选自如下一种：
根据本发明的实施例，所述Y具有式(I)所示结构、式(I)所示结构的立体异构体 或药学上可接受的盐，
其中每个y独立地选自0、1或2；
R1x、R2x及R3x’各自独立地选自H、-OH、卤素、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；
R3x选自H、-CN、-B(OH)2、-C(O)烷基、-C(O)芳基-、-C＝C-C(O)芳基、-C＝CS(O)2芳基-CO2H、-SO3H、-SO2NH2、-PO3H2或5-四唑基；
其中表示所述结合成纤维细胞活化蛋白-α的配体与所述连接子的连接点，其中所述连接点可通过所述成纤维细胞活化蛋白-α结合配体的所述喹啉环的第5、6、7或8个碳原子中的任何一个与所述连接子相连。
根据本发明的实施例，Y结构选自如下一种：
根据本发明的具体实施例中，Y结构选自如下一种：

根据本发明的实施例，L选自(a)、(b)和(c)中的一种或多种，
(a)
其中：
V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W1选自-NR-、-RC(＝O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m1选自0、1、2、3、4、5或6；
(b)
其中：
V2选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W2选自-NR-、-RC(＝O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m2及m3分别独立地选自0、1、2、3、4、5或6；
(c)
其中：
V3选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W3选自-R-、-NR-、-RC(＝O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m4及m5分别独立地选自0、1、2、3、4、5或6；
式(a)、(b)或(c)中的R、R’和R”分别独立地选自H、烷基、取代的烷基、环 烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基的至少之一，其余变量如本发明所定义。
根据本发明的实施例，L选自(a-1)、(a-2)、(b)和(c)中的一种或多种，
(a-1)
其中：
V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W1选自-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m1选自0、1、2、3、4、5或6；
(a-2)
其中：
V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W4选自-NR-、-R-、-RC(O)-、-C(O)NR-或-NR-C(O)-的至少之一；
M选自-NR-、-O-、-OC(O)-、-C(O)NR-、-C(O)-或-RC(O)-的至少之一；
m6及m7分别独立地选自0、1、2、3、4、5或6；
(b)
其中：
V2选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W2选自-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m2及m3分别独立地选自0、1、2、3、4、5或6；
(c)
其中：
V3选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W3选自-R-、-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m4及m5分别独立地选自0、1、2、3、4、5或6；
式(a-1)、(a-2)、(b)或(c)中的R、R’和R”分别独立地选自H、烷基、取代的烷基、环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基的至少之一，其余变量如本发明所定义。
根据本发明的实施例，R、R’和R”分别独立地选自H、C1-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、哌嗪、内酯、环状酸酐、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、二氢吲哚基、奎宁环基、吗啉基、硫代吗啉基、噻二嗪基、四氢咲喃基、取代的杂环烷基、苯基、萘基、取代的芳基、嘧啶、吡啶、吡嗪、呋喃、噻吩或取代的杂芳基的至少之一，其余变量如本发明所定义。
根据本发明的实施例，R、R’和R”分别独立地选自H、C1-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、其余变量如本发明所定义。
根据本发明的实施例，所述L具有以下其中之一的结构：
其余 变量如本发明所定义。
根据本发明的实施例，所述L具有以下其中之一的结构：
其余变量如本发明所定义。
根据本发明的实施例，所述结合白蛋白的配体具有以下其中之一的结构：
其余变量如本发明所定义。
根据本发明的实施例，所述细胞毒性药物选自喜树碱类或其衍生物、微管蛋白抑制剂或其衍生物、RNA或DNA的合成抑制剂或其衍生物。具体地，其中所述喜树碱类或其衍生物包括伊立替康、SN38、DXd；所述微管蛋白抑制剂或其衍生物包括美登木素生物碱、澳瑞他汀类及其衍生物、特别是DM1、MMAE；所述RNA或DNA的合成抑制剂或其衍生物包括多柔比星及其衍生物，其余变量如本发明所定义。
根据本发明的具体实施例，所述细胞毒性药物选自以下结构及其衍生物中的一种：
其余变量如本发明所定义。
根据本发明的具体实施例，所述细胞毒性药物衍生自以下结构中的一种或以下结构中的一种的衍生物：
其余变量如本发明所定义。
根据本发明的具体实施例，所述衍生物包括但不限于氨基化衍生物、硫化衍生物、氮 化衍生物、羰基化衍生物、烷基化衍生物。
根据本发明的实施例，所述螯合剂衍生自1,4,7,10-四氮杂环十二烷-N,N`,N``,N```,-四乙酸、1,4,7-三氮杂环壬烷-1,4,7-三乙酸、2-(4,7-双(羧甲基)-1,4,7-三偶氮壬-1-基)戊二酸、2-(4,7,10-三(羧甲基)-1,4,7,10-四氮杂环十二烷-1-基)戊二酸、1,4,7-三氮杂环壬烷次膦酸、1,4,7-三氮杂环壬烷-1-[甲基(2-羧乙基)次膦酸]-4,7-双[甲基(2-羧甲基)次膦酸]、N’-{5-[乙酰基(羟基)氨基]戊基}-N-[5-({4-[5-氨基戊基)(羟基)氨基]-4-氧丁酰基}氨基)戊基]-N-羟基琥珀酰胺、二乙三胺五乙酸、反式-环己基-二乙三胺五乙酸、对异氰硫基苄基-二乙三胺五乙酸、1-(异氰硫基苄基)-3-甲基-二乙三胺五乙酸、1-(异氰硫基苄基)-4-甲基-二乙三胺五乙酸、1-(2)-甲基-4-异氰基苄基-二乙三胺五乙酸、1-氧杂-4,7,10-三氮杂环十二烷-4,7,10-三乙酸、6-肼基烟酸琥珀酰亚胺酯盐酸盐和巯基乙酰基三甘氨酸，其余变量如本发明所定义。
根据本发明的实施例，前面所述的化合物中结构选自如下(a)、(b)和(c)中的一种：
(a)
其中：
V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W1选自-NR-、-RC(＝O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m1选自0、1、2、3、4、5或6；
Z为细胞毒性药物；
(b)
其中：
V2选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W2选自-NR-、-RC(＝O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m2及m3分别独立地选自0、1、2、3、4、5或6；
Z为细胞毒性药物；
X为结合白蛋白的配体；
(c)
其中：
V3选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W3选自-R-、-NR-、-RC(＝O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m4及m5分别独立地选自0、1、2、3、4、5或6；
Z、X分别独立地选自结合白蛋白的配体、细胞毒性药物或螯合剂；
式(a)、(b)或(c)中的R、R’和R”分别独立地选自H、烷基、取代的烷基、环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基的至少之一，其余变量如本发明所定义。
根据本发明的实施例，前面所述的化合物中结构选自如下(d-1)、(d-2)、(d-3)和(d-4)中的一种：
(d-1)
其中：
V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W1选自-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m1选自0、1、2、3、4、5或6；
Z为细胞毒性药物；
X不存在；
(d-2)
其中：
V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W4选自-NR-、-R-、-RC(O)-、-C(O)NR-或-NR-C(O)-的至少之一；
M选自-NR-、-O-、-OC(O)-、-C(O)NR-、-C(O)-或-RC(O)-的至少之一；
m6及m7分别独立地选自0、1、2、3、4、5或6；
Z为细胞毒性药物；
X不存在；
(d-3)
其中：
V2选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W2选自-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m2及m3分别独立地选自0、1、2、3、4、5或6；
Z为细胞毒性药物或螯合剂；
X为结合白蛋白的配体；
(d-4)
其中：
V3选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
W3选自-R-、-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
m4及m5分别独立地选自0、1、2、3、4、5或6；
Z、X分别独立地选自结合白蛋白的配体、细胞毒性药物或螯合剂；
其中，Z选自细胞毒性药物或螯合剂；X选自结合白蛋白的配体；
式(d-1)、(d-2)、(d-3)或(d-4)中的R、R’和R”分别独立地选自H、烷基、取代的烷基、环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基的至少之一，其余变量如本发明所定义。
在本发明的第二方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物由前面所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，其结构选自如下一种：




在本发明的第三方面，本发明涉及一种络合物。根据本发明的实施例，所述络合物由前面所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药与放射性核素或非放射性元素A’络合而成，其结构如式(II)所示，
其中，Z为螯合剂，X为结合白蛋白的配体、细胞毒性药物或不存在，其余变量如本发明所定义。
在本发明的第四方面，本发明涉及一种络合物。根据本发明的实施例，所述络合物由前面所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药与放射性核素或非放射性元素A’络合而成，其结构如式(III)所示，
其中，X为螯合剂，Z为结合白蛋白的配体、细胞毒性药物或不存在，其余变量如本发明所定义。
在本发明的第五方面，本发明涉及一种化合物。根据本发明的实施例，所述化合物由第一方面所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，其特征在于，其结构选自如下一种：

在本发明的第六方面，本发明涉及一种络合物。根据本发明的实施例，所述络合物由第五方面所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药与放射性核素或非放射性元素B’络合而成。
根据本发明的实施例，放射性核素或非放射性元素A’与放射性核素或非放射性元素B’相同或不同。
根据本发明的实施例，所述放射性核素A’或B’，分别独立地选自：68Ga、18F、99mTc、89Zr、111In、45Ti、59Fe、64Cu、94mTc、67Ga、71/72/74As、43/44Sc、82mRb、52Mn、86Y、76Br、177Lu、90Y、153Sm、67Cu、89Sr、137Cs、166Ho、177Yb、105Rh、186/188Re、47Sc、212/213Bi、225Ac、212Pb、149Pm和227Th的至少之一，其余变量如本发明所定义。
根据本发明的实施例，所述非放射性元素A’或B’分别独立地选自Ga、Fe和Gd的至少之一，其余变量如本发明所定义。
根据本发明的实施例，所述放射性核素选自18F，其余变量如本发明所定义。
根据本发明的实施例，所述放射性核素18F络合是通过放射性同位素氟化铝形成的，其余变量如本发明所定义。
在本发明的第七方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药 物组合物包含第一、第二或第五方面所述的化合物，或第三、第四或第六方面所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐。
根据本发明的实施例，所述药物组合物，其进一步包含药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
在本发明的第八方面，本发明提出了第一、第二或第五方面所述的化合物，或第三、第四或第六方面所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或第七方面所述的药物组合物在制备一种或多种用于诊断和/或治疗和/或预防表达FAP的肿瘤、癌症或细胞的试剂和/或药物中的应用。
根据本发明的实施例，所述表达FAP的肿瘤、癌症选自黑色素瘤、食管癌、乳腺癌、胆管癌、肺癌、肝癌、结直肠癌、纤维肉瘤、骨肉瘤等肉瘤类恶性肿瘤、胰腺癌、卵巢癌、头颈部癌、神经内分泌肿瘤的至少之一。
根据本发明的具体实施例，所述表达FAP的肿瘤、癌症选自纤维肉瘤、骨肉瘤等肉瘤类恶性肿瘤、胰腺癌和卵巢癌的至少之一。
在本发明的第九方面，本发明提出了第一、第二或第五方面所述的化合物，或第三、第四或第六方面所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或第七方面所述的药物组合物在用于诊断和/或治疗和/或预防高表达FAP相关的疾病的应用。
在本发明的第十方面，本发明提出了第一、第二或第五方面所述的化合物，或第三、第四或第六方面所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或第七方面所述的药物组合物在用于在制备一种或多种用于抑制FAP表达的试剂和/或药物中的应用。
在本发明的第十一方面，本发明提出了一种对表达FAP组织进行成像的方法。根据本发明的实施例，所述方法包括：向所述组织施加第三、第四或第六方面所述的络合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或第七方面所述的药物组合物；对所述组织采用PET成像。
在本发明的第十二方面，本发明提出了第一、第二或第五方面所述的化合物，或第三、第四或第六方面所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或第七方面所述的药物组合物，在用于诊断和/或治疗和/或预防表达FAP相关的疾病中的用途。
在本发明的第十三方面，本发明提出了第一、第二或第五方面所述的化合物，或第三、第四或第六方面所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学 上可接受的盐或它的前药，或第七方面所述的药物组合物，在用于诊断和/或治疗和/或预防表达FAP的肿瘤、癌症中的用途。
在本发明的第十四方面，本发明还提出了一种诊断和/或治疗和/或预防表达FAP的肿瘤、癌症方法，其特征在于，给与患者药学上可接受剂量的第一、第二或第五方面所述的化合物，或第三、第四或第六方面所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或第七方面所述的药物组合物。
根据本发明的实施例，所述表达FAP的肿瘤、癌症选自黑色素瘤、食管癌、乳腺癌、胆管癌、肺癌、肝癌、结直肠癌、头颈部癌、纤维肉瘤、骨肉瘤、胰腺癌、卵巢癌、神经内分泌肿瘤的至少之一。
根据本发明的具体实施例，所述表达FAP的肿瘤、癌症选自纤维肉瘤、骨肉瘤、胰腺癌和卵巢癌的至少之一。
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
本发明将应用以下定义除非其他方面表明。根据本发明的目的，化学元素根据元素周期表，CAS版本和化学物理手册，75th Ed.，1994来定义。另外，有机化学一般原理见“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito,1999,和“March's Advanced Organic Chemistry”,Michael B.Smith和Jerry March,John Wiley&Sons,New York,2007，所有上述参考文献均通过引用并入本文中。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指 一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。 如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“取代的”一般表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个被取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代时，那么取代基可以相同或不同地在各个可取代的位置取代。
术语“未取代的”，表示指定基团不带有取代基。
如本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面 的通式化合物，或者如实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或未取代的”这个术语可以交换使用。一般而言，术语“任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷硫基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、杂芳氧基、氧代(＝O)、羧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O)2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O)2-、羧基取代的烷氧基等等。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。以R为例，-RC(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-之间R的具体选项互相之间不受影响；同时，在同一化学式如果出现2个或2个以上的R，R的具体选项互相之间也不受影响。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。如本文所用，表示基团的连接位点。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
在本发明的各部分，式(I’)结构式中的与式(I)结构式中的表示同一种结构，其两种结构表示的系列化合物的范围一致。
术语“烷基”，表示1-20个碳原子，或1-10个碳原子，或1-8个碳原子，或1-6个碳原 子，或1-4个碳原子，或1-3个碳原子的饱和直链或支链的单价烃基，其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代，取代基包括但不限于，氘、氨基、羟基、氰基、F、Cl、Br、I、巯基、硝基、氧代(＝O)等等。烷基的实例包括，但并不限于，甲基(Me，-CH3)、乙基(Et，-CH2CH3)、正丙基(n-Pr，-CH2CH2CH3)、异丙基(i-Pr，-CH(CH3)2)、正丁基(n-Bu，-CH2CH2CH2CH3)、异丁基(i-Bu，-CH2CH(CH3)2)、仲丁基(s-Bu，-CH(CH3)CH2CH3)、叔丁基(t-Bu，-C(CH3)3)、正戊基(-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、正己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)、正庚基、正辛基等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。术语“烷撑”在此处使用，表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基，这样的实例包括，但并不限于，亚甲基、次乙基、次异丙基等等。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一实施方案中，亚烷基基团含有1-6个碳原子；在另一实施方案中，亚烷基基团含有1-4个碳原子；在又一实施方案中，亚烷基基团含有1-3个碳原子；还在一实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-)，亚乙基(-CH2CH2-)，亚异丙基(-CH(CH3)CH2-)等等。
术语“烯基”表示直链或支链一价烃基，其中至少有一个碳-碳sp2双键，其包括“cis”和“trans”的定位，或者“E”和“Z”的定位。其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，烯基基团包含2-12个碳原子；在另一实施方案中，烯基基团包含3-12个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH2)、烯丙基(-CH2CH＝CH2)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含3-12个碳原子；在另一实施方案中，炔基基团包含2-6个碳 原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(-C≡C-CH3)等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH3)，乙氧基(EtO、-OCH2CH3)，1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)，1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)，1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)，2-戊氧基(-OCH(CH3)CH2CH2CH3)，3-戊氧基(-OCH(CH2CH3)2)，2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)，3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2)，3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)，2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3)，等等。
术语“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代；所述烷基具有本发明所描述的含义。其中一些实施例是，烷基氨基是一个或两个C1-6烷基连接到氮原子上形成的的较低级的烷基氨基基团。另外一些实施例是，烷基氨基是一个或两个C1-4的较低级的烷基连接到氮原子上形成的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基、N-乙氨基、N,N-二甲氨基、N,N-二乙氨基等等。
术语“羟基烷基”表示烷基基团被一个或多个羟基所取代，其中烷基基团具有如本发明所述的含义。这样的实例包含，但并不限于，羟甲基、2-羟基乙基、2-羟基-1-丙基、3-羟基-1-丙基、2,3-二羟基丙基等。
术语“氨基烷基”表示烷基基团被一个或多个氨基所取代，其中烷基基团具有如本发明所述的含义。这样的实例包含，但并不限于，氨基甲基、2-氨基乙基、3-氨基-1-丙基、4-氨基-1-丁基等。
术语“卤代烷基”，“卤代烯基”，“卤代烷氧基”或“卤代烷基氨基”表示烷基，烯基，烷氧基或烷基氨基基团被一个或多个卤素原子所取代，其中烷基，烯基，烷氧基或烷基氨基基团具有如本发明所述的含义，这样的实例包含，但并不限于，三氟甲基、2,2,3,3-四氟丙基、三氟甲氧基、三氟甲基氨基等。
术语“环烷基”表示含有3-12个环碳原子的，单价或多价的饱和单环，双环或三环体系。在一实施方案中，环烷基包含7-12个环碳原子；在又一实施方案中，环烷基包含3-8个环碳原子；在又一实施方案中，环烷基包含3-6个环碳原子。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“碳环基”或“碳环”表示含有3-12个环碳原子的，单价或多价的非芳香性的饱和或部分不饱和单环、双环或者三环体系。碳双环基包括螺碳双环基和稠合碳双环基。合适的碳环基基团包括，但并不限于，环烷基、环烯基和环炔基。在一实施方案中，碳环基包含3-8个环碳原子；在又一实施方案中，碳环基包含3-6个环碳原子。碳环基基团的实例进一步包括，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。所述碳环基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“杂烷基”本身或与另一术语组合是指一稳定的直链或支链、或环状烃基、或其组合，其由至少一个碳原子和至少一个杂原子组成，所述杂原子选自于由O、N、P及Si及S组成的群组，并且其中所述氮、磷及硫原子可以选择性地被氧化，并且所述氮杂原子可以选择性地被季铵化。杂原子O、N、P及S及Si可以位于所述杂烷基基团的任意内部位置，或位于烷基基团与所述分子的其余部分连接的位置。多个示例包括但不限于：-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH25-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-Si(CH3)3、-CH2-CH＝N-OCH 3、-CH＝CH-N(CH3)-CH3、O-CH3、-O-CH2-CH3及-CN。多达两个或三个杂原子可以是连续的，例如：-CH2-NH-OCH3及-CH2-O-Si(CH3)3。
如上所述，本说明书所用的杂烷基基团包括通过杂原子至分子其余部分连接的那些基团，例如：C(O)NR’、NR’R”、OR’、SR、S(O)R及/或-S(O2)R’。当列举“杂烷基”而随后列举具体的杂烷基基团，例如：-NR’R等时，应当理解，所述术语杂烷基和-NR’R”不是多余的或互斥的。而是，列举所述多个具体的杂烷基基团以增加清楚性。因此，所述术语“杂烷基”在本说明书中不应被解释为排除多个具体的杂烷基基团，例如：-NR’R”等。
术语“环杂烷基”或“杂环烷基”是指非芳族环系统，不饱和或部分不饱和的环系统，例如3至10元取代或未取代的环烷基环系统，包括一个或多个杂原子，其可以是相同或不同，并且选自于氮(N)，氧(O)，硫(S)，磷(P)及硅(Si)，并且可以选择性地包括一个或多个双键。
所述环杂烷基环可以选择性地与其他环杂烷基环和/或非芳族烃环稠合或以其它方式 连接。多个杂环包括具有一至三个独立地选自于氧、硫及氮的杂原子的那些杂环，其中氮及硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。在某些实施例中，术语杂环是指非芳族5元环、6元环或7元环或多环基团，其中至少一个环原子是选自于O、S及N的杂原子(其中所述氮原子及硫杂原子可以选择性地被氧化)，其包括但不限于：双环或三环基团，其包括具有一至三个杂原子的多个稠合六元环，所述杂原子独立地选自于氧、硫和氮，其中(i)每个5元环具有0至2个双键，每个6元环具有0至2个双键，并且每个7元环具有0至3个双键，(ii)所述氮原子及硫杂原子可以选择性地被氧化，(iii)所述氮杂原子可以选择性地被季铵化，以及(iv)任意上述杂环的环可以与芳基或杂芳基环稠合。多个代表性环杂烷基环的体系包括但不限于：吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、二氢吲哚基、奎宁环基、吗啉基、硫代吗啉基、噻二嗪基、四氢咲喃基等。
术语“环烷基”及“杂环烷基”本身或与其它术语组合，分别表示“烷基”及“杂烷基”的环状形式。另外，对于杂环烷基，一杂原子可以占据所述杂环与所述分子的其余部分连接的位置。环烷基的多个示例包括但不限于：环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环烷基的多个示例包括但不限于：1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基、2-哌嗪基等。术语“环烯基”及“杂环烯基”分别指环烷基及杂环烷基的二价衍生物。
一不饱和烷基基团是具有一个或多个双键或三键的基团。不饱和烷基基团的多个示例包括但不限于：乙烯基、2-丙烯基、巴豆基(crotyl)、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-丙炔基及3-丙炔基、3-丁炔基和更高级的同系物和异构体。限于烃基的烷基被称为“同烷基(homoalkyl)。
术语“芳基”是指芳族烃取代基，所述芳族烃取代基可以是单环或稠合在一起或共价连接的单环或多环(例如：1至3个环)。术语“杂芳基”是指包含选自于含有N、O及S的一至四个杂原子(在多环的情况下在每个单环中)的多个芳基(或多个环)，其中所述氮及所述硫原子可选地被氧化，并且所述(多个)氮原子可选地被季铵化。杂芳基可通过碳原子或杂原子连接至所述分子的其余部分。芳基及杂芳基的多个非限制性示例包括：苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、 5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基及6-喹啉基。上述芳基和杂芳基环体系中的每一个的取代基选自于下面描述的可接受的取代基组。术语“亚芳基”及“杂亚芳基”分别指芳基及杂芳基的二价形式。
为简洁起见，当术语“芳基”与其他术语(例如：芳氧基、芳基硫基、芳基烷基)组合使用时，术语“芳基”包括如上定义的芳基及杂芳基环。因此，术语“芳基烷基”及“杂芳基烷基”旨在包括其中芳基或杂芳基连接至烷基的那些基团(例如：苄基、苯乙基、吡啶基甲基、呋喃基甲基等)，包括其中碳原子(例如：亚甲基)已被例如氧原子(例如：苯氧基甲基、2-吡啶基氧基甲基、3-(1-萘氧基)丙基等)取代。然而，本说明书所用的术语“卤代芳基”是指仅涵盖被一个或多个卤素取代的芳基。
术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分，表示共含有5-14元环的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中杂原子具有本发明所述的含义，其中每一个环体系包含3-7元环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O)2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O)2-、羧基取代的烷氧基等等。
另外一些实施方案是，芳杂环包括以下的单环，但并不限于这些单环：2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、4-甲基异噁唑-5-基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、嘧啶-5-基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、1,3,4-噻二唑-2-基、吡嗪基、吡嗪-2-基、1,3,5-三嗪基、苯并[d]噻唑-2-基、咪唑并[1,5-a]吡啶-6-基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基、3-喹啉基、4-喹啉基)和异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)。
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H- 吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,J.Pharmaceutical Sciences,66,1-19,1977所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐，和有机酸盐，如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等等。通过适当的碱得到的盐包括碱金属、碱土金属，铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠、锂、钾、钙、镁等等。药学上可接受的盐进一步包括适当的、无毒的铵/季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C1-8磺酸化物和芳香磺酸化物。
多个药学上可接受的盐通常为本领域普通技术人员所熟知，并且包括根据本说明书中所描述的所述多个化合物上存在的多个特定取代部分，以多个相对无毒的酸或碱制备而成的多个活性化合物的盐。当本揭露的多个化合物含有多个相对地酸性的官能团时，可以通过在无溶剂(neat)条件下或在一合适的惰性溶剂中或通过离子交换(由此一离子复合物中的一个碱性抗衡离子(碱)被另一个取代)，使所述多个化合物的中性形式与一足够量的所需的碱接触来获得多个碱加成盐。多个药学上可接受的碱加成盐的多个示例包括：钠盐、钾盐、钙盐、铵盐、有机氨基盐或镁盐或类似的盐。
当本揭露的多个化合物含有多个相对碱性的官能团时，可以通过直接在无溶剂条件下或在一合适的惰性溶剂中或通过离子交换(由此离一子复合物中的一个酸性抗衡离子(酸)被另一个取代)，使所述多个化合物的中性形式与一足够量的所需酸接触来获得多个酸加成盐。多个药学上可接受的酸加成盐的多个示例包括：衍生自多个无机酸的多个酸加成盐， 例如：盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢氟酸或亚磷酸等的盐，以及衍生自相对无毒的有机酸的盐，例如：乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等的盐，还包括氨基酸的盐，例如：精氨酸盐等，以及有机酸的盐、例如：葡糖醛酸或半乳糖醛酸等(参见，例如，Berge等人，“药用盐”，药物科学杂志，1977，66，1-19)。本揭露内容的某些特定化合物同时包含碱性官能团及酸性官能团，其允许所述多个化合物被转化成碱加成盐或酸加成盐。
因此，适合与本揭露的主题一起使用的多个药学上可接受的盐包括但不限于：乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、依地酸钙、樟脑磺酸盐、碳酸盐、柠檬酸盐、依地酸盐、乙二磺酸盐、丙酸酯十二烷硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酰对氨基苯基砷酸盐(glycollylarsanilate)、己基间苯二酚盐(hexylresorcinate)、哈胺(hydrabamine)、氢溴酸盐、盐酸盐、羟萘酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、粘酸盐、萘磺酸盐、硝酸盐、双羟萘酸盐(恩波酸盐)、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖酸酸盐、水杨酸盐、硬脂酸盐、次醋酸盐、琥珀酸盐、硫酸盐、丹宁酸盐、酒石酸盐或8-氯茶碱盐。其他药学上可接受的盐可在，例如，《雷明顿药物科学与实践》(第20版)利平科特，威廉斯和威尔金斯出版社(2000年)中找到。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(X)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-C24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述 的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时，可以使用术语“水合物”。在一些实施例中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另外一些实施例中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物，还有一些实施例中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
在治疗和/或诊断应用中，本揭露的所述多个化合物可以配制为多种给药模式，包括全身或局部给药。技术和配方通常可在《雷明顿药物科学与实践》(第20版)利平科特，威廉斯和威尔金斯出版社(2000年)中找到。
根据所治疗的具体条件，可以将这些试剂配制成液体或固体剂型，并且全身或局部给药。如以本领域技术人员已知的，所述多个药剂可以定时或持续缓慢释放的形式递送。可以在《雷明顿：药学科学与实践》(第20版)利平科特，威廉斯和威尔金斯出版社(2000年)中找到制剂及给药的多个技术。多个合适的途径可包括：经吸入喷雾、透皮、或透粘膜施用；肠道外递送，包括肌内、皮下、髓内注射，以及鞘内(intrathecal)、直接心室内、静脉内、关节内、胸骨内、滑膜内、肝内、病灶内、颅内、腹膜内、鼻内或眼内注射或其他递送模式。
对于注射，本揭露的所述多个试剂可以在多个水溶液中配制并稀释，例如在生理上相容的缓冲液如汉克氏溶液、林格氏溶液或生理盐水缓冲液中。对于这种透粘膜施用，在制剂中使用适合于待透过的屏障的渗透剂，这种渗透剂在本领域中通常是已知的。
适用于本揭露的药物组合物包括：当中含有一有效量的活性成分以实现其预期目的的多个组合物。所述多个有效量的确定完全在本领域技术人员的能力范围内，特别是根据本说明书提供的详细的揭露内容。通常地，根据本发明的所述多个化合物在一宽剂量范围内有效。例如：在成年人的治疗中，每天使用0.01至1000毫克(mg)、0.5至100毫克、每天1至50毫克以及每天5至40毫克的多个剂量为可以使用的剂量的多个示例。一非限制性剂量为每天10至30毫克。确切的剂量将取决于给药途径、所述化合物的给药形式、待治 疗的所述对象、待治疗的所述对象的体重、所述(多个)化合物的所述生物利用度、吸附、分布、新陈代谢及所述(多个)化合物的排泄(ADME)毒性、以及主治医生的偏好及经验。
除所述多个活性成分外，所述多个药物组合物还可含有多个合适的药学上可接受的载体，所述载体包括多个有助于加工所述多个活性化合物制成可药用的多个制剂的辅料及助剂。
在本公开的方法的许多实施例中，通过本公开的方法治疗的所述对象理想地为一人类对象，尽管应当理解，本说明书所描述的所述多个方法对于所有脊椎动物物种都是有效的，所述多个脊椎动物物种旨在包括在术语“对象”中。因此，一“对象”可以包括出于多个医学目的的一人类对象，例如：用于治疗一现有病症或疾病或用于预防一病症或疾病发作的一预防性治疗、或、用于医疗、兽医或发展目的的一动物(非人类)对象。多个合适的动物对象包括：哺乳动物，包括但不限于：灵长类动物，例如：人，猴，猿等；牛科动物，例如：牛(cattle)、牛(oxen)等；绵羊科动物，例如：绵羊(sheep)等；山羊科动物，例如：山羊(goat)等；猪科动物，例如：猪(pigs)、猪(hogs)等；马科动物，例如：马、驴、斑马等；猫科动物，包括：野猫及家猫；犬科动物，包括：狗；兔类动物，包括：兔子、野兔等；以及啮齿动物，包括：小鼠、大鼠等。一动物可以是一转基因动物。在一些实施例中，所述对象是一人类，包括但不限于：胎儿、新生儿、婴儿、青少年及成人对象。此外，“对象”可以包括患有或怀疑患有病症或疾病的患者。因此，术语“对象”及“患者”在本文可互换使用。在一些实施例中，所述对象是人类。在其他实施例中，所述对象是非人类。
如本说明书所用，术语“治疗”可以包括逆转、减轻、抑制所述疾病的发展、预防或降低所述疾病或所述术语所适用的状况或所述疾病或病症的一个或多个症状或表现。
“预防”是指不引起一疾病、病症、症状或表现或严重程度的恶化。因此，可以预防性地以当前公开的所述多个化合物进行给药，以预防或减少所述疾病或病症的发生或复发。
如本发明所使用的术语“治疗”任何疾病或病症，是指所有可以减缓、中断、阻止、控制或停止疾病或病症的进展，但不一定表示所有疾病或病症的症状全部消失，其也包括对所述症状的预防性治疗，尤其是在容易患有这样疾病或障碍的患者中。在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
如本发明所使用的术语“治疗有效量”或“治疗有效剂量”是指能够引发个体的生物 学或医学响应(例如降低或抑制酶或蛋白质活性，或改善症状、缓解病症、减缓或延迟疾病发展，或预防疾病等)的本发明化合物的量。在一项非限定性的实施方案中，术语“治疗有效量”是指当向个体施用本发明化合物时，对以下情况有效的量：(1)至少部分地缓解、抑制、预防和/或改善(i)由FAP介导，或者(ii)与FAP活性相关，或者(iii)由FAP的异常活性表征的病症或疾病；或者(2)降低或抑制FAP的活性；或者(3)降低或抑制FAP的表达。在另一实施方案中，术语“治疗有效量”是指当向细胞、或器官、或非细胞生物物质、或介质施用时，能至少部分地降低或抑制FAP活性；或者至少部分地降低或抑制FAP表达的有效的本发明化合物的量。
如本发明所使用的术语化合物“给予”和“给药”化合物应当理解为向需要其的个体提供本发明的化合物或本发明化合物的前药。应当认识到本领域技术人员通过使用有效量的本发明化合物治疗目前患有表达FAP的疾病，例如纤维肉瘤、骨肉瘤、胰腺癌卵巢癌等。
如本发明所使用的术语“组合物”是指包含规定量的规定成分的产物，以及规定量的规定成分的组合所直接或间接地产生的任何产物。与药物组合物相关的这种术语的含义包括包含活性成分(单个或者多个)和组成载体的惰性成分(单个或者多个)的产物，以及由任何两种或多种成分混合、复合或聚集，或者由一种或多种成分分解，或者由一种或多种成分的其他类型的反应或相互作用而直接或间接产生的任何产物。因此，本发明药物组合物包括通过将本发明化合物与可药用载体混合而制备的任何组合物。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1是根据本发明实施例的NYM030的核磁共振谱图；
图2是根据本发明实施例的NYM030的LC-MS图；
图3是根据本发明实施例的NYM030的HPLC谱图；
图4是根据本发明实施例的NYM031的核磁共振谱图；
图5是根据本发明实施例的NYM031的LC-MS图；
图6是根据本发明实施例的NYM031的HPLC谱图；
图7是根据本发明实施例的NYM030体外抗肿瘤活性测试结果；
图8是根据本发明实施例的HT1080荷瘤鼠模型上的肿瘤体积大小趋势图；
图9是根据本发明实施例的HT1080荷瘤鼠的体重趋势图；
图10是根据本发明实施例SJSA-1荷瘤鼠的肿瘤体积变化情况；
图11是根据本发明实施例SJSA-1荷瘤鼠的体重变化情况；
图12是根据本发明实施例的ICR小鼠体重变化情况；
图13是根据本发明实施例的ICR小鼠的体重趋势图。
具体实施方式
下面参考具体实施例，对本发明进行描述，需要说明的是，这些实施例仅仅是描述性的，而不以任何方式限制本发明。
实施例1化合物的制备过程
1.化合物NYM030分子的制备过程
将化合物(1)(6.00g，24.0mmol，1.00eq)溶于50.0mLTHF溶剂中，加入NMM(3.23g，31.9mmol，3.51mL，1.30eq)和甲基磺酰甲磺酸盐(5.56g，31.9mmol，1.30eq)，于20℃下搅拌2小时。反应溶液用H2O(50.0mL)稀释，用乙酸乙酯提取3次，每次用50mL(50.0mL*3)。萃取后的有机层用50.0mL盐水洗涤，再经过无水硫酸钠干燥，减压蒸去溶剂，得到黄色油状化合物(2)(7.50g，23.2mmol)。
步骤二：
将化合物(2)(7.50g，23.2mmol，1.00eq)与MeNH2(52.2g，504mmol，50.0mL，纯度30.0％，21.7eq)的混合物在密封管中70℃下搅拌12小时。然后用1.00M HCl将反应混合物淬灭并调整pH至7，然后抽滤得到无色油状化合物(3)(6.2g)。
步骤三：
将化合物(4-1)(10.0g,39.6mmol,1.00eq)溶于100mL MeCN溶剂内，向此溶液中添加Cs2CO3(19.4g,59.5mmol,1.50eq)和BnBr(6.79g,39.6mmol,4.71mL,1.00eq)。反应混合液在20℃下搅拌12小时后用150mL水稀释，用乙酸乙酯进行萃取3次，每次用50mL(50.0mL*3)。萃取后的有机层用100mL盐水洗涤，再经过无水硫酸钠干燥，减压蒸去溶剂，得到残留物。残留物通过柱色谱法(二氧化硅，石油醚/乙酸乙酯＝20/1-5/1)(石油醚：乙酸乙酯＝3：1，Rf～0.60)进行分离和纯化，得到黄色油状化合物(4)(12.0g，35.0mmol)。
步骤四：
将化合物(3)(5.60g,21.7mmol,1.00eq和化合物(4)(7.45g,21.7mmol,1.00eq)溶于50.0mL二氧杂环已烷中，向此溶液中添加Pd2(dba)3(1.99g、2.18mmol、0.10eq)、Xphos(1.04g、2.18mmol，0.10eq)和Cs2CO3(14.2g、43.5mmol，2.00eq)。混合物在100℃下搅拌12小时。用100mL水稀释反应产物，用乙酸乙酯进行萃取(50.0mL*3)，萃取3次，每次用50mL。萃取后的有机层用100mL盐水洗涤，再经过无水硫酸钠干燥，减压蒸去溶剂，得到残留物。用prep-HPLC(TFA试剂)对残留物进行纯化，得到黄色油状化合物(5)(4.24g，8.18mmol)。
步骤五：
将化合物(5)(7.00g，13.5mmol，1.00eq)溶于70.0mLTHF溶剂中，在N2吹扫下向此溶液中加入Pd/C(700mg，纯度10％)。将得到的悬浮液在真空下脱气，并用氢气吹扫几次。在H2(15psi)吹扫下，将混合物在20℃下搅拌12小时，过滤将滤液在真空下除去溶剂得到残留物。用prep-HPLC(TFA试剂)进行纯化，得到红色固体化合物(6)(4.70g，10.9mmol，产率81.2％)。
步骤六：
将化合物(6)(650mg、1.52mmol、1.02mmol、1.00eq)和化合物(7)(1.03g、1.52mmol,53％purity,1.00eq,TsOH)溶于5.00mLDMF溶剂内，向此溶液添加HATU(864mg,2.27mmol,1.50eq)和DIEA(390mg,3.02mmol,2.00eq)。将此混合物在20℃下搅拌1小时后在真空下去除溶剂。用prep-HPLC(TFA试剂)对混合物进行纯化得到化合物(8)(624mg，1.04mmol)，其为黄色固体。
步骤七：
取化合物(8)(600mg，1.00mmol，1.00eq)溶于6.00mLMeCN溶剂内，向此溶液中加入TsOH·H2O(390mg,2.05mmol,2.05eq)。将混合物在20℃下搅拌12小时后真空下除去溶剂。得到化合物(9)(712mg，TsOH)，其为红色固体。
步骤八：
将化合物(10)(500mg,1.27mmol,1.00eq)溶于5mL的THF溶剂中；向此溶液中加入DIEA(247mg，1.91mmol，1.50eq)和化合物(11)(308mg，1.53mmol，1.20eq)，将混合物在25℃下搅拌12小时得到反应混合物，真空下去除溶剂后，将所得产物在10mL的MTBE的溶剂中研磨得到黄色固体化合物(12)(512mg，918umol)。
步骤九：
将化合物(9)(350mg，521umol，1.00eq)和上述步骤得到的化合物(12)(291mg，521umol，1.00eq)溶于3.00mLDMF溶剂中，在溶液内加入三乙胺TEA(158mg，1.56mmol，3.00eq)。将混合物在20℃下搅拌2小时。用prep-HPLC(TFA试剂)对混合物进行纯化，得到化合物(NYM030)(60.0mg，65.1umol，纯度99.6％)，为橙色固体，NYM030的HPLC谱图见图3。
2.化合物NYM031分子的制备过程
NYM031分子结构(其核磁共振谱图见图4，LC-MS谱图见图5)
合成路线：
步骤一：
化合物(10)(2.00g，5.10mmol，1.00eq)溶于20mL的DCM溶剂中，向所述溶液内加入叔丁基二甲基氯硅烷TBSCl(1.92g，12.7mmol，2.50eq)和N,N-二异丙基乙胺DIEA(1.98g，15.3mmol，3.01eq)，将混合物在20℃下搅拌2小时。在真空下去除溶剂后，经prep-HPLC(TFA试剂)纯化，得到化合物(13)(2.45g，4.84mmol)，为白色固体。
步骤二：
将上述步骤得到的化合物(13)溶于5mL的DCM溶剂中，向所述溶液中加入DMAP(398mg，3.26mmol，3.30eq)和硫酸钠(281mg，1.97mmol，2.00eq)，将混合物在25℃下搅拌1小时。将化合物(11)(239mg，1.18mmol，1.20eq)在0℃溶于2.0mL DCM溶剂中，然后将此溶液加入到前述混合物内。混合溶液在25℃下搅拌11小时。在真空下去除所述溶剂后，得到黄色固体化合物(14)(720mg)。
步骤三：
将化合物(9)(350mg、521umol、1.00eq)和化合物(14)(350mg、521umol、1.00eq、 TsOH)溶于3.00mL的DCM溶剂内，向此溶液中加入TEA(158mg、1.56mmol、3.00eq)。将混合物在20℃下搅拌1小时后真空下去除溶剂。用prep-HPLC(TFA条件)对混合物进行纯化，得到化合物(NYM031)(61mg，65.7umol，纯度98.9％)，为橙色固体，NYM031的HPLC谱图见图6。
实施例2 NYM030药物化合物的SPR亲和力测试
利用Biacore 8K蛋白互作系统测定了NYM030化合物对FAP的亲和力。BR102910作为阳性对照，其对FAP有很强的亲和力。
将FAP(购于ACROBiosystems Inc)偶联到CM5芯片表面，运行缓冲液由50mM Tris,150mM NaCl,0.05％P20(Tween20),和5％DMSO组成,pH 7.2-7.4，配置一系列不同浓度的待测样BR102910(一种选择性的成纤维细胞活化蛋白(FAP)抑制剂，购于MedChemExpress LLC)、NYM030分子，等比例稀释一系列不同浓度待测样溶液(最高浓度为：70nM，稀释比例为：2，5个不同浓度)，进样并测量待测样BR102910、NYM030与FAP的亲和力。待测样BR102910、NYM030与FAP的亲和力由平衡解离常数KD(Kd/Ka)值表示，其中Kd为解离常数，Ka为结合常数，KD值越小，表明化合物与蛋白的亲和力越高。
测试结果如下表1所示，NYM030显示出了对FAP的低纳摩尔亲和性，与BR102910相比，对FAP的亲和力更高。
表1 SPR亲和力检测结果
实施例3 NYM030药物对肿瘤细胞增殖的抑制活性
收集处于指数生长期的ES-2(卵巢癌)、HS746T(胃癌)、SJSA-1(骨肉瘤)、5637(膀胱癌)、SHP-77(肺癌)细胞并用Vi-Cell XR细胞计数仪进行活细胞计数，将细胞悬液调整到适当浓度，培养不同细胞所用的培养基和每孔加入的细胞数信息如表2所示。每孔加90μl细胞悬液于96孔细胞培养板，在37℃,5％CO2和95％湿度培养24小时；
用供试品储存液(NYM030的DMSO溶液，浓度为6mg/ml)和DMSO按照1:3等比配置一系列梯度稀释液。然后用培养基各稀释100倍。最后每株细胞每孔分别加入10μl相 应的100倍稀释液，每个药物浓度各3个复孔，置于37℃,5％CO2孵箱中培养72小时；
药物处理72小时后，按照细胞活力检测方法CTG(CELL TITER-GLO)发光法操作说明，每孔加入50μl预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2分钟，于室温放置10分钟后用Envision2104读板仪测定萤光信号值。
NYM030体外抗肿瘤活性测试结果和细胞活力结果分别见表3、图7所示，结果显示，NYM030对ES2、SJSA-1、5637细胞有较强的的体外抗肿瘤作用，能够显著抑制ES2、SJSA-1、5637细胞的增殖，其中对ES-2的抑制活性最高，而对HS746T、SHP-77细胞的抗肿瘤活性低，显示出NYM030的特异性抗肿瘤活性。
表2细胞系培养信息
表3 NYM030体外抗肿瘤活性IC50值以及最大抑制率
实施例4 NYM030药物在HT1080肿瘤模型疗效实验
实验动物HT1080模型由苏州恒佳生物技术有限公司提供，是基于BALB/c裸鼠建立的HT1080皮下异位移植瘤模型，该模型为人纤维肉瘤细胞构建的小鼠模型。随机选择20只雌性HT1080异位人纤维肉瘤模型鼠进行实验。实验前先测量肿瘤大小，并根据肿瘤大小按顺序排列，选出瘤体积在合适大小的16只肿瘤鼠入组，分为三组：编号分别为G1、G2、G3。其中G1组(治疗组)六只肿瘤鼠，每只动物经尾静脉注射NYM030的生理盐水溶液，给药量约为10mg/kg，按照每只荷瘤鼠体重计算注射药物量。G2组(阳性对照组)六只肿瘤鼠，每只动物经尾静脉注射伊立替康的生理盐水溶液，给药量约为5mg/kg(NYM030和伊立替康的给药摩尔量相同，即细胞毒性药物给药量相同)。G3组(对照组)四只肿瘤鼠，每只动物经尾静脉注射生理盐水溶液，给药量与G1、G2组体积接近，并记录各组注射时间。G1组、G2组、G3组于给药前、给药后2、4、6、8、10、12、14天测量肿瘤体积大小(长径和短径)和称量体重，同时观察小鼠状态，并做好准确记录。肿瘤 疗效评价期间测量的肿瘤长径和短径用于计算肿瘤体积大小，计算公式如下：肿瘤体积(tumor volume，TV)＝a×b2/2(a为长径、b为短径)。各组肿瘤体积大小趋势图见图8，小鼠体重变化趋势图见图9，可以看到NYM030相对于伊立替康和生理盐水，其抑制肿瘤生长的速度更加明显，且小鼠体重并无明显变化，说明NYM030有很好地抗肿瘤效果且具有较好的安全性。
实施例5 NYM030药物SJSA-1肿瘤模型疗效实验
实验动物SJSA-1模型由中美冠科生物技术(太仓)有限公司提供，是人源SJSA-1细胞株皮下异种移植雌性BALB/c nude小鼠动物模型。BALB/c nude小鼠于右侧背部皮下接种2×106SJSA-1细胞，肿瘤生长至平均体积约100mm3。
实验分为阴性对照和NYM030的3个剂量(10mg/kg，3mg/kg和1mg/kg，使用5％葡萄糖溶液配置成给药溶液)的各自单药组，每组8只，尾静脉注射给药，给药体积为10μL/g，共给药两周，实验于第28天结束。具体给药信息详见表4。在给药开始前，称量所有动物的体重，并用游标卡尺测量肿瘤体积。给药前、给药后测量肿瘤体积大小(长径和短径)和称量体重，同时观察肿瘤生长及治疗对动物正常行为的影响，包括实验动物的活动性，摄食和饮水情况，体重增加或降低情况及其它异常情况。根据肿瘤体积的抑制率(TGI)进行疗效评价，根据动物体重变化(如附图11)和死亡情况进行安全性评价。计算肿瘤抑制率，TGI(％)，计算公式如下：TGI％＝(1-T/C)×100％，T和C分别为治疗组和对照组在某一特定时间点的平均肿瘤体积；肿瘤体积(tumor volume，TV)＝a×b2/2(a为长径、b为短径)。
如附图10所示，在第24天，阴性对照组有小鼠肿瘤体积超过3000mm3，被安乐死。在第24天,阴性对照组平均肿瘤体积为2997.74mm3；NYM030(10mg/kg,3mg/kg和1mg/kg)各剂量组均能显著性抑制肿瘤生长，TGI分别为60.69％，46.59％和44.46％，其中，高剂量组的肿瘤抑制效果更好，阴性对照组和NYM030各个剂量组无明显体重下降，小鼠均无异常情况出现，说明NYM030安全性良好。
表4给药信息
实施例6连续给药毒性实验
小鼠模型为6-8周龄雌性ICR小鼠购自苏州恒佳生物技术有限公司。随机选取6只ICR小鼠给予NYM030药物，单次给药10mg/kg，连续给药7天，观察动物一般指标(动物毛发、活动度、饮食等)、动物死亡情况(死亡时间等)及称量动物体重变化(给药前、观察期间、试验结束处死前)，并于实验最后一天处死，解剖观察其心、肝、脾、肺、肾等主要脏器的组织变化。图12中体重变化用于评价某一时间点体重与实验开始前体重的变化情况，计算公式为：体重变化＝称量时体重/初始体重*100％。
如图12所示，连续给药7天后，所有小鼠无死亡，无异常反应，解剖观察脏器无异常，且实验过程中体重并无明显变化。可见，NYM030分子安全性良好。
实施例7 ICR鼠急性毒性实验
小鼠模型为6-8周龄雌性ICR小鼠购自苏州恒佳生物技术有限公司。随机选取9只ICR小鼠分三组，每组3只小鼠，实验组给予100mg/kg NYM031，阳性对照给予50mg/kg伊立替康，对照组给予生理盐水，每组并于给药前、给药后2、4、6、8天观察动物一般指标情况(动物毛发、活动度、饮食等)、动物死亡情况(死亡时间等)及称量动物体重，并于实验最后一天处死解剖观察各主要脏器有无异常。如图13所示，8天观察中，所有小鼠无死亡，无异常反应，解剖观察脏器无异常，且实验完成后体重均有增加；在有效药(细胞毒性药物)量一致的前提下，实验组小鼠体重下降少于阳性对照组。实验结束时实验组小鼠相比于给药前，体重增加，而阳性对照组没增加。可见，NYM031分子安全性好。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (28)

  1. 一种化合物，其为式(X)所示的化合物或式(X)所示化合物的立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    其中，Y选自结合成纤维细胞活化蛋白-α的配体；
    L选自连接子；
    X和Z至少存在之一，X、Z分别独立地选自结合白蛋白的配体、细胞毒性药物或螯合剂，且X与Z至少之一为细胞毒性药物或螯合剂。
  2. 根据权利要求1所述的化合物，其特征在于，所述Y具有式(I)所示结构、式(I)所示结构的立体异构体或药学上可接受的盐，
    其中每个y独立地选自0、1或2；
    R1x、R2x及R3x’各自独立地选自H、-OH、卤素、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；
    R3x选自H、-CN、-B(OH)2、-C(O)烷基、-C(O)芳基-、-C＝C-C(O)芳基、-C＝CS(O)2芳基、-CO2H、-SO3H、-SO2NH2、-PO3H2或5-四唑基；
    其中表示所述结合成纤维细胞活化蛋白-α的配体与所述连接子的连接点，其中所述连接点可通过所述成纤维细胞活化蛋白-α结合配体的所述喹啉环的第5、6、7或8个碳原子中的任何一个与所述连接子相连。
  3. 根据权利要求2所述的化合物，其特征在于，Y结构选自如下一种：

  4. 根据权利要求3所述的化合物，其特征在于，Y结构选自如下一种：
  5. 根据权利要求1-4任一项所述的化合物，其特征在于，L选自(a-1)、(a-2)、(b)和(c)中的一种或多种，
    其中：
    V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
    W1选自-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
    m1选自0、1、2、3、4、5或6；
    其中：
    V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
    W4选自-NR-、-R-、-RC(O)-、-C(O)NR-或-NR-C(O)-的至少之一；
    M选自-NR-、-O-、-OC(O)-、-C(O)NR-、-C(O)-或-RC(O)-的至少之一；
    m6及m7分别独立地选自0、1、2、3、4、5或6；
    其中：
    V2选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
    W2选自-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
    m2及m3分别独立地选自0、1、2、3、4、5或6；
    其中：
    V3选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
    W3选自-R-、-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
    m4及m5分别独立地选自0、1、2、3、4、5或6；
    式(a-1)、(a-2)、(b)或(c)中的R、R’和R”分别独立地选自H、烷基、取代的烷基、环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基的至少之一。
  6. 根据权利要求5所述的化合物，其特征在于，R、R’和R”分别独立地选自H、C1-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、哌嗪、内酯、环状酸酐、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、二氢吲哚基、奎宁环基、吗啉基、硫代吗啉基、噻二嗪基、四氢咲喃基、取代的杂环烷基、苯基、萘基、取代的芳基、嘧啶、吡啶、吡嗪、呋喃、噻吩或取代的杂芳基的至少之一。
  7. 根据权利要求5所述的化合物，其特征在于，R、R’和R”分别独立地选自H、C1-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、
  8. 根据权利要求1-7任一项所述的化合物，其特征在于，L具有以下其中之一的结构：
  9. 根据权利要求1所述的化合物，其特征在于，所述结合白蛋白的配体具有以下其中之一的结构：
  10. 根据权利要求1所述的化合物，其特征在于，所述细胞毒性药物选自喜树碱类或其衍生物、微管蛋白抑制剂或其衍生物、RNA或DNA的合成抑制剂或其衍生物；
    优选地，所述细胞毒性药物衍生自以下结构中的一种：
  11. 根据权利要求1所述的化合物，其特征在于，所述螯合剂衍生自1,4,7,10-四氮杂环十二烷-N,N`,N``,N```,-四乙酸、1,4,7-三氮杂环壬烷-1,4,7-三乙酸、2-(4,7-双(羧甲基)-1,4,7-三偶氮壬-1-基)戊二酸、2-(4,7,10-三(羧甲基)-1,4,7,10-四氮杂环十二烷-1-基)戊二酸、1,4,7-三氮杂环壬烷次膦酸、1,4,7-三氮杂环壬烷-1-[甲基(2-羧乙基)次膦酸]-4,7-双[甲基(2-羧甲基)次膦酸]、N’-{5-[乙酰基(羟基)氨基]戊基}-N-[5-({4-[5-氨基戊基)(羟基)氨基]-4-氧丁酰基}氨基)戊基]-N-羟基琥珀酰胺、二乙三胺五乙酸、反式-环己基-二乙三胺五乙酸、对异氰硫基苄基-二乙三胺五乙酸、1-(异氰硫基苄基)-3-甲基-二乙三胺五乙酸、1-(异氰硫基苄基)-4-甲基-二乙三胺五乙酸、1-(2)-甲基-4-异氰基苄基-二乙三胺五乙酸、1-氧杂-4,7,10-三氮杂环十二烷-4,7,10-三乙酸、6-肼基烟酸琥珀酰亚胺酯盐酸盐和巯基乙酰基三甘氨酸。
  12. 根据权利要求1-11任一项所述的化合物，其特征在于，结构选自如下(d-1)、(d-2)、(d-3)和(d-4)中的一种：
    其中：
    V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
    W1选自-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
    m1选自0、1、2、3、4、5或6；
    Z为细胞毒性药物；
    X不存在；
    其中：
    V1选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
    W4选自-NR-、-R-、-RC(O)-、-C(O)NR-或-NR-C(O)-的至少之一；
    M选自-NR-、-O-、-OC(O)-、-C(O)NR-、-C(O)-或-RC(O)-的至少之一；
    m6及m7分别独立地选自0、1、2、3、4、5或6；
    Z为细胞毒性药物；
    X不存在；
    其中：
    V2选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
    W2选自-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
    m2及m3分别独立地选自0、1、2、3、4、5或6；
    Z为细胞毒性药物或螯合剂；
    X为结合白蛋白的配体；
    其中：
    V3选自-NR-、-O-、-C(O)-、-OC(O)-、-NRC(O)-或-NRC(S)-的至少之一；
    W3选自-R-、-NR-、-RC(O)-、-RCH2C(O)-、-NRC(S)NR’-、-NRC(O)O-、-C(O)NR-或-NR-C(O)-的至少之一；
    m4及m5分别独立地选自0、1、2、3、4、5或6；
    Z为细胞毒性药物或螯合剂；
    X为结合白蛋白的配体；
    式(d-1)、(d-2)、(d-3)或(d-4)中的R、R’和R”分别独立地选自H、烷基、取代的烷基、环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基的至少之一。
  13. 一种化合物，所述化合物由权利要求1-12任一项所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，其特征在于，其结构选自如下一种：




  14. 一种络合物，其特征在于，所述络合物由权利要求1-12任一项所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药与放射性核素或非放射性元素A’络合而成，其结构如式(II)所示，
    其中，Z为螯合剂，X为结合白蛋白的配体、细胞毒性药物或不存在。
  15. 一种络合物，其特征在于，所述络合物由权利要求1-12任一项所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药与放射性核素或非放射性元素A’络合而成，其结构如式(III)所示，
    其中，X为螯合剂，Z为结合白蛋白的配体、细胞毒性药物或不存在。
  16. 一种化合物，所述化合物由权利要求1-12任一项所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，其特征在于，其结构选自如下一种：

  17. 一种络合物，其特征在于，所述络合物由权利要求16所述的化合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药与放射性核素或非放射性元素B’络合而成。
  18. 根据权利要求14～15、17任一项所述的络合物，其特征在于，所述放射性核素A’或B’，分别独立地选自：68Ga、18F、99mTc、89Zr、111In、45Ti、59Fe、64Cu、94mTc、67Ga、71/72/74As、43/44Sc、82mRb、52Mn、86Y、76Br、177Lu、90Y、153Sm、67Cu、89Sr、137Cs、166Ho、177Yb、105Rh、186/188Re、47Sc、212/213Bi、225Ac、212Pb、149Pm和227Th的至少之一；
    任选地，所述非放射性元素A’或B’分别独立地选自Ga、Fe和Gd的至少之一；
    任选地，所述放射性核素选自18F；
    任选地，所述放射性核素18F络合是通过放射性同位素氟化铝形成的。
  19. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1～13、16任一项所述的化合物，或权利要求14～15、17～18任一项所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐。
  20. 根据权利要求19所述的药物组合物，其进一步包含药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
  21. 权利要求1～13、16任一项所述的化合物或权利要求14～15、17～18任一项所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或权利要求19～20任一项所述的药物组合物在制备一种或多种用于诊断和/或治疗和/或预防表达FAP的肿瘤、癌症或细胞的试剂和/或药物中的应用。
  22. 根据权利要求21所述的应用，其特征在于，所述表达FAP的肿瘤、癌症选自黑色素瘤、食管癌、乳腺癌、胆管癌、肺癌、肝癌、结直肠癌、头颈部癌、纤维肉瘤、骨肉瘤、胰腺癌、卵巢癌、神经内分泌肿瘤的至少之一；
    优选地，所述表达FAP的肿瘤、癌症选自纤维肉瘤、骨肉瘤、胰腺癌和卵巢癌的至少之一。
  23. 权利要求1～13、16任一项所述的化合物或权利要求14～15、17～18任一项所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前 药，或权利要求19～20任一项所述的药物组合物在用于诊断和/或治疗和/或预防高表达FAP相关的疾病的应用。
  24. 权利要求1～13、16任一项所述的化合物或权利要求14～15、17～18任一项所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或权利要求19～20任一项所述的药物组合物在制备一种或多种用于抑制FAP表达的试剂和/或药物中的应用。
  25. 一种对表达FAP组织进行成像的方法，其特征在于，所述方法包括：
    向所述组织施加权利要求14～15、17～18任一项所述的络合物或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或权利要求19～20任一项所述的药物组合物；
    对所述组织采用PET成像。
  26. 权利要求1～13、16任一项所述的化合物或权利要求14～15、17～18任一项所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或权利要求19～20任一项所述的药物组合物在用于诊断和/或治疗和/或预防表达FAP的肿瘤、癌症中的用途。
  27. 一种诊断和/或治疗和/或预防表达FAP的肿瘤、癌症方法，其特征在于，给与患者药学上可接受剂量的权利要求1～13、16任一项所述的化合物或权利要求14～15、17～18任一项所述的络合物，或其立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，或权利要求19～20任一项所述的药物组合物。
  28. 根据权利要求26所述的用途或权利要求27所述的方法，其特征在于，所述表达FAP的肿瘤、癌症选自黑色素瘤、食管癌、乳腺癌、胆管癌、肺癌、肝癌、结直肠癌、头颈部癌、纤维肉瘤、骨肉瘤、胰腺癌、卵巢癌、神经内分泌肿瘤的至少之一；
    优选地，所述表达FAP的肿瘤、癌症选自纤维肉瘤、骨肉瘤、胰腺癌和卵巢癌的至少之一。
PCT/CN2023/124323 2022-10-14 2023-10-12 靶向成纤维细胞活化蛋白的药物及其应用 WO2024078592A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211260609.3 2022-10-14
CN202211260609 2022-10-14

Publications (1)

Publication Number Publication Date
WO2024078592A1 true WO2024078592A1 (zh) 2024-04-18

Family

ID=90639905

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/124323 WO2024078592A1 (zh) 2022-10-14 2023-10-12 靶向成纤维细胞活化蛋白的药物及其应用

Country Status (2)

Country Link
CN (1) CN117883585A (zh)
WO (1) WO2024078592A1 (zh)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111511408A (zh) * 2017-10-23 2020-08-07 约翰霍普金斯大学 靶向成纤维细胞活化蛋白-α(FAP-α)的成像剂及放射治疗剂
CN111699181A (zh) * 2018-02-06 2020-09-22 海德堡大学 Fap抑制剂
WO2021160825A1 (en) * 2020-02-12 2021-08-19 Philochem Ag Fibroblast activation protein ligands for targeted delivery applications
CN114790195A (zh) * 2020-12-21 2022-07-26 苏州药明博锐生物科技有限公司 成纤维细胞活化蛋白抑制剂
CN114790194A (zh) * 2020-12-21 2022-07-26 苏州药明博锐生物科技有限公司 成纤维细胞活化蛋白抑制剂
CN114790193A (zh) * 2020-12-21 2022-07-26 苏州药明博锐生物科技有限公司 成纤维细胞活化蛋白抑制剂
WO2022212958A1 (en) * 2021-04-02 2022-10-06 The Johns Hopkins University Heterobivalent and homobivalent agents targeting fibroblast activation protein alpha and/or prostate-specific membrane antigen
WO2023236778A1 (zh) * 2022-06-10 2023-12-14 北京大学 一种三功能化合物及其用途

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111511408A (zh) * 2017-10-23 2020-08-07 约翰霍普金斯大学 靶向成纤维细胞活化蛋白-α(FAP-α)的成像剂及放射治疗剂
CN111699181A (zh) * 2018-02-06 2020-09-22 海德堡大学 Fap抑制剂
WO2021160825A1 (en) * 2020-02-12 2021-08-19 Philochem Ag Fibroblast activation protein ligands for targeted delivery applications
CN114790195A (zh) * 2020-12-21 2022-07-26 苏州药明博锐生物科技有限公司 成纤维细胞活化蛋白抑制剂
CN114790194A (zh) * 2020-12-21 2022-07-26 苏州药明博锐生物科技有限公司 成纤维细胞活化蛋白抑制剂
CN114790193A (zh) * 2020-12-21 2022-07-26 苏州药明博锐生物科技有限公司 成纤维细胞活化蛋白抑制剂
WO2022212958A1 (en) * 2021-04-02 2022-10-06 The Johns Hopkins University Heterobivalent and homobivalent agents targeting fibroblast activation protein alpha and/or prostate-specific membrane antigen
WO2023236778A1 (zh) * 2022-06-10 2023-12-14 北京大学 一种三功能化合物及其用途

Also Published As

Publication number Publication date
CN117883585A (zh) 2024-04-16

Similar Documents

Publication Publication Date Title
TWI401255B (zh) 用以抑制有絲分裂之化合物
JP2021519766A (ja) ＸＩＩａ因子インヒビター
JP2021523887A (ja) ＸＩＩａ因子インヒビター
CN102131390A (zh) 三唑并吡啶jak抑制剂化合物和方法
RU2762893C2 (ru) Применение ингибитора ezh2 в комбинации с ингибитором btk в получении лекарственного средства для лечения опухоли
CN114026072A (zh) 治疗特发性肺纤维化的方法
KR20220120629A (ko) 단백질 분해제 화합물의 제조방법 및 용도
CN109563088B (zh) MEK/PI3K和mTOR/MEK/PI3K的多功能抑制剂和治疗用途
JP2021519312A (ja) カルパインモジュレーター及びその治療的使用
CN112409376A (zh) 一种基于dcaf15的蛋白降解靶向嵌合体及其制备方法和应用
KR20220115557A (ko) 아마이드 유도체 및 그 제조방법과 의학적 응용
CN114516857A (zh) Hpk1抑制剂及其用途
WO2023125928A1 (zh) Menin抑制剂及其用途
KR20230118593A (ko) Alk-5 억제제 및 이의 용도
JP2024511466A (ja) Ａｌｋ－５阻害剤及びその使用
JP6885390B2 (ja) Ａｘｌ阻害剤と免疫チェックポイント阻害剤とを組み合わせて投与することを特徴とする癌治療のための医薬
EP2008658A1 (en) Synergistic combination of anthranilamide pyridinureas and benzamide derivatives
JP2010507626A (ja) Ｖｅｇｆｒ３阻害剤としての大環状キナゾリン誘導体
WO2024078592A1 (zh) 靶向成纤维细胞活化蛋白的药物及其应用
TW201343169A (zh) 使用奧諾拉（ａｕｒｏｒａ）激酶抑制劑治療癌症的方法
WO2022051616A1 (en) Cdk targeted heterobifunctional small molecule proteolysis targeting chimeras
CN118681033A (zh) 靶向成纤维细胞活化蛋白的药物及其用途
WO2021218992A1 (zh) 取代的吡咯烷类化合物及其在药物中的应用
TW201628621A (zh) 泛素活化酶抑制劑及輻射之施用
TW202346293A (zh) 含氮雜環衍生物及其组合物和藥學上的應用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23876791

Country of ref document: EP

Kind code of ref document: A1