WO2023025248A1 - 一种甾体化合物及其缀合物 - Google Patents
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
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- 229950009675 nerelimomab Drugs 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
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- 229950004327 ozoralizumab Drugs 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- KBHBDZQAQRNXRB-UHFFFAOYSA-N propan-2-olate;titanium(3+) Chemical compound [Ti+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] KBHBDZQAQRNXRB-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N tetraisopropyl titanate Substances CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
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Images
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
Definitions
- the present application relates to the field of biomedicine, in particular to a steroid compound and a conjugate thereof.
- Inflammation is an adaptive response triggered by a variety of noxious stimuli and states that underlies many human immune system-related diseases.
- Steroids are a class of anti-inflammatory drugs that may have the potential to affect immune system function, treat or prevent diseases and/or symptoms associated with glucocorticoid receptor signaling, however some existing steroids have anti-inflammatory effects Not strong, other steroids can have many unwanted side effects. Therefore, there is an urgent need to further develop various steroid-forming antibody-conjugated drugs and steroidal compounds as drugs that can exert better curative effect or have better safety.
- the application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof , which can have one or more effects selected from the following groups: (1) have the ability to affect the activity of immune cells; (2) their conjugates have a targeting effect; (3) have plasma stability; (4) It has biological safety; (5) has the ability to affect the cytokine release of immune cells; (6) has the ability to affect the transcription of IFN signaling pathway response genes; (7) has the ability to affect the degree of skin fibrosis; (8) has the ability to affect (9) the ability to affect the collagen content of the skin; (10) the ability to affect the expression level of GRE; (11) the ability to affect the cytokine release of monocytes; (12) ) has the ability to affect contact hypersensitivity; (13) has the ability to affect skin swelling and (14) has the ability to affect arthritis symptoms.
- the application provides immunoconjugates comprising a glucocorticoid receptor agonist linked to a protein (eg, an antibody or antigen-binding fragment thereof and a soluble receptor protein).
- a protein eg, an antibody or antigen-binding fragment thereof and a soluble receptor protein.
- the antibody or antigen-binding fragment thereof is human, humanized, chimeric or murine.
- proteins eg, antibodies, antigen-binding fragments thereof, or soluble receptor proteins
- proteins can bind to targets on the cell surface and become internalized.
- the application provides a compound of formula I:
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group
- B does not exist or B is any group
- W does not exist or W is any group
- A1 is a substituted benzene ring
- X is selected from: -O-, -S-, -NR-;
- Y 1 is any group, and m is any integer from 0 to 4.
- the present invention provides a compound represented by the following formula or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof, wherein said compound is selected from:
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group
- B does not exist or B is any group
- W does not exist or W is any group
- A2 is a substituted benzene ring
- X is selected from: -O-, -S-, -NR-;
- Y 1 is any group, and m is any integer from 0 to 4.
- Y2 is selected from -O-, -S- and -NR-;
- the present application provides a conjugate comprising the aforementioned compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or in the form of a mixture, or a pharmaceutically acceptable salt thereof.
- the present application provides a pharmaceutical composition, which comprises the aforementioned compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or A mixture thereof, or a pharmaceutically acceptable salt thereof and/or the aforementioned conjugate, and optionally a pharmaceutically acceptable carrier.
- the present application provides a method for affecting the function of the immune system, comprising administering the aforementioned compounds or their tautomers, mesoforms, racemates, enantiomers, non- Enantiomers, or their mixtures, or their pharmaceutically acceptable salts, the aforementioned conjugates and/or the aforementioned pharmaceutical compositions.
- glucocorticoid generally refers to a naturally occurring steroid hormone or a synthetic steroid hormone that interacts with the glucocorticoid receptor.
- halogen generally refers to fluorine, chlorine, bromine, iodine, for example, it may be fluorine, chlorine.
- alkyl generally refers to a residue derived from an alkane by removing a hydrogen atom. Alkyl groups can be substituted or unsubstituted, substituted or unsubstituted.
- alkyl generally refers to a saturated straight or branched chain aliphatic hydrocarbon group having a residue derived by removing a hydrogen atom from the same carbon atom or two different carbon atoms of a parent alkane, which may be in the range of 1 to A linear or branched chain group of 20 carbon atoms, for example an alkyl group containing 1 to 12 carbon atoms, for example an alkyl group containing 1 to 6 carbon atoms.
- alkyl groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, and the like.
- Alkyl groups may be substituted or unsubstituted, substituted or unsubstituted, for example when substituted, substituents may be substituted at any available point of attachment, said substituents may be independently optionally selected from alkyl , alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, substituted by one or more substituents, such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , - CN, -OH,
- alkylene generally refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two hydrogen atoms derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane , which may be a straight-chain or branched group containing 1 to 20 carbon atoms, for example, the term “methylene” may refer to a residue derived from a group of 1 carbon atom minus two hydrogen atoms base. A methylene group may be substituted or unsubstituted, substituted or unsubstituted; for example an alkylene group containing 1 to 12 carbon atoms, for example containing 1 to 6 carbon atoms.
- Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and 1,5-butylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) wait.
- Alkylene may be substituted or unsubstituted, substituted or unsubstituted, for example when substituted, substituents may be substituted at any available point of attachment, said substituents may be independently optionally selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy
- substituents in group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group and oxo group such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH
- alkenyl generally refers to a straight or branched chain hydrocarbon group containing one or more double bonds.
- alkenyl groups include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, and the like.
- C2-6 alkenyl groups having more than one double bond include butadienyl, pentadienyl, hexadienyl, and hexatrienyl and branched forms thereof.
- the position of the unsaturated bond (double bond) can be any position in the carbon chain.
- Alkenyl groups can be substituted or unsubstituted.
- alkenylene generally refers to a residue derived by removing two hydrogen atoms from an alkene carbon atom.
- alkenylene groups can be substituted or unsubstituted.
- alkynyl generally refers to an unsaturated straight chain or branched chain alkynyl, such as ethynyl, 1-propynyl, propargyl, butynyl and the like. Alkynyl groups can be substituted or unsubstituted.
- alkynylene generally refers to a residue having two hydrogen atoms removed from the carbon atoms of an alkyne.
- alkynylene groups can be substituted or unsubstituted.
- aryl generally refers to a residue derived from an aromatic ring by removing a hydrogen atom.
- aromatic ring may refer to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (that is, a ring sharing adjacent pairs of carbon atoms) having a conjugated ⁇ -electron system, which may be 6 to 10 membered, such as benzene and naphthalene.
- the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring where the ring bonded to the parent structure is an aryl ring.
- Aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , and heterocycloalkylthio.
- Aryl groups can be substituted or unsubstituted.
- arylene generally refers to a residue derived by removing two hydrogen atoms from a carbon atom of an aromatic ring.
- phenylene and naphthylene may be mentioned.
- Arylene groups can be substituted or unsubstituted.
- heteroaryl generally refers to a residue having a hydrogen atom removed from a carbon atom of a heteroaryl ring.
- heteroaryl ring refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen.
- Heteroaryl can be 5 to 10 membered, can be 5 or 6 membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazole Base etc.
- the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
- Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents may be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy radical, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, and heterocycloalkylthio.
- Heteroaryl groups can be substituted or unsubstituted.
- heteroarylene generally refers to a residue derived by removing two hydrogen atoms from a carbon atom of a heteroaryl ring.
- it may be a furylylene group, a thienylene group, a pyridylene group, a pyrrolylene group, a pyrimidinylene group, a pyrazinylene group, an imidazolyl group, a tetrazolyl group and the like.
- Heteroarylene groups can be substituted or unsubstituted.
- cycloaliphatic and “cycloalkyl” are used interchangeably, and the term “cycloaliphatic” generally refers to a group having a hydrogen atom removed from the same carbon atom or multiple different carbon atoms of the aliphatic ring. derived residues.
- cycloalkane generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocycle containing 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms.
- Non-limiting examples of cycloaliphatic groups include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclo Heptatrienyl, cyclooctyl, etc.; polycyclic carbocycles may include spiro, fused and bridged carbocycles. Alicyclic groups may be substituted or unsubstituted.
- the term "carbocyclyl" generally refers to a residue derived from a carbon atom having a carbocyclic ring by removing one hydrogen atom.
- carbocycle generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocycle contains 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms.
- Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane etc.; polycyclic carbocycles may include spiro, fused and bridged carbocycles. Carbocyclyl groups can be substituted or unsubstituted. In some instances, alicyclic and carbocyclic rings can be used interchangeably.
- partially unsaturated generally refers to a ring structure containing at least one double or triple bond between ring molecules.
- partially unsaturated encompasses cyclic structures with multiple sites of unsaturation, but is not intended to include aromatic or heteroaromatic rings as defined herein.
- unsaturated means that the moiety has one or more degrees of unsaturation.
- alicyclic group and “cycloalkylene” can be used interchangeably, and the term “alicyclic group” generally refers to a Residues.
- polycyclic carbocycles may include spiro rings, fused rings and bridged ring carbocycles.
- Alicyclylene groups may be substituted or unsubstituted.
- aliphatic heterocyclic group and “heterocyclic group” can be used interchangeably, and the term “aliphatic heterocyclic group” generally refers to a stable non-aromatic 3-7 membered monocyclic carbon ring structure , fused 7-10-membered bicyclic heterocyclic ring structure or bridged 6-10-membered bicyclic heterocyclic ring structure, these ring structures can be saturated or partially saturated, except for carbon atoms, these rings
- the structure also contains one or more heteroatoms, wherein the heteroatoms can be selected from the following group: oxygen, sulfur and nitrogen. For example, it contains 1-4 heteroatoms as defined above.
- the term "nitrogen” may include substituted nitrogen.
- the aliphatic heterocyclic group can include “heterocycloalkyl", and the heterocycloalkyl group can refer to a stable non-aromatic 3-7-membered monocycloalkane structure, a fused 7-10-membered bicyclic heterocyclic structure or Bridged 6- to 10-membered bicyclic heterocyclic structures, in addition to carbon atoms, these ring structures also contain one or more heteroatoms, wherein the heteroatoms can be selected from the following group: oxygen, sulfur and nitrogen. For example, it contains 1-4 heteroatoms as defined above.
- Heterocycloalkyl groups can be substituted or unsubstituted.
- Alicyclic groups may be substituted or unsubstituted.
- aliphatic heterocyclic group and “heterocyclic group” can be used interchangeably, and the term “aliphatic heterocyclic group” generally refers to a derived residues.
- the heteroalicyclic group may be substituted or unsubstituted.
- ring structures such as cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl, heteroarylene, etc.
- prefixes for example, C 3 -C 20 , C 3 -C 7 , C 5 -C 6 , etc.
- C 5 -C 6 heterocyclyl as used in this application relates to a heterocyclyl group having 5 or 6 ring atoms.
- C 5 -C 10 heteroaryl described in this application refers to a heteroaryl group having 5 to 10 ring atoms.
- ring atom or "ring atom” generally refers to an atom contained on a ring structure.
- the ring-forming atom may be a carbon atom on a benzene ring, or a nitrogen atom on a pyridine ring.
- the ring-forming atom may be substituted or unsubstituted.
- each independently generally means that the variables apply in any one instance, regardless of the presence or absence of variables with the same or different definitions in the same compound.
- the variable may refer to the type and number of substituents in the compound or the type of atoms in the compound.
- R occurs twice in a compound and R is defined as "independently carbon or nitrogen”
- both R may be carbon, both R may be nitrogen, or one R may be carbon and the other R may be nitrogen.
- a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description may include cases where a heterocyclic group is substituted by an alkyl group and cases where a heterocyclic group is not substituted by an alkyl group. situation.
- substituted generally refers to one or more hydrogen atoms in a group, for example up to 5, for example 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents. Substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
- the substituents of an "optionally substituted" group may include, but are not limited to, one or more substituents independently selected from the following groups or a specified group of groups, alone or in combination: lower alkane lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy group, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyl ester, lower methyl Amido, cyano, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower
- Two substituents may be joined together to form a five-, six- or seven-membered aromatic or non-aromatic carbocyclic or heterocyclic ring containing one to three heteroatoms, for example to form methylenedioxy or ethylenedioxy.
- Optionally substituted groups can be under-substituted (eg -CH 2 CH 3 ), fully substituted (eg -CF 2 CF 3 ), mono-substituted (-CH 2 CH 2 F) or between fully substituted and mono Any horizontal substitution between substitutions (eg -CH 2 CF 3 ).
- substitutions eg -CH 2 CF 3
- substituent When a substituent is identified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents for a particular moiety may be defined as desired; in these cases, the optional substitution is defined, usually immediately following the phrase “optionally substituted by".
- the term “lower” when used in connection with an organic group or compound means that the compound or group may be branched or unbranched, having up to and including 7 carbon atoms, eg 1-4 carbon atoms.
- Lower alkyl represents, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and branched pentyl, n-hexyl and branched hexyl.
- the term 0 or more (eg, 0 or more, 0 or 1, 0) methylene units are "substituted" generally refers to when the structure contains 1 or more
- alkyl alkenyl
- cycloalkyl and the like can be preceded by a mark to indicate the presence of The number of atoms, for example, C 1 -C 4 alkyl, C 3 -C 7 cycloalkoxy, C 1 -C 4 alkylcarbonylamino, etc., the subscript numbers following "C” indicate the presence in the group number of carbon atoms.
- C3 alkyl refers to an alkyl group having three carbon atoms (e.g., n-propyl, isopropyl); in C1-10 , the members of the group can have any number falling within the range of 1-10 of carbon atoms.
- One or more hydrogen atoms in a group eg up to 5, eg 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents.
- Substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
- an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
- the term "compound” generally refers to a substance having two or more different elements.
- the compound of the present application can be an organic compound, for example, the compound of the present application can be a compound with a molecular weight of 500 or less, a compound with a molecular weight of 1,000 or less, or a compound with a molecular weight of 1,000 or more, or a compound with a molecular weight of 10,000 or more, or 100,000 or more. compound.
- a compound may also refer to a compound connected by a chemical bond, for example, a compound in which one or more molecules with a molecular weight below 1000 are connected to a biomacromolecule through a chemical bond, and the biomacromolecule may be a polysaccharide, protein , nucleic acids, peptides, etc.
- the compound of the present application may include a compound in which a protein is linked to one or more molecules with a molecular weight below 1000, may include a compound in which a protein is linked to one or more molecules with a molecular weight below 10,000, or may include a compound in which a protein is linked to one or more molecules with a molecular weight of Compounds with less than 100,000 molecules connected.
- the pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
- sterile fixed oils are conveniently employed as a solvent or suspending medium. For example, any blend of fixed oils including synthetic mono- or diglycerides may be employed.
- fatty acids such as oleic acid are prepared as injectables.
- the compounds of the present application include tautomers, mesoforms, racemates, enantiomers, and/or diastereoisomers of the compounds.
- the term “diastereomer” generally refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers can have different physical properties, eg, melting points, boiling points, spectral properties and reactivity.
- the terms “tautomer” or “tautomeric form” are used interchangeably and generally refer to structural isomers of different energies that are interconvertible through a low energy barrier.
- proton tautomers also known as prototropic tautomers
- proton tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol isomerization Amine isomerization.
- Valence tautomers include interconversions by recombination of some of the bonding electrons.
- the term “mesoform” generally refers to an atom containing asymmetry in a molecule, but having a symmetry factor so that the total optical rotation in the molecule is zero.
- racemate or “racemic mixture” refers to a composition consisting of equimolar amounts of two enantiomeric species.
- certain atoms of the compounds of the present application may occur in more than one isotopic form.
- hydrogen may exist as protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H), and carbon may occur naturally as three different isotopes ( 12 C, 13 C, and 14 C).
- isotopes that may be incorporated into compounds of the present application also include, but are not limited to , 15 N, 18 O, 17 O, 18 F, 32 P, 33 P, 129 I, 131 I, 123 I, 124 I, 125 I, or the like isotopes. Accordingly, compounds of the present application may be enriched in one or more of these isotopes relative to their natural abundance.
- Such isotopically enriched compounds are useful for a variety of purposes, as is known to those skilled in the art.
- substitution with heavy isotopes such as deuterium ( 2H ) may afford certain therapeutic advantages, possibly due to greater metabolic stability.
- deuterium ( 2H ) has a natural abundance of about 0.015%. Therefore, there is one deuterium atom for about every 6500 hydrogen atoms in nature. Accordingly, deuterium-containing compounds of the present invention have a deuterium abundance at one or more positions (as the case may be) greater than 0.015%.
- structures depicted herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, except that the hydrogen atom is replaced by deuterium or tritium, or the carbon atom is replaced by carbon 13 or carbon 14, the compounds whose structure is consistent with the present application are within the scope of the present application.
- isomers generally refer to different compounds having the same molecular formula.
- Stepoisomers generally refer to isomers that differ only in the arrangement of their atoms in space.
- the term “isomer” includes any and all geometric isomers and stereoisomers.
- isomers include geometric double bond cis and trans isomers, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof falling within the scope of the present disclosure.
- enantiomer generally refers to a pair of stereoisomers that are non-superimposable mirror images of each other.
- a 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
- the term “( ⁇ )” is used to denote a racemic mixture.
- “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. The stereochemistry at each chiral carbon may be designated by R or S when the compound is a pure enantiomer.
- Resolved compounds whose absolute configuration is unknown can be assigned (+) or (-) according to the direction in which they rotate plane polarized light (dextrorotatory or levorotatory) at the wavelength of the sodium D line.
- Certain compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers and other stereoisomeric forms that can be defined in terms of absolute stereochemistry, such as (R)- or (S)-.
- the chemical entities, pharmaceutical compositions and methods of the present application are intended to embrace all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
- Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that the compounds include both E and Z geometric isomers.
- the term "enantiomeric purity” generally refers to the relative amount, expressed as a percentage, of a particular enantiomer present relative to the other enantiomer. For example, if a compound that may have (R)- or (S)-isomeric configuration exists as a racemic mixture, then for either (R)- or (S)-isomer, the The enantiomeric purity was about 50%. If one conformational form of the compound is superior to the other, for example, 80% (S)- and 20% (R)-, then the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80 %.
- the enantiomeric purity of a compound can be determined by a variety of means known in the art, including but not limited to chromatography using chiral supports, polarimetry by rotation of polarized light, using chiral shift reagents (including but not limited to those containing NMR spectroscopy of chiral complexes of lanthanides or Pirkle alcohols), or derivatization of compounds with chiral compounds such as Mosher acids followed by chromatography or NMR spectroscopy.
- tautomer generally refers to a type of isomer that includes at least one form of migration from a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond , triple bond to double bond or triple bond to single bond, and vice versa) resulting in two or more interconvertible compounds.
- Tautomerization includes prototropic or proton-moving tautomerization, which is considered a subset of acid-base chemistry.
- Prototropic tautomerization or “proton shift tautomerization” involves the migration of protons with a concomitant change in bond order. The exact ratio of tautomers depends on many factors including temperature, solvent and pH.
- Tautomerization ie, a reaction affording a pair of tautomers
- exemplary tautomerisms include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(different)enamine tautomerisms structure.
- keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
- tautomerization is phenol-keto tautomerization.
- a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
- the term "pharmaceutical composition” generally refers to a mixture containing one or more compounds described in this application or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components Classes such as physiological/pharmaceutically acceptable carriers and excipients.
- the pharmaceutical composition can promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.
- the preparation of conventional pharmaceutical compositions can be found in Chinese Pharmacopoeia.
- the term "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” generally refers to the salt of the compound or the ligand-drug conjugate of the present application, or the salt of the compound described in the present application, Such salts may have safety and/or effectiveness when used in mammals, and may have proper biological activity.
- the antibody-antibody drug conjugate compound of the present application may form a salt with an acid, and the pharmaceutically acceptable salt
- Non-limiting examples include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, pear salt, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethyl Sulfonate, benzenesulfonate, p-toluenesulfonate.
- Immunoconjugates can also be defined by the following general formula in reverse order: A-(Q-L-SM)n.
- linker generally refers to any chemical moiety capable of linking a protein (eg, antibody, antibody fragment (eg, antigen-binding fragment) or functional equivalent) to a glucocorticoid.
- the linker may be sensitive to cleavage ("cleavable linker"), thereby facilitating the release of the glucocorticoid.
- cleavable linkers may be sensitive to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage under conditions in which glucocorticoids and/or antibodies remain active .
- the linker can be substantially resistant to cleavage ("non-cleavable linker").
- drug antibody ratio refers to the ratio of A (i.e. protein, such as antibody or antigen-binding fragment thereof, anti-TNF protein, anti-TNF-alpha antibody or fragment thereof, soluble receptor or soluble TNF receptor)-linked SMs (ie, groups derived from small molecule glucocorticoid receptor agonists (eg, glucocorticoids)).
- A i.e. protein, such as antibody or antigen-binding fragment thereof, anti-TNF protein, anti-TNF-alpha antibody or fragment thereof, soluble receptor or soluble TNF receptor
- SMs ie, groups derived from small molecule glucocorticoid receptor agonists (eg, glucocorticoids)
- DAR When referring to a compound of formula (SM-L-Q)n-A representing an individual immunoconjugate, DAR generally refers to the number of SMs attached to an individual A (eg, n is an integer from 1 to 10).
- DAR When referring to a compound of formula (SM-L-Q)n-A representing a variety of immunoconjugates, DAR generally refers to the average number of SMs attached to A (eg, n is an integer or fraction from 1 to 10). Thus, by way of example, a DAR of a compound of formula (SM-L-Q)n-A comprising a first immunoconjugate containing 3 SMs per A and a second immunoconjugate containing 4 SMs per A (ie, "n") was 3.5.
- a non-cleavable linker is generally any chemical moiety capable of linking a glucocorticoid to an antibody in a stable covalent manner and does not fall off under the categories listed above for cleavable linkers.
- a non-cleavable linker is substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.
- non-cleavable means that the chemical bonds in or adjacent to the linker are subjected to cleavage by acids, photolabile cleavage agents, peptidases, esterases, or cleavage disulfides without the glucocorticoid and/or antibody losing their activity.
- acids photolabile cleavage agents
- peptidases peptidases
- esterases or cleavage disulfides without the glucocorticoid and/or antibody losing their activity.
- the ability of a bond to be cleaved induced by a chemical or physiological compound.
- cleavable linkers are cleaved by peptidases ("peptidase cleavable linkers"). Only certain peptides are prone to cleavage inside or outside the cell, see e.g. Trout et al., Proc. Natl. Acad. Sci. USA [Proc. [International Journal of Cancer], 677-684 (1989). Furthermore, peptides are composed of ⁇ -amino acid units and peptide bonds, which are chemically amide bonds between the carboxylic acid of one amino acid and the amino group of a second amino acid. Other amide bonds (such as the bond between the carboxylic acid of lysine and the ⁇ -amino acid group) are understood not to be peptide bonds and are considered non-cleavable.
- linkers are cleaved by esterases ("esterase cleavable linkers"). Only certain esters can be cleaved by esterases present inside or outside the cell. Esters are formed by the condensation of carboxylic acids and alcohols. Simple esters are those produced with simple alcohols such as aliphatic alcohols and small cyclic and small aromatic alcohols.
- the cleavable linker component may comprise a peptide comprising 1 to 10 amino acid residues.
- the peptide allows proteases to cleave the linker, thereby promoting the release of glucocorticoids upon exposure to intracellular proteases such as lysosomal enzymes (Doronina et al. (2003) Nat.Biotechnol. [Natural Biotechnology] 21 :778-784).
- Exemplary peptides include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides.
- Exemplary dipeptides include, but are not limited to, alanine-alanine (ala-ala); valine-citrulline (vc or val-cit); alanine-phenylalanine (af or ala-phe ); phenylalanine-lysine (fk or phe-lys); phenylalanine-homolysine (phe-homolys); and N-methyl-valine-citrulline (Me-val -cit).
- Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (glv-val-cit) and glycine-glycine-glycine (gly-gly-gly).
- a peptide may comprise naturally occurring amino acid residues and/or non-natural amino acid residues.
- naturally occurring amino acid generally refers to Ala, Asp, Cys, Glu, Phe, Gly, His, He, Lys, Leu, Met, Asn, Pro, Gin, Arg, Ser, Thr, Val, Trp, and Tyr.
- non-natural amino acids include homoserine, homoarginine, citrulline, phenylglycine, taurine, iodotyrosine, seleno Cysteine, Norleucine ("Nle”), Norvaline (“Nva”), Beta-Alanine, L-Naphthylalanine or D-Naphthylalanine, Ornithine (“Orn”) etc.
- Peptides can be designed and optimized for enzymatic cleavage by specific enzymes (eg, tumor-associated proteases, cathepsins B, C, and D, or plasmin proteases).
- Amino acids can also include D-forms of natural and unnatural amino acids.
- D- indicates an amino acid having a “D” (dextrorotatory) configuration, as opposed to the configuration in naturally occurring (“L-”) amino acids.
- Natural and unnatural amino acids are either commercially available (Sigma Chemical Co., Advanced Chemtech) or can be synthesized using methods known in the art.
- the term "pharmaceutically acceptable carrier” generally refers to a vehicle for administering therapeutic agents, such as antibodies or polypeptides, genes and other therapeutic agents.
- the term refers to any pharmaceutical carrier that does not itself induce antibody production deleterious to the individual receiving the composition and that can be administered without undue toxicity.
- Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polyamino acids, amino acid copolymers, lipid aggregates and inactivated virus particles. Such vectors are well known to those skilled in the art.
- Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may also be present in these carriers.
- anti-TNF ⁇ protein generally refers to a protein capable of (i) binding to TNF ⁇ and (ii) inhibiting the binding of soluble TNF- ⁇ to cell surface TNF receptors (p55 and/or p75) and/or in the presence of complement
- the protein is lysed in vitro from cells expressing surface TNF ⁇ or TNF ⁇ receptors.
- Anti-TNFa proteins include, for example, anti-TNF antibodies or antigen-binding fragments thereof (eg, adalimumab or infliximab) and soluble TNF receptors (eg, etanercept).
- antibody generally refers to an immunoglobulin reactive with a specified protein or peptide or a fragment thereof.
- Antibodies can be antibodies from any class, including but not limited to IgG, IgA, IgM, IgD, and IgE, and antibodies from any subclass (eg, IgGl, IgG2, IgG3, and IgG4).
- the antibody can have a heavy chain constant region selected from, for example, IgGl, IgG2, IgG3, or IgG4.
- Antibodies may also have light chains selected from eg kappa ( ⁇ ) or lambda ( ⁇ ).
- Antibodies of the present application may be derived from any species.
- the term "antibody” may include intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising antibodies, and any other modified immunoglobulin molecule so long as these antibodies exhibit produce the desired biological activity.
- an antigen binding domain generally refers to a portion of an antibody molecule comprising the amino acids responsible for the specific binding between the antibody and the antigen.
- the portion of an antigen that is specifically recognized and bound by an antibody is called an "epitope" as described above.
- an antigen binding domain may typically comprise an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH); however, it need not necessarily comprise both.
- Fd fragments for example, have two VH regions and typically retain some antigen-binding function of the full antigen-binding domain.
- antigen-binding fragments of antibodies include (1) Fab fragments, monovalent fragments having VL, VH, constant light chain (CL) and CH1 domains; (2) F(ab')2 fragments, having two Bivalent fragment of two Fab fragments connected by sulfur bridge; (3) Fd fragment with two VH and CH1 domains; (4) Fv fragment with VL and VH domains of antibody single arm, (5) dAb fragment (Ward et al., "Binding Activities of a Repertoire of Single Immunoglobulin Variable Domains Secreted From Escherichia coli," Nature 341:544-546 (1989), which is incorporated herein by reference in its entirety), which has a VH domain; ( 6) Isolated Complementarity Determining Regions (CDRs); (7) Single-chain Fv (scFv), for example derived from a scFv-library.
- Fab fragments monovalent fragments having VL, VH, constant light chain (CL) and CH1 domain
- the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows it to be produced as a single protein in which the VL and VH regions pair to form a monovalent molecule chain (termed single-chain Fv (scFv)) (see, e.g., Huston et al., "Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in Escherichia coli," Proc. Natl.
- VHH relates to a variable antigen-binding domain from a heavy chain antibody of Camelidae (camel, dromedary, llama, alpaca, etc.) (see Nguyen V.K. et al., 2000, The EMBO Journal, 19, 921-930; Muyldermans S., 2001, J Biotechnol., 74, 277-302 and review Vanlandschoot P. et al., 2011, Antiviral Research 92, 389-407) . VHHs may also be referred to as Nanobodies (Nb).
- variable region or “variable domain” generally refers to the domains of the heavy or light chain of an antibody that participate in the binding of the antibody to an antigen.
- variable generally means that certain parts of the sequence of variable domains of antibodies vary strongly, resulting in the binding and specificity of various specific antibodies to their specific antigens. The variability is not evenly distributed throughout the variable regions of antibodies. It is concentrated in three segments in the light chain variable region and the heavy chain variable region, called complementarity determining regions (CDR) or hypervariable regions (HVR), respectively LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3. The more highly conserved portions of variable domains are called the framework regions (FR).
- CDR complementarity determining regions
- HVR hypervariable regions
- variable domains of native heavy and light chains each comprise four FR regions (H-FR1, H-FR2, H-FR3, H-FR4, L-FR1, L-FR2, L-FR3, L-FR4) , most adopt a ⁇ -sheet configuration, connected by three CDR structural loop regions.
- the CDRs in each chain are in close proximity together by the FR regions and, together with the CDRs from the other chain, form the antigen-binding site of the antibody.
- variable regions of antibodies can be encoded or the CDRs of antibodies can be delimited by various methods, such as the Kabat numbering scheme and definition rules based on sequence variability (see, Kabat et al., Protein Sequences in Immunology, 5th ed., National Institutes of Health, Bethesda, MD (1991), Chothia numbering scheme and definition rules based on the location of structural loop regions (see, A1-Lazikani et al., JMol Biol 273:927-48, 1997 ), efranc et al.'s IMGT numbering scheme and definition rules based on the amino acid sequence alignment of germline V genes, as well as Honneger's numbering scheme (AHo's), Martin numbering scheme, Gelfand numbering scheme, etc., can be found in Mathieu Dondelinger et al., Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition, Front. Immuno
- percent (%) sequence identity generally refers to the amino acids with which two or more aligned amino acid sequences are identical compared to the number of amino acid residues that make up the total length of these amino acid sequences The number of matches ("hits") for .
- alignment is used, for two or more sequences, when the sequences are compared and aligned for maximum correspondence (as measured using sequence comparison algorithms known in the art), or when manually aligned and visually Upon inspection, the percentage of amino acid residues that are identical (eg, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity) can be determined.
- sequences compared to determine sequence identity can be distinguished by one or more amino acid substitutions, additions or deletions.
- Suitable programs for aligning protein sequences are known to those skilled in the art.
- the percent sequence identity of protein sequences can be determined, for example, with programs such as CLUSTALW, Clustal Omega, FASTA or BLAST, for example using the NCBI BLAST algorithm (AltschulSF et al. (1997), Nucleic Acids Res. 25:3389-3402) .
- antibody analogue is generally used in the broadest sense and encompasses in particular molecules which specifically bind a target molecule with a monospecificity and which differ structurally from natural antibodies.
- antibody analog refers to an antibody comprising a segment of substantial identity to a portion of the amino acid sequence and having at least one of the following properties : (1) specific binding to PD-1 or PD-L1 under appropriate binding conditions, (2) ability to inhibit at least one biological activity of PD-1 or PD-L1.
- antibody analogs contain conservative amino acid substitutions (or insertions or deletions) relative to the native sequence.
- Analogs are typically at least 20 or 25 amino acids in length, at least 50, 60, 70, 80, 90, 100, 150, or 200 amino acids in length or longer, and typically can be as long as a full-length heavy or light chain of an antibody .
- Some examples include antibody analogs having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 substitutions compared to the germline amino acid sequence .
- the term "effective amount” or “therapeutically effective amount” generally refers to the amount of the compound or pharmaceutical composition described in the application that is sufficient to achieve the intended application described below, including but not limited to disease treatment .
- the therapeutically effective amount can vary according to: the intended application (in vivo or in vitro); or the subject and the condition to be treated, for example, the weight and age of the subject, the severity of the condition; the mode of administration, etc., which can be determined by ordinary skill in the art Personnel are easily identified.
- the term also applies to doses that will induce a specific response in target cells, such as platelet adhesion and/or cell migration.
- the specific dosage will vary according to, for example, the particular compound chosen, the dosing regimen followed, whether it is administered in combination with other agents, the time of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.
- in vivo generally refers to events that occur within the body of a subject.
- an in vitro assay generally refers to events that occur outside the body of a subject.
- an in vitro assay includes any assay performed outside of a subject.
- In vitro assays include cell-based assays in which live or dead cells are employed.
- In vitro assays also include cell-free assays, in which intact cells are not used.
- treatment and “treating” generally refer to a method of obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit.
- a therapeutic benefit includes, but is not limited to, eradicating, inhibiting, reducing or ameliorating the underlying disorder being treated. Additionally, therapeutic benefit is achieved by eradicating, reducing or ameliorating one or more physiological symptoms associated with the underlying disorder such that improvement is observed in a patient, but the patient may still suffer from the underlying disorder.
- prevention and preventing generally refer to methods of obtaining beneficial or desired results, including but not limited to prophylactic benefits.
- pharmaceutical compositions may be administered to patients at risk of developing a particular disease or to patients reporting one or more physical symptoms of a disease, even if the disease has not yet been diagnosed.
- the term "subject” or “patient” generally refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, adolescent) or an adult subject (e.g., a young humans, middle-aged or elderly)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially related birds such as chickens, ducks, geese, quail, and/or turkeys.
- a human i.e., male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, adolescent) or an adult subject (e.g., a young humans, middle-aged or elderly)) and/or other primates (e.g.
- the terms “about” or “approximately” generally refer to an acceptable error for a particular value as determined by one of ordinary skill in the art, depending in part on the manner in which the value was measured or determined. In certain embodiments, the term “about” or “approximately” generally refers to 1, 2, 3 or 4 standard deviations. In certain embodiments, the term “about” or “approximately” generally refers to 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5% of a given value or range , 4%, 3%, 2%, 1%, 0.5% or 0.05%.
- Figure 1 Inhibitory effect of drug conjugates of the present invention on R848-induced IFN ⁇ , TNF ⁇ , IL-6 and IL-8 in human peripheral blood mononuclear cells.
- FIG. 1 Bioactivity assay in a mouse model of fluorescein isothiocyanate (FITC)-induced delayed type IV hypersensitivity.
- FITC fluorescein isothiocyanate
- Figure 3 Arthritis scores in the DBA/1 mouse arthritis model induced by bovine collagen type II mixed adjuvant. 3a: arthritis score; 3b: AUC of arthritis score.
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group
- B does not exist or B is any group
- W does not exist or W is any group
- A1 is a substituted benzene ring
- X is selected from: -O-, -S-, -NR-;
- Y 1 is any group, and m is any integer from 0 to 4.
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group
- B does not exist or B is any group
- W does not exist or W is any group
- A1 is a substituted benzene ring
- X is selected from: -O-, -S-, -NR-;
- Y 1 is any group, m is 0 or 1;
- R 4 and R 5 together form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl.
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable A salt for use, wherein said R 4 and R 5 are each independently selected from: H, F, Cl, -OH, -NH 2 , C 1 -C 6 alkyl, or said R 4 and R 5 together form C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl; said n is selected from 1, 2 or 3.
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the salt used, wherein said -(CR 4 R 5 ) n - are each independently selected from: -CH 2 -, -CH 2 CH 2 -,
- Y 1 is absent or selected from: protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2.
- each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen substituted C 1 -C 6 alkyl, and halogen substituted C 1 -C 6 alkoxy.
- Y 1 is absent or selected from: protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy radical, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen substituted C 1 -C 6 alkyl, and halogen substituted C 1 -C 6 alkoxy.
- Y 1 is absent or selected from: hydroxyl, mercapto, amino and optionally substituted C 1 -C 6 alkyl.
- A1 structural unit
- R 1 and R 2 are each independently selected from: H, F, Cl, Br and optionally substituted C 1 -C 6 alkyl.
- R 1 and R 2 can be independently selected from: H, F, Cl, Br and optionally substituted methyl.
- R 3 is selected from the group consisting of: hydrogen, optionally substituted -OH, optionally substituted -SH, and optionally substituted C 1 -C 6 alkyl.
- said R 31 is selected from the group consisting of hydrogen, halogen, optionally substituted -OH, and optionally substituted -SH.
- said R 311 is selected from the group consisting of hydrogen, optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted
- said R 32 is selected from the group consisting of hydrogen, and optionally substituted C 1 -C 6 alkyl.
- said R 321 is selected from the group consisting of hydrogen, halogen, -CN, and optionally substituted C 1 -C 6 alkyl.
- said R 321 is selected from the group consisting of hydrogen, F, Cl, -CN, and optionally substituted methyl.
- said R 33 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 6 alkyl.
- said R 33 is optionally substituted methyl.
- said R 331 is selected from the group consisting of hydrogen, chlorine, fluorine, and -CN.
- R 3 can be selected from: optionally substituted -CH 2 Cl, optionally substituted -CH 2 SH, optionally substituted -CH 2 OH, optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted -OH, optionally substituted -OCH3 , optionally substituted -OCH2F , optionally substituted -OCH2Cl , optionally substituted -OCH2CN , optionally substituted -OCH2CH 3.
- Optionally substituted mercapto optionally substituted -SCH 2 F, optionally substituted -SCH 2 Cl, optionally substituted -SCH 2 CF 3 , and optionally substituted -SCH 2 CN.
- said R 1 and R 2 are each independently selected from hydrogen, protium, deuterium, tritium and halogen
- said R 3 is selected from -CH 2 OH, -SCH 2 F
- optionally substituted Optionally substituted Optionally substituted X is selected from the group consisting of N and optionally substituted CH.
- said R6 is selected from the group consisting of hydrogen and optionally substituted -OH.
- said R 61 is selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl.
- the X 1 is selected from the group consisting of CH, C(-O-CH 3 ), and N.
- said B is selected from:
- Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted X2 and X3 are each independently selected from the group consisting of O, S and optionally substituted NH.
- said R 71 is selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl.
- said X2 or X3 is selected from the group consisting of NH, N( CH3 ), O and S.
- said B can be selected from:
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the salt used, wherein said B is selected from:
- the R 8 is optionally substituted methyl.
- said R 81 is selected from the group consisting of halogen and optionally substituted cycloalkyl.
- said R 81 is selected from the group consisting of F and optionally substituted cyclopropyl.
- said W may be absent or W may be selected from:
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the salt used, wherein said W does not exist or W is
- said B may not exist or be selected from:
- Said W may be absent or W is selected from:
- the A1 can be selected from:
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the salt used is selected from
- the X is selected from -O-, -S- and -NH-;
- R 4 and R 5 are each independently selected from the following group: H, F, Cl, -OH, -NH 2 and C 1 -C 6 alkyl;
- n is selected from 1, 2 or 3;
- Said Y does not exist or is selected from: hydroxyl, mercapto, amino and C 1 -C 6 alkyl;
- the R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine and methyl;
- the R 3 is selected from: -CH 2 Cl, -CH 2 SH, -CH 2 OH, -OCH3 , -OCH2F , -OCH2Cl , -OCH2CN, -OCH2CH3 , -SH, -SCH2F , -SCH2Cl , -SCH2CF3 , and -SCH2CN .
- the present invention provides a compound represented by the following formula or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof, wherein said compound is selected from:
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group
- B does not exist or B is any group
- W does not exist or W is any group
- A2 is a substituted benzene ring
- X is selected from: -O-, -S-, -NR-;
- Y 1 is any group, and m is any integer from 0 to 4.
- Y2 is selected from -O-, -S- and -NR-;
- the wavy line in formula IIa or IIb Indicates that it is directly connected to the ligand through the X or Y2 group, or connected to the ligand through the Linker fragment.
- R 4 and R 5 together form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl.
- said R4 and R5 may together form cyclopropyl or cyclobutyl.
- the compounds of the present invention or their tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable A salt for use wherein said R 4 and R 5 are each independently selected from the following groups: H, F, Cl, -OH, -NH 2 and C 1 -C 6 alkyl; said n is selected from 1, 2 or 3.
- Y 1 is selected from the group consisting of: protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , optionally substituted C 1 -C 6 alkyl , optionally substituted C 1 -C 6 alkoxy; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, halogen substituted C 1 -C 6 alkyl, and halogen substituted C 1 -C 6 alkoxy.
- said Y 1 is absent or selected from: -OR, -SR, -N(R) 2 and optionally substituted C 1 -C 6 alkyl; wherein each R is independently selected from hydrogen, Protium, deuterium, tritium, C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
- said Y 1 is absent or selected from: hydroxyl, mercapto, amino and C 1 -C 6 alkyl.
- said Y 2 includes -NR-; wherein each R is independently selected from hydrogen, protium, deuterium, tritium, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl radical, heteroaryl, cycloalkyl, heterocycloalkyl, halogen substituted C 1 -C 6 alkyl, and halogen substituted C 1 -C 6 alkoxy.
- the A2 (structural unit ) can be selected from:
- R 1 and R 2 are each independently selected from: H, F, Cl, Br and optionally substituted C 1 -C 6 alkyl.
- R 1 and R 2 are each independently selected from: H, F, Cl, Br and optionally substituted methyl.
- R 3 is selected from the group consisting of: hydrogen, optionally substituted -OH, optionally substituted -SH, and optionally substituted C 1 -C 6 alkyl.
- said R 31 is selected from the group consisting of hydrogen, halogen, optionally substituted -OH, and optionally substituted -SH.
- said R 311 is selected from the group consisting of hydrogen, optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted
- said R 32 is selected from the group consisting of hydrogen, and optionally substituted C 1 -C 6 alkyl.
- said R 321 is selected from the group consisting of hydrogen, halogen, -CN, and optionally substituted C 1 -C 6 alkyl.
- said R 321 is selected from the group consisting of hydrogen, F, Cl, -CN, and optionally substituted methyl.
- said R 33 is selected from the group consisting of hydrogen, and optionally substituted C 1 -C 6 alkyl.
- said R331 is selected from the group consisting of hydrogen, chlorine, fluorine and -CN.
- R 3 can be selected from: optionally substituted -CH 2 Cl, optionally substituted -CH 2 SH, optionally substituted -CH 2 OH, optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted -OH, optionally substituted -OCH3 , optionally substituted -OCH2F , optionally substituted -OCH2Cl , optionally substituted -OCH2CN , optionally substituted -OCH2CH 3.
- Optionally substituted mercapto optionally substituted -SCH 2 F, optionally substituted -SCH 2 Cl, optionally substituted -SCH 2 CF 3 , and optionally substituted -SCH 2 CN.
- the compounds of the present invention or tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or A pharmaceutically acceptable salt, wherein said R 3 is selected from: -CH 2 Cl, -CH 2 SH, -CH 2 OH, -OCH3 , -OCH2F , -OCH2Cl , -OCH2CN, -OCH2CH3 , -SH, -SCH2F , -SCH2Cl , -SCH2CF3 , and -SCH2CN .
- said R 1 and R 2 are each independently selected from hydrogen, protium, deuterium, tritium and halogen
- said R 3 is selected from -CH 2 -OH, -SCH 2 F
- optionally substituted Optionally substituted Optionally substituted X is selected from the group consisting of N and optionally substituted CH.
- said R6 is selected from the group consisting of hydrogen and optionally substituted -OH.
- said R 61 is selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl.
- the X 1 is selected from the group consisting of CH, C(—O—CH 3 ) and N.
- said B can be selected from: optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted X2 and X3 are each independently selected from the group consisting of O, S and optionally substituted NH.
- said R 7 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 6 alkyl.
- said R 71 is selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl.
- said X2 or X3 is selected from the group consisting of NH, N( CH3 ), O and S.
- said B is selected from:
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the salt used, wherein said B is selected from:
- the R 8 is optionally substituted methyl.
- said R 81 is selected from the group consisting of halogen and optionally substituted cycloalkyl.
- said R 81 is selected from the group consisting of F and optionally substituted cyclopropyl.
- W may be absent or W is selected from:
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the salt used, wherein said W does not exist or W is
- said B may be absent or selected from:
- Said W may be absent or W is selected from:
- the A2 can be selected from:
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the salt used is selected from
- the X is selected from -O-, -S- and -NH-;
- R 4 and R 5 are each independently selected from the following group: H, F, Cl, -OH, -NH 2 and C 1 -C 6 alkyl;
- n is selected from 1, 2 or 3;
- Said Y does not exist or is selected from: hydroxyl, mercapto, amino and C 1 -C 6 alkyl;
- the R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine and methyl;
- the R 3 is selected from: -CH 2 Cl, -CH 2 SH, -CH 2 OH, -OCH3 , -OCH2F , -OCH2Cl , -OCH2CN, -OCH2CH3 , -SH, -SCH2F , -SCH2Cl , -SCH2CF3 , and -SCH2CN .
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable A salt for use, wherein the compound is selected from the group consisting of:
- the compound of formula IIa or IIb or its tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof also includes a Trigger fragment (Tr), and said compound includes the following structure:
- Tr is selected from the following structures:
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group
- B does not exist or B is any group
- W does not exist or W is any group
- X is selected from: -O-, -S-, -NR-;
- Y 1 is any group, and m is any integer from 0 to 4.
- Y2 is selected from -O-, -S- and -NR-;
- R 1 and R 2 can be independently selected from: H, F, Cl, Br and optionally substituted methyl.
- R 3 can be selected from: optionally substituted -CH 2 Cl, optionally substituted -CH 2 SH, optionally substituted -CH 2 OH, optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted -OH, optionally substituted -OCH3 , optionally substituted -OCH2F , optionally substituted -OCH2Cl , optionally substituted -OCH2CN , optionally substituted -OCH2CH 3.
- Optionally substituted mercapto optionally substituted -SCH 2 F, optionally substituted -SCH 2 Cl, optionally substituted -SCH 2 CF 3 , and optionally substituted -SCH 2 CN.
- said B can be selected from:
- said W may be absent or W may be selected from:
- the Linker fragment includes L1 fragment, L2 fragment and/or L3 fragment, and the compound has the following structure:
- Tr does not exist or Tr is any group
- L3 is selected from polypeptide fragments
- L2 is absent or selected from a linking fragment
- L is selected from a coupling unit
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group
- B does not exist or B is any group
- W does not exist or W is any group
- X is selected from: -O-, -S-, -NR-;
- Y 1 is any group, and m is any integer from 0 to 4.
- Y2 is selected from -O-, -S- and -NR-;
- L3 is selected from dipeptides, tripeptides and tetrapeptides.
- the dipeptide is selected from the group consisting of: GA, GG, AG, EG, EA, GE, DG, DA, GD, VC, VA, AA and VK.
- the tripeptide is selected from the group consisting of: EAG, EGG, GEG, GEA, DAG, DGG, GDG, GDA, GGA, GAG, GFG, AAG, AAA, VAG, VCG, VKG.
- tetrapeptide is selected from the group consisting of: GGFG, GGAG, GGGG, GEGG, GEAG, GDGG, GDAG, AAAG, and EAGG.
- said L3 is selected from the group consisting of glycine-glycine-phenylalanine-glycine (GGFG), alanine-alanine-alanine-glycine (AAAG), glycine-glycine - Glycine-Glycine (GGGG), Valine-Alanine-Glycine (VAG), Valine-Citrulline-Glycine (VCG), Alanine-Alanine-Glycine (AAG), Alanine -Alanine-Alanine (AAA), Valine-Alanine (VA), Valine-Citrulline (VC), Alanine-Alanine (AA), Glutamate-Alanine Acid-Glycine-Glycine (EAGG), Glycine-Glutamate-Alanine-Glycine (GEAG), Glycine-Glutamate-Glycine-Glycine (GEGG), Glutamate-Glycine-Glycine (EGG), Glutamine Amino-Alanine-
- L2 includes or does not include PEG branched chains or PEG linear chains.
- said L when said L does not comprise PEG, said L is selected from:
- said L 2 when said L 2 comprises a PEG linear chain, said L 2 is selected from:
- p is any integer from 1 to 20.
- said L 2 when said L 2 comprises a PEG linear chain, said L 2 is selected from:
- said L2 when said L2 comprises a PEG branch, said L2 is selected from:
- q is selected from any integer from 1 to 30.
- said L2 when said L2 comprises a PEG branch, said L2 is selected from:
- said L when L is coupled via a sulfhydryl group of a ligand, said L is selected from:
- said R L1a , R L1b , R L1c are each independently selected from: hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O) H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O ) NH2 , -SO2NH2 , -OC(O)H, -N(H) SO2H , alkyl, alkenyl, alkynyl, alicyclic, heterocyclyl, aryl and heteroaryl.
- each of R L1a , R L1b , R L1c is independently selected from the group consisting of hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted aryl, and optionally substituted benzyl.
- said L when L is coupled to a ligand through an amino group, said L is selected from:
- said L when L is coupled by click chemistry, said L is selected from:
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable A salt for use, wherein the compound of formula IVa or IVb is selected from the following structures:
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable A salt for use, wherein the compound also includes a Linker fragment, the compound of the formula IIa or IIb can be coupled with a ligand through the Linker fragment, and the compound has the following structure:
- Tr does not exist or Tr is any group
- L3 is selected from polypeptide fragments
- L2 is absent or selected from a linking fragment
- L 1 is selected from the coupling unit; L 1 is connected in the general formula IVa-1 and IVb-1;
- R 1 , R 2 , R 3 , R 4 , R 5 , B, W, CR 4 R 5 , n, X, Y 1 and Y 2 are as described in any one of the present invention
- wavy line Indicates that it is connected to the ligand through the L group.
- a compound of the present invention or a tautomer, meso, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the salt used, wherein said structural unit -Tr-L 3 -L 2 -L 1 - is selected from:
- the present application provides a conjugate comprising the aforementioned compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or in the form of a mixture, or a pharmaceutically acceptable salt thereof.
- the conjugate can include an antibody-drug conjugate.
- the ligand comprises an antibody or antigen-binding fragment thereof.
- the antibody is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, multispecific antibodies, monoclonal antibodies and polyclonal antibodies.
- said antigen-binding fragment is selected from the group consisting of: Fab, Fab', F(ab')2, Fv, scFv, diabody, Fd, dAb, VHH, large antibody and complementarity determining region (CDR) fragment.
- said ligand specifically binds an antigen selected from the group consisting of AXL, BAFFR, BCMA, BCR-list components (BCR-list components), BDCA2, BDCA4, BTLA, BTNL2BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD163, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25 , CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, cluster of differentiation 40 (CD40), CD44, CD45, CD46, CD47, CD48, CD5, CD52, CD55, CD56, CD59, CD62E , CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80
- said ligand specifically binds: TNF ⁇ , CD40, and/or IFNAR1.
- the ligand is selected from the group consisting of anti-TNF ⁇ antibody or antigen-binding fragment thereof, anti-CD40 antibody or antigen-binding fragment thereof, and anti-IFNAR1 antibody or antigen-binding fragment thereof. In certain embodiments, wherein the ligand is selected from the group consisting of: anti-TNF ⁇ antibody or antigen-binding fragment thereof, anti-CD40 antibody or antigen-binding fragment thereof, anti-BDCA2 antibody or antigen-binding fragment thereof and anti-IFNAR1 antibody or antigen-binding fragment thereof .
- the ligand can be selected from: anti-TNF ⁇ monoclonal antibody, anti-CD40 monoclonal antibody, and anti-IFNAR1 monoclonal antibody.
- the present disclosure also provides immunoconjugates comprising a glucocorticoid receptor agonist linked to an anti-TNF ⁇ protein.
- the anti-TNF ⁇ protein is an antibody or antigen-binding fragment thereof.
- the anti-TNFa protein is an antibody or antigen-binding fragment thereof that binds TNFa (eg, soluble TNFa and/or membrane-bound TNFa).
- the anti-TNFa protein is a soluble TNF receptor protein, eg, a soluble TNF receptor protein fused to a heavy chain constant domain or fragment thereof (eg, Fc).
- an anti-TNF ⁇ protein eg, an anti-TNF antibody, an antigen-binding fragment thereof, or a soluble TNF receptor
- an anti-TNF ⁇ protein can bind to TNF ⁇ on the surface of a cell and become internalized.
- an anti-TNF ⁇ protein eg, an anti-TNF antibody, an antigen-binding fragment thereof, or a soluble TNF receptor
- US2014/0294813 discloses anti-TNF proteins that exhibit internalization upon binding to cell surface human TNF.
- the antibody or antigen-binding fragment thereof binds human and/or mouse TNF-alpha.
- Antibodies and antigen-binding fragments that bind TNF- ⁇ are known in the art.
- Anti-TNF- ⁇ antibodies and antigen-binding fragments thereof include, for example, adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozola Ozoralizumab, praculumab, golimumab and anti-mouse TNF ⁇ mlgG2a. Additional anti-TNF- ⁇ antibodies and antigen-binding fragments are provided, for example, in WO 2013/087912, WO 2014/152247, and WO 2015/073884, each of which is incorporated herein by reference in its entirety.
- Adalimumab is described in US Patent No. 6,258,562, which is incorporated herein by reference in its entirety. Infliximab is described in US Patent No. 5,656,272, which is incorporated herein by reference in its entirety. Certolizumab is discussed in WO01/94585, which is hereby incorporated by reference in its entirety. Afelimomab (also known as MAK195) is discussed in Vincent, Int. J. Clin. Pract. [International Journal of Clinical Practice] 54: 190-193 (2000), which is incorporated by reference in its entirety This article. Ozolazumab (also known as ATN-103) is a nanobody. It contains three heavy chain variable regions fused by a GlySer linker.
- Variable regions 1 and 3 are identical, and ozolazumab does not contain a heavy chain.
- Ozolazumab is discussed in WO 2012/131053, which is hereby incorporated by reference in its entirety.
- Pracurumab (also known as CEP-37247) is a domain antibody consisting of a dimer of VL-pCH1-CH2-CH3 or [V- ⁇ ]2-Fc, and was described in Gay et al., Mabs 2 : 625-638 (2010), which is incorporated herein by reference in its entirety.
- Golimumab (also known as CNTO 148) is discussed in WO2013/087912 and the sequences are provided in GenBank: DI496971.1 and GenBank DI 496970.1, each of which is incorporated herein by reference in its entirety.
- Anti-mouse TNF ⁇ mlgG2a described in McRae BL et al. J Crohns Colitis 10(1):69-76 (2016), each of which is incorporated herein by reference in its entirety.
- Anti-TNF- ⁇ antibodies and their antigen-binding fragments also include competitively inhibited adalimumab, infliximab, certolizumab, afelimomab, nerimomab, ozolazumab, Antibodies and antigen-binding fragments of pracurumab or golimumab binding to TNF- ⁇ .
- Anti-TNF- ⁇ antibodies and their antigen-binding fragments also include adalimumab, infliximab, certolizumab, afelimomab, nerimomab, ozolatuzumab, pula Antibodies and antigen-binding fragments of culumab or golimumab that bind the same TNF- ⁇ epitope.
- the anti-TNF- ⁇ antibody or antigen-binding fragment thereof competitively inhibits the binding of adalimumab to TNF- ⁇ . In certain embodiments, the anti-TNF- ⁇ antibody or antigen-binding fragment thereof binds to the same TNF- ⁇ epitope as adalimumab. In certain embodiments, the anti-TNF- ⁇ antibody or antigen-binding fragment thereof is adalimumab or an antigen-binding fragment thereof. In certain embodiments, the anti-TNF- ⁇ antibody or antigen-binding fragment thereof is adalimumab.
- the anti-TNF- ⁇ antibody or antigen-binding fragment thereof comprises adalimumab, infliximab, certolizumab, afelimomab, nerimomab, ozolazumab Sequences of mAb, pracurumab or golimumab, such as complementarity determining regions (CDRs), variable heavy chain domains (VH) and/or variable light chain domains (VL).
- CDRs complementarity determining regions
- VH variable heavy chain domains
- VL variable light chain domains
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) of an antibody
- said heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, each of which is associated with the following HCDR1, HCDR2, HCDR3 of the molecule have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: adalimumab ( Adalimumab), Infliximab, Afelimomab, or golimumab.
- the anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region is at least about 80% identical to the heavy chain variable region of each of , About 85%, About 90%, About 95%, About 96%, About 97%, About 98%, About 99% sequence identity: Adalimumab (Adalimumab), Infliximab (Infliximab), A Afelimomab or golimumab.
- the anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain of an antibody, wherein the heavy chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Adalimumab, Infliximab, Afelimomab or Ge Golimumab.
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) of an antibody
- said light chain variable region comprises LCDR1, LCDR2, LCDR3, which are each associated with the following LCDR1, LCDR2, LCDR3 of the molecules have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: adalimumab ( Adalimumab), Infliximab, Afelimomab, or golimumab.
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein said light chain variable region shares at least about 80% with the light chain variable region of each of , About 85%, About 90%, About 95%, About 96%, About 97%, About 98%, About 99% sequence identity: Adalimumab (Adalimumab), Infliximab (Infliximab), A Afelimomab or golimumab.
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a light chain of an antibody, wherein said light chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Adalimumab, Infliximab, Afelimomab or Ge Golimumab.
- the present application provides antibodies or antigen-binding fragments thereof, which can specifically bind TNF- ⁇ and comprise adalimumab, infliximab, certolizumab, afelimomab, Chothia VL CDR of the VL of nerimumab, ozolatuzumab, pracurumab, or golimumab.
- antibodies or antigen-binding fragments thereof that specifically bind TNF-alpha and comprising adalimumab, infliximab, certolizumab, afelimomab, nerimumab Chothia VH CDR of the VH of anti, ozolazumab, pracurumab, or golimumab.
- antibodies or antigen-binding fragments thereof that specifically bind TNF-alpha and comprising adalimumab, infliximab, certolizumab, afelimomab, nerimumab Chothia VL CDR of the VL of anti, ozolazumab, pracurumab, or golimumab and contains adalimumab, infliximab, certolizumab, afelimomab Chothia VH CDR of the VH of , nerimumab, ozolazumab, pracurumab, or golimumab.
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) of an antibody
- said heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, each of which is associated with the following HCDR1, HCDR2, HCDR3 of the molecule have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: adalimumab ( Adalimumab, Infliximab, Afelimomab, Golimumab or anti-mouse TNF ⁇ mlgG2a 8c11.
- the anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region is at least about 80% identical to the heavy chain variable region of each of , About 85%, About 90%, About 95%, About 96%, About 97%, About 98%, About 99% sequence identity: Adalimumab (Adalimumab), Infliximab (Infliximab), A Afelimomab, golimumab or anti-mouse TNF ⁇ mIgG2a 8c11.
- the anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain of an antibody, wherein the heavy chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Adalimumab, Infliximab, Afelimomab, Ge Golimumab or anti-mouse TNF ⁇ mIgG2a 8c11.
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) of an antibody
- said light chain variable region comprises LCDR1, LCDR2, LCDR3, which are each associated with the following LCDR1, LCDR2, LCDR3 of the molecules have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: adalimumab ( Adalimumab, Infliximab, Afelimomab, Golimumab or anti-mouse TNF ⁇ mlgG2a 8c11.
- the anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, HCDR3
- the The light chain variable region comprises LCDR1, LCDR2, LCDR3, each of which has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Adalimumab (Adalimumab), Infliximab (Infliximab), Afelimomab (Afelimomab), Golimumab ( golimumab) or anti-mouse TNF ⁇ mIgG2a 8c11.
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein said light chain variable region shares at least about 80% with the light chain variable region of each of , About 85%, About 90%, About 95%, About 96%, About 97%, About 98%, About 99% sequence identity: Adalimumab (Adalimumab), Infliximab (Infliximab), A Afelimomab, golimumab or anti-mouse TNF ⁇ mIgG2a 8c11.
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of an antibody, wherein said heavy chain variable region and said light chain variable region are respectively Having at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity to the light chain variable region of: adalimumab Anti-(Adalimumab), Infliximab (Infliximab), Afelimomab (Afelimomab), Golimumab (golimumab) or anti-mouse TNF ⁇ mIgG2a 8c11.
- said anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a light chain of an antibody, wherein said light chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Adalimumab, Infliximab, Afelimomab, Ge Golimumab or anti-mouse TNF ⁇ mIgG2a 8c11.
- the anti-TNF ⁇ antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain of an antibody, wherein the heavy chain and light chain share at least about 80%, about 85%, about 90%, respectively, of the light chain of , about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Adalimumab, Infliximab, Afelimomab, Golimumab or anti-mouse TNF ⁇ mIgG2a 8c11.
- the antibody or antigen-binding portion thereof is an antagonist antibody or antigen-binding portion thereof that elicits CD40 activity or function compared to CD40 activity or function in the absence of said antibody or antigen-binding portion thereof. Reduced functionality.
- the antibody or antigen-binding portion thereof is substantially free of agonist activity, i.e., the antibody or antigen-binding portion thereof does not elicit the same activity as CD40 in the absence of the antibody or antigen-binding portion thereof or The magnitude of CD40 activity or function is increased compared to function.
- the anti-CD40 antibody is a polyclonal antibody, monoclonal antibody, chimeric antibody, humanized antibody, human antibody, or an antigen-binding portion thereof.
- the anti-CD40 antibody is Iscalimab (CFZ533) (Novartis; as described in US Pat. Nos. 8828396 and 9221913); the anti-CD40 antibody is lucatumumab (Novartis; as described in US Pat. 8277810); antibodies 5D12, 3A8 and 3C6, or humanized versions thereof (Novartis; as described in U.S. Patent No. 5874082); antibody 15B8 (Novartis; as described in U.S. Patent No. 7445780 described); Antibody 4 D1 1 (Kyowa Hakko Kirin; as described in U.S. Patent No.
- Temeliximab (Bristol Myers Squibb; as described in U.S. Patent No. 6,051,228); Antibody PG102 (PanGenetics; as described in U.S. Patent No. 8669352); antibody 2C10 (Primatope; U.S. Patent Application Publication No. 20140093497); anti-CD40 antibody described in U.S. Patent Nos. 8591900 and 8778345 (Boehringer Ingelheim) ; an anti-CD40 antibody (Amgen) as described in US Patent No. 5801227; or APX005 (Boehringer Ingelheim; as described in US Patent Application Publication No. 20120301488.
- the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, which are each associated with the following HCDR1, HCDR2, HCDR3 of the molecule have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Iscalimab (CFZ533).
- the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region is at least about 80% identical to the heavy chain variable region of each of , about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Iscalimab (CFZ533).
- the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain of an antibody, wherein the heavy chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity Iscalimab (CFZ533).
- said anti-CD40 antibody or antigen-binding fragment thereof comprises an antibody light chain variable region (VL), wherein said light chain variable region comprises LCDR1, LCDR2, LCDR3, each of which is associated with the following LCDR1, LCDR2, LCDR3 of the molecules have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Iscalimab (CFZ533).
- VL antibody light chain variable region
- the anti-CD40 antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein the light chain variable region is at least about 80% identical to the light chain variable region of each of , about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Iscalimab (CFZ533).
- the anti-CD40 antibody or antigen-binding fragment thereof comprises a light chain of an antibody, wherein the light chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Iscalimab (CFZ533).
- an antibody of the invention is specific for (ie specifically binds to) IFNAR1. Such antibodies may also be referred to herein as "anti-IFNAR1 antibodies of the invention".
- the antibodies of the invention are specific for human IFNAR1.
- the anti-IFNAR1 antibodies of the invention may cross-react with IFNAR1 of species other than human or other proteins structurally related to human IFNAR1 (eg, human IFNAR1 homologues).
- the anti-IFNAR1 antibodies of the invention may be specific only for human IFNAR1 and exhibit no species or other types of cross-reactivity.
- the anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) of an antibody
- the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, which are each associated with the following HCDR1, HCDR2, HCDR3 of the molecule share at least about 80% sequence identity: Anifrolumab (MEDI-546).
- said anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein said heavy chain variable region shares at least about 80% with the heavy chain variable region of each of , about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Anifrolumab (MEDI-546).
- the anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a heavy chain of an antibody, wherein the heavy chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity Anifrolumab (MEDI-546).
- said anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) of an antibody
- said light chain variable region comprises LCDR1, LCDR2, LCDR3, which are each associated with the following LCDR1, LCDR2, LCDR3 of the molecules have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Anifrolumab (MEDI-546 ).
- said anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein said light chain variable region shares at least about 80% with the light chain variable region of each of , about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Anifrolumab (MEDI-546).
- said anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a light chain of an antibody, wherein said light chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Anifrolumab (MEDI-546).
- said anti-BDCA2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein said heavy chain variable region shares at least about 80% with the heavy chain variable region of each of Sequence identity for: Litifilimab (BIIB059).
- said anti-BDCA2 antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein said light chain variable region shares at least about 80% with the light chain variable region of each of Sequence identity for: Litifilimab (BIIB059).
- the anti-BDCA2 antibody or antigen-binding fragment thereof comprises a heavy chain of an antibody, wherein each of the heavy chains has at least about 80% sequence identity to the heavy chain of: Litifilimab (BIIB059) .
- the anti-BDCA2 antibody or antigen-binding fragment thereof comprises a light chain of an antibody, wherein each of the light chains has at least about 80% sequence identity to a light chain of the following molecule: Litifilimab (BIIB059) .
- said anti-BDCA2 antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region (VH), wherein said heavy chain variable region has at least About 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Litifilimab (BIIB059).
- VH antibody heavy chain variable region
- said anti-BDCA2 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) of an antibody, wherein said light chain variable region has at least About 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Litifilimab (BIIB059).
- said anti-BDCA2 antibody or antigen-binding fragment thereof comprises a heavy chain of an antibody, wherein said heavy chain shares at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Litifilimab (BIIB059).
- said anti-BDCA2 antibody or antigen-binding fragment thereof comprises a light chain of an antibody, wherein said light chain has at least about 80%, about 85%, about 90%, About 95%, about 96%, about 97%, about 98%, about 99% sequence identity: Litifilimab (BIIB059).
- variants and equivalents that are substantially homologous to the anti-TNF- ⁇ antibody, anti-CD40 antibody, or anti-IFNAR1 antibody set forth herein.
- variants and equivalents may contain, for example, conservative substitution mutations, ie, one or more amino acids are replaced by similar amino acids.
- conservative substitution refers to the substitution of an amino acid by another amino acid within the same general class, such as one acidic amino acid by another acidic amino acid, one basic amino acid by another basic amino acid, or one A neutral amino acid is replaced by another neutral amino acid.
- the purpose of conservative amino acid substitutions is well known in the art.
- Antibodies can be recombinant, natural or synthetic polypeptides of antibodies.
- the present application further includes variants of polypeptides which exhibit significant activity or which comprise regions of antibodies.
- Such mutants include deletions, insertions, inversions, duplications and type substitutions.
- the ligand is selected from: Adalimumab, Iscalimab (CFZ533), Anifrolumab (MEDI-546), Infliximab (Infliximab), Afelimomab (Afelimomab ), Golimumab, anti-mouse TNF ⁇ mIgG2a 8c11, Litifilimab (BIIB059), derivatives thereof, and biosimilars thereof.
- Adalimumab Iscalimab (CFZ533), Anifrolumab (MEDI-546), Infliximab (Infliximab), Afelimomab (Afelimomab ), Golimumab, anti-mouse TNF ⁇ mIgG2a 8c11, Litifilimab (BIIB059), derivatives thereof, and biosimilars thereof.
- the ligand is selected from: Adalimumab, Iscalimab (CFZ533) and Anifrolumab (MEDI-546).
- ligand-drug conjugate has the following structure:
- Ab represents a ligand capable of binding to a target, including but not limited to antibodies and antigen-binding fragments thereof;
- N aI is any number from 1 to 10;
- Tr does not exist or Tr is any group
- L3 is selected from polypeptide fragments
- L2 is absent or selected from a linking fragment
- L is selected from a coupling unit
- R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group
- B does not exist or B is any group
- W does not exist or W is any group
- X is selected from: -O-, -S-, -NR-;
- Y 1 is any group, and m is any integer from 0 to 4.
- Y2 is selected from -O-, -S- and -NR-;
- ligand generally means any molecule capable of specifically binding and or reactively binding or complexing a target molecule, such as a receptor, substrate, antigenic determinant or other binding site on a target cell or tissue.
- ligands include antibodies and fragments thereof (such as monoclonal antibodies or fragments thereof), enzymes (such as fibrinolytic enzymes), biological response modifiers (such as interleukins, interferons, erythropeoitin, or colony-stimulating factors), peptide hormones and antigen-binding fragments thereof, polysaccharides, lipids, oligonucleotides, polynucleotides, synthetic molecules, inorganic molecules, organic molecules, and any combination thereof.
- target or “target molecule” can include a wide variety of substances and molecules, ranging from simple molecules to complex targets.
- a target molecule can be a protein, nucleic acid, lipid, carbohydrate, or any other molecule that can be recognized by a polypeptide domain.
- target molecules can include compounds (i.e., non-biological compounds such as organic molecules, inorganic molecules, or molecules with both organic and inorganic atoms, but excluding polynucleotides and proteins), mixtures of compounds, spatially localized compounds Arrays of biomacromolecules, phage peptide display libraries, polysomal peptide display libraries, extracts made from biological materials such as bacterial, plant, fungal, or animal (e.g., mammalian) cells or tissues, proteins, toxins , peptide hormones, cells, viruses, etc.
- Other target molecules include, for example, whole cells, whole tissues, mixtures of related or unrelated proteins, mixtures of viral or bacterial strains, and the like.
- telomere binding generally refers to a measurable and reproducible interaction, such as between a target and an antibody, that can determine a target in the presence of a heterogeneous population of molecules, including biomolecules The presence.
- an antibody that specifically binds a target (which may be an epitope) can be an antibody that binds that target with greater affinity, avidity, greater ease, and/or for a greater duration than it binds other targets .
- an antibody specifically binds an epitope on a protein that is conserved among proteins of different species.
- specific binding can include, but does not require exclusive binding.
- the structure of the coupling unit L1 can change before and after coupling with the ligand, that is, in the Linker-Payload structure (such as formula IVa or formula IVb) and the drug-ligand conjugate structure (such as formula Va or formula Vb),
- the structure of L1 will vary and such variations can be readily determined by one of ordinary skill in the art.
- L1 when L1 is coupled to a ligand through a sulfhydryl group, the structure of L1 changes as follows:
- the mercapto group can come from a ligand
- the R L1a , R L1b , R L1c are each independently selected from: hydrogen, an optionally substituted alkyl group, and an optionally substituted aryl group; for example, the R L1a , R L1b , R L1c may each be independently selected from hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted aryl, and optionally substituted benzyl.
- L1 when L1 is coupled to a ligand through an amino group, the structure of L1 changes as follows:
- amino group can come from the ligand.
- L1 when L1 is coupled to a ligand by click chemistry, the structure of L1 changes as follows:
- R 1 and R 2 can be independently selected from: H, F, Cl, Br and optionally substituted methyl.
- R 3 can be selected from: optionally substituted -CH 2 Cl, optionally substituted -CH 2 SH, optionally substituted -CH 2 OH, optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted -OH, optionally substituted -OCH3 , optionally substituted -OCH2F , optionally substituted -OCH2Cl , optionally substituted -OCH2CN , optionally substituted -OCH2CH 3.
- Optionally substituted mercapto optionally substituted -SCH 2 F, optionally substituted -SCH 2 Cl, optionally substituted -SCH 2 CF 3 , and optionally substituted -SCH 2 CN.
- said B can be selected from:
- said W may be absent or W may be selected from:
- conjugate can be selected from the following structures:
- N aI is any number from 1 to 10.
- the conjugate of the present invention wherein the ligand-drug conjugate has the following structure:
- Ab represents a ligand capable of binding to a target, preferably an antibody or an antigen-binding fragment thereof;
- N aI is any number from 1 to 10;
- the X is selected from -O-, -S- and -NH-;
- R 4 and R 5 are each independently selected from the following group: H, F, Cl, -OH, -NH 2 and C 1 -C 6 alkyl;
- n is selected from 1, 2 or 3;
- Said Y does not exist or is selected from: hydroxyl, mercapto, amino and C 1 -C 6 alkyl;
- the R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine and methyl;
- the R 3 is selected from: -CH 2 Cl, -CH 2 SH, -CH 2 OH, -OCH3 , -OCH2F , -OCH2Cl , -OCH2CN, -OCH2CH3 , -SH, -SCH2F , -SCH2Cl , -SCH2CF3 , and -SCH2CN .
- the conjugate of the present invention is selected from the following structures:
- N aI is any number from 1 to 10
- Ab is selected from antibodies or antigen-binding fragments thereof.
- the conjugate of the present invention is selected from the following structures:
- N aI is any number in 1 to 10.
- the active metabolite of the conjugate comprises the aforementioned compound.
- the present application provides a pharmaceutical composition, which comprises the aforementioned compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or A mixture thereof, or a pharmaceutically acceptable salt thereof and/or the aforementioned conjugate, and optionally a pharmaceutically acceptable carrier.
- the present application provides a method for affecting the function of the immune system, comprising administering the aforementioned compounds or their tautomers, mesoforms, racemates, enantiomers, non- Enantiomers, or their mixtures, or their pharmaceutically acceptable salts, the aforementioned conjugates and/or the aforementioned pharmaceutical compositions.
- said affecting the function of the immune system comprises affecting the function of immune cells.
- the immune cells are selected from the group consisting of granular leukocytes and agranular leukocytes.
- the immune cells are selected from the group consisting of neutrophils, eosinophils, and basophils.
- the immune cells are selected from the group consisting of lymphocytes and phagocytes.
- the immune cells are selected from the group consisting of B cells, T cells, natural killer cells, monocytes, macrophages, mast cells, and dendritic cells.
- the present application provides the aforementioned compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable
- the disease and/or condition comprises a disease and/or condition associated with glucocorticoid receptor signaling.
- the disease and/or condition is selected from the group consisting of proliferative disease and/or condition, metabolic disease and/or condition, inflammatory disease and/or condition and neurodegenerative disease and/or condition .
- the disease and/or symptoms are selected from the group consisting of systemic autoimmune diseases and/or symptoms, blood system related diseases and/or symptoms, neuromuscular system related diseases and/or symptoms, digestive system Related diseases and/or symptoms, urinary system related diseases and/or symptoms, endocrine system related diseases and/or symptoms, skin muscular system related diseases and/or symptoms, and respiratory system related diseases and/or symptoms.
- the disease and/or condition is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, ankylosing spondylitis, Wegener's granulomatosis, and systemic sexual sclerosis.
- the disease and/or condition is selected from the group consisting of autoimmune hemolytic anemia, pernicious anemia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, and vasculitis.
- the disease and/or condition is selected from the group consisting of multiple sclerosis, myasthenia gravis, and Guillain-Barré syndrome.
- the disease and/or condition is selected from the group consisting of ulcerative colitis, Crohn's disease, autoimmune liver disease, and atrophic gastritis.
- the disease and/or condition is selected from the group consisting of IgA nephropathy, primary nephrotic syndrome, autoimmune glomerulonephritis, pulmonary renal hemorrhage syndrome, and lupus nephritis.
- the disease and/or condition is selected from the group consisting of type 1 diabetes, Grave's disease, Hashimoto's thyroiditis, primary adrenal atrophy, and chronic thyroiditis.
- the disease and/or condition is selected from the group consisting of psoriasis, pediospora vulgaris, cutaneous lupus erythematosus, dermatomyositis, and polymyalgia rheumatica.
- the disease and/or condition is asthma.
- the present application provides a method for preventing and/or treating diseases and/or symptoms, the method comprising administering the aforementioned compound or its tautomer, mesomer to a subject in need thereof , racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the aforementioned conjugate and/or the aforementioned pharmaceutical composition.
- the disease and/or condition comprises a disease and/or condition associated with glucocorticoid receptor signaling.
- the disease and/or condition is selected from the group consisting of proliferative disease and/or condition, metabolic disease and/or condition, inflammatory disease and/or condition and neurodegenerative disease and/or condition .
- the disease and/or symptoms are selected from the group consisting of systemic autoimmune diseases and/or symptoms, blood system related diseases and/or symptoms, neuromuscular system related diseases and/or symptoms, digestive system Related diseases and/or symptoms, urinary system related diseases and/or symptoms, endocrine system related diseases and/or symptoms, skin muscular system related diseases and/or symptoms, and respiratory system related diseases and/or symptoms.
- the disease and/or condition is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, ankylosing spondylitis, Wegener's granulomatosis, and systemic sexual sclerosis.
- the disease and/or condition is selected from the group consisting of autoimmune hemolytic anemia, pernicious anemia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, and vasculitis.
- the disease and/or condition is selected from the group consisting of multiple sclerosis, myasthenia gravis, and Guillain-Barré syndrome.
- the disease and/or condition is selected from the group consisting of ulcerative colitis, Crohn's disease, autoimmune liver disease, and atrophic gastritis.
- the disease and/or condition is selected from the group consisting of IgA nephropathy, primary nephrotic syndrome, autoimmune glomerulonephritis, pulmonary renal hemorrhage syndrome, and lupus nephritis.
- the disease and/or condition is selected from the group consisting of type 1 diabetes, Grave's disease, Hashimoto's thyroiditis, primary adrenal atrophy, and chronic thyroiditis.
- the disease and/or condition is selected from the group consisting of psoriasis, pediospora vulgaris, cutaneous lupus erythematosus, dermatomyositis, and polymyalgia rheumatica.
- the disease and/or condition is asthma.
- the following examples are only for illustrating the compounds, preparation methods and uses of the present application, and are not intended to limit the scope of the present invention.
- Reagents that provide brominated conditions include but are not limited to bromine water, N-bromosuccinimide, dibromohydantoin, phosphorus tribromide, liquid bromine, liquid bromine/triphenylphosphine, hydrobromic acid, tetrabromide carbon;
- Titanium catalysts include but are not limited to tetraisopropyl titanate, triisopropoxytitanium chloride, titanium tetrachloride, titanium triisopropoxide;
- Palladium catalysts include, but are not limited to, palladium tetrakistriphenylphosphine, palladium acetate, palladium chloride, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone) )dipalladium, bis(acetonitrile)palladium dichloride, [1,1'-bis ⁇ diphenylphosphino ⁇ ferrocene]palladium dichloride, [1,1'-bis ⁇ diphenylphosphino ⁇ Ferrocene]palladium dichloride dichloromethane complex, dibenzonitrile palladium dichloride, 1,4-bis(diphenylphosphine)butane-palladium chloride, allyl palladium chloride dimer, Allyl cyclopentadienyl palladium;
- Borate dimers include but are not limited to pinacol diboronate, neopentyl glycol diboronate, bis(2-methyl-2,4-pentanediol) borate, bis-phthalate Phenol borate, bis(diisopropyl-L-diethyltartrate) diboronate, bis[(-)pinanediol]diboronate, bis(1S,2S,3R,5S)(+ )-Pinanediol Diborate, Tetramethylaminodiborane, Bis(N,N,N',N'-tetramethyl-D-tartrate amide glycolate)diboron, Tetrahydroxydiborane , bis(N,N,N',N'-tetramethyl-L-tartrate amide glycolate) diboron, bis(diisopropyl-D-tartrate glycolate) diboronate, bis (D-diethyl
- Metallic copper salts include but are not limited to copper sulfate, copper sulfate pentahydrate, cuprous sulfate, cupric chloride, cuprous chloride, copper carbonate, copper phosphate, copper acetate and its hydrate, copper oxalate, copper fluoroborate and its hydrate Copper Dimethoxide, Copper Tartrate, Copper Formate, Cuprous Iodide, Copper Trifluoroacetate, Copper Trifluoromethanesulfonate, Copper Basic Carbonate, Copper Bromide, Cuprous Bromide, Cuprous Oxide;
- Ligands can be selected from any commonly used ligands for Ullmann reaction, including but not limited to L-proline, tyrosine, phenylalanine, 1,10-phenanthroline, N,N'-dimethylethyl Diamine, ethylene glycol, 1,1'-binaphthyl-2,2'diol, ethyl 2-carbonylcyclohexylcarboxylate, salicylaldehyde hydrazone;
- the condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride, 1-hydroxybenzotriazole and 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide , O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole , O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole))-N,N,N',N '-Tetramethyluronium hexafluorophosphate, benzotriazol-1-
- Reagents providing alkaline conditions include organic bases and inorganic bases
- the organic bases include but not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, N,N-diisopropyl ethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.
- the inorganic base includes but not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, Sodium Hydroxide, Lithium Hydroxide, Sodium Phosphate, Potassium Phosphate;
- Reagents providing acidic conditions include protic acids and Lewis acids
- said protic acids include but are not limited to hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, Benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid;
- such Lewis acids include but are not limited to boron trifluoride, zinc chloride, magnesium chloride, chlorine Aluminum chloride, tin chloride, ferric chloride;
- Hydrogenation conditions include but are not limited to: Pb/C/hydrogen, Pt/C/hydrogen, palladium chloride/hydrogen, Raney nickel/hydrogen, palladium hydroxide carbon/hydrogen, palladium hydroxide/hydrogen;
- Reagents that provide oxidation conditions include but are not limited to Dess Martin oxidizers, hydrogen peroxide, sodium chlorite, sodium hypochlorite, potassium perchlorate;
- Reagents providing reducing conditions include, but are not limited to, sodium hydride, calcium hydride, lithium hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium triethylborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride ;
- Reagents that provide oxidizing conditions include, but are not limited to, Dess Martin oxidizing agents, hydrogen peroxide, sodium chlorite, sodium hypochlorite, and potassium perchlorate.
- NMR nuclear magnetic resonance
- MS mass spectroscopy
- UPLC UPLC
- a Waters AcquityUPLCSQD liquid mass spectrometer (Poroshell 120 EC-C18, 2.1mm x 50mm, 1.9 micron chromatographic column).
- HPLC high pressure liquid chromatograph
- UV was measured using a Thermonodrop2000 UV spectrophotometer.
- EnVision microplate reader (PerkinElmer Company) was used for enzyme-linked immunoassay.
- the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm0.2mm, and the specification of thin-layer chromatography separation and purification product is 0.4mm0. 5mm silica gel board.
- the known starting materials of the present application can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (AccelaChemBioInc), Darui Chemicals and other companies.
- the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
- the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
- the solution in the reaction refers to an aqueous solution.
- the temperature of the reaction is room temperature. Room temperature is the most suitable reaction temperature, and the temperature range is 20°C to 30°C.
- the eluent system of the column chromatography and the developer system of the thin-layer chromatography of the purified compound include: A: dichloromethane and isopropanol system, B: dichloromethane and methanol system, C: sherwood oil and In the ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents.
- TOF-LC/MS uses an Agilent 6230 time-of-flight mass spectrometer and an Agilent 1290-Infinity ultra-high performance liquid chromatograph.
- the exemplary preparation route of the present application is as follows:
- the first step the compound of general formula (P1) introduces a bromine atom on the benzene ring under optional bromination conditions;
- the second step the compound of the general formula (P2) is reacted with the borate dimer under optional palladium reagent catalyst conditions to obtain the compound of the general formula (P3);
- the third step the compound of general formula (P3) reacts with the compound of general formula (Y1) under optional palladium reagent catalytic conditions to obtain the compound of general formula (P4);
- the fourth step the compound of general formula (P4) reacts with the compound of general formula (Y2) under optional acidic or basic conditions to obtain the compound of general formula (P5);
- Step 5 The compound of general formula (P5) is optionally removed from the protecting group PG under acidic or basic conditions, and separated by preparative HPLC to obtain the compound of general formula (P6).
- PG can be the protecting group of common hydroxyl
- Ring B is optionally substituted aryl or heteroaryl
- -B(OR) 2 is a borate-based monomer, in which two Rs can be connected to form a heterocyclic ring, a heterobridged ring or a heterospiro ring, and the ring can be optionally covered by C 1 -C 6 alkyl, aryl, Heteroaryl, carboxyl or acyloxy C 1 -C 6 alkyl substitution;
- X is chlorine, bromine or iodine
- each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycle Alkyl, halogen substituted C 1 -C 6 alkyl, and halogen substituted C 1 -C 6 alkoxy;
- R, R 1 , R 2 and R 3 can be as any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) in this application respectively R, R 1 , R 2 and R 3 are as defined.
- the first step the compound of the general formula (Y1) reacts with the compound (P1) under optional metal copper salt and optional ligand catalysis under optional basic conditions to obtain the compound of the general formula (P2);
- Second step the compound of general formula (P2) is reacted under optional reducing conditions to obtain general formula (P3);
- the third step the compound of general formula (P3) obtains general formula (P4) under optional oxidation conditions;
- the fourth step the compound of the general formula (P4) reacts with the compound of the general formula (Y2) under optional acidic or basic conditions to obtain the compound of the general formula (P5);
- Step 5 The compound of general formula (P5) is optionally removed from the protecting group PG under acidic or basic conditions, and separated by preparative HPLC to obtain the compound of general formula (P6).
- PG can be the protecting group of common hydroxyl
- Ring B is optionally substituted aryl or heteroaryl
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 .
- the first step the compound of the general formula (P1) undergoes a carbonyl insertion reaction under optional palladium reagent catalysis conditions to obtain the compound of the general formula (P2);
- Second step the compound of general formula (P2) is reacted under optional reducing conditions to obtain general formula (P3);
- the third step the compound of the general formula (P3) is optionally brominated to obtain the compound of the general formula (P4);
- the fourth step the compound of general formula (P4) reacts with the compound of general formula (Y1) under optional basic conditions to obtain the compound of general formula (P5);
- the sixth step the compound of the general formula (P6) is optionally oxidized to obtain the general formula (P7);
- the seventh step the compound of general formula (P7) reacts with the compound of general formula (Y2) under optional acidic or basic conditions to obtain the compound of general formula (P8);
- the eighth step the compound of the general formula (P8) is optionally removed under acidic or basic conditions, and the protecting group PG is removed, and separated by preparative HPLC to obtain the compound of the general formula (P9).
- PG 1 and PG 2 can be protecting groups for common hydroxyl or ester groups
- R can be optionally substituted C 1 -C 6 alkyl
- Ring B is optionally substituted aryl or heteroaryl
- R, R 1 , R 2 and R 3 can be as any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) in this application respectively R, R 1 , R 2 and R 3 are as defined.
- the first step the compound of the general formula (P1) is optionally brominated, and a bromine atom is introduced at the methyl group to obtain the compound of the general formula (P2);
- the second step the compound of general formula (P2) reacts with the compound of general formula (Y1) under optional palladium reagent catalytic conditions to obtain the compound of general formula (P3);
- the third step the compound of general formula (P3) reacts with the compound of general formula (Y2) under optional acidic or basic conditions to obtain the compound of general formula (P4);
- the fourth step the compound of the general formula (P4) is optionally removed from the protecting group PG under acidic or basic conditions, and separated by preparative HPLC to obtain the compound of the general formula (P5).
- PG 1 can be a protecting group for common hydroxyl groups
- Ring B is optionally substituted aryl or heteroaryl
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- the first step the compound of general formula (P1) is reacted under optional reducing conditions to obtain general formula (P2);
- the second step the compound of the general formula (P2) is optionally under acidic or basic conditions, and the protecting group PG is added to obtain the general formula (P3);
- the third step the compound of general formula (P3) reacts with the compound of general formula (Y1) under optional alkaline conditions to obtain the compound of general formula (P4);
- the fourth step the compound of general formula (P4) is reacted under optional reducing conditions to obtain general formula (P5);
- the fifth step the compound of the general formula (P5) is optionally oxidized to obtain the general formula (P6);
- the sixth step the compound of general formula (P6) reacts with the compound of general formula (Y2) under optional acidic or basic conditions to obtain the compound of general formula (P7);
- the seventh step the compound of the general formula (P7) is optionally removed under acidic or basic conditions, and the protecting group PG is removed, and separated by preparative HPLC to obtain the compound of the general formula (P8).
- Ring B is optionally substituted aryl or heteroaryl
- PG 1 and PG 2 can be common hydroxyl or hydroxyl protecting groups
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- the first step the compound of general formula (P1) reacts with the compound of general formula (Y1) under optional condensation conditions to obtain the compound of general formula (P2)
- Second step the compound of general formula (P2) is reacted under optional reducing conditions to obtain the compound of general formula (P3);
- the third step the compound of general formula (P3) is reacted under optional oxidation conditions to obtain the compound of general formula (P4);
- the fourth step the compound of the general formula (P4) reacts with the compound of the general formula (Y2) under optional acidic or basic conditions to obtain the compound of the general formula (P5);
- the fifth step the compound of general formula (P5) is reacted under optional reducing conditions to obtain the compound of general formula (P6);
- PG 1 and PG 2 can be protecting groups for common hydroxyl or ester groups
- Ring B is optionally substituted aryl or heteroaryl
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- the first step the compound of general formula (P1) is introduced into the nitro group on the benzene ring under nitration conditions to obtain the compound of general formula (P2);
- the second step the compound of the general formula (P2) is reacted with the borate dimer under optional palladium reagent catalyst conditions to obtain the compound of the general formula (P3);
- the third step the compound of general formula (P3) reacts with the compound of general formula (Y1) under optional palladium reagent catalytic conditions to obtain the compound of general formula (P4);
- the fourth step the compound of general formula (P4) reacts with the compound of general formula (Y2) under optional acidic or basic conditions to obtain the compound of general formula (P5);
- the fifth step the compound of the general formula (P5) is optionally hydrogenated to obtain the compound of the general formula (P6);
- Step 6 The compound of general formula (P6) is optionally deprotected by PG under acidic or basic conditions, and separated by preparative HPLC to obtain the compound of general formula (P7).
- PG can be the protecting group of common hydroxyl
- -B(OR) 2 is a borate-based monomer, in which two Rs can be connected to form a heterocyclic ring, a heterobridged ring or a heterospiro ring, and the ring can be optionally covered by C 1 -C 6 alkyl, aryl, Heteroaryl, carboxyl or acyloxy C 1 -C 6 alkyl substitution;
- each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycle Alkyl, halogen substituted C 1 -C 6 alkyl, and halogen substituted C 1 -C 6 alkoxy;
- Ring B is optionally substituted aryl or heteroaryl
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- the first step the compound of general formula (P1) is introduced into the nitro group on the benzene ring under nitration conditions to obtain the compound of general formula (P2);
- the second step the compound of the general formula (P2) is reacted with an ethyl Grignard reagent under optional titanium catalysis conditions to obtain the compound of the general formula (P3);
- the third step the compound of the general formula (P2) reacts with the borate dimer under optional palladium reagent catalyst conditions to obtain the compound of the general formula (P3);
- the fourth step the compound of general formula (P3) reacts with the compound of general formula (Y1) under optional palladium reagent catalytic conditions to obtain the compound of general formula (P4);
- the fifth step the compound of general formula (P4) reacts with the compound of general formula (Y2) under optional acidic or basic conditions to obtain the compound of general formula (P5);
- Step 6 The compound of the general formula (P5) is optionally hydrogenated, the nitro group is reduced, and separated by preparative HPLC to obtain the compound of the general formula (P6).
- Ring B is optionally substituted aryl or heteroaryl
- -B(OR) 2 is a borate-based monomer, in which two Rs can be connected to form a heterocyclic ring, a heterobridged ring or a heterospiro ring, and the ring can be optionally covered by C 1 -C 6 alkyl, aryl, Heteroaryl, carboxyl or acyloxy C 1 -C 6 alkyl substitution;
- each R is independently selected from hydrogen, protium, deuterium, tritium, oxygen, hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycle Alkyl, halogen substituted C 1 -C 6 alkyl, and halogen substituted C 1 -C 6 alkoxy;
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- the first step the compound of general formula (P1) reacts with the compound of general formula (Y1) under optional basic conditions to obtain the compound of general formula (P2);
- Second step the compound of general formula (P2) is reacted under optional reducing conditions to obtain general formula (P3);
- the third step the compound of general formula (P3) obtains general formula (P4) under optional oxidation conditions;
- the fourth step the compound of the general formula (P4) reacts with the compound of the general formula (Y2) under optional acidic or basic conditions to obtain the compound of the general formula (P5)
- Step 5 The compound of general formula (P5) is optionally removed from the protecting group PG under acidic or basic conditions, and separated by preparative HPLC to obtain the compound of general formula (P6).
- PG can be the protecting group of common hydroxyl
- Ring B is optionally substituted aryl or heteroaryl
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- the first step the compound of general formula (P1) reacts with the compound of general formula (Y1) under optional palladium catalysis conditions to obtain the compound of general formula (P2);
- Second step the compound of general formula (P2) is reacted under optional reducing conditions to obtain general formula (P3);
- the third step the compound of general formula (P3) obtains general formula (P4) under optional oxidation conditions;
- the fourth step the compound of the general formula (P4) reacts with the compound of the general formula (Y2) under optional acidic or basic conditions to obtain the compound of the general formula (P5)
- Step 5 The compound of general formula (P5) is optionally removed from the protecting group PG under acidic or basic conditions, and separated by preparative HPLC to obtain the compound of general formula (P6).
- X is NR or -O-, R is optionally substituted C 1 -C 6 alkyl;
- PG can be the protecting group of common hydroxyl
- Ring B is optionally substituted aryl or heteroaryl
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- the first step the compound of general formula (P1) reacts with the compound of general formula (Y1) under optional condensation conditions to obtain the compound of general formula (P2)
- Second step the compound of general formula (P2) is reacted under optional reducing conditions to obtain the compound of general formula (P3);
- the third step the compound of general formula (P3) is reacted under optional oxidation conditions to obtain the compound of general formula (P4);
- the fourth step the compound of the general formula (P4) reacts with the compound of the general formula (Y2) under optional acidic or basic conditions to obtain the compound of the general formula (P5);
- the fifth step the compound of general formula (P5) is reacted under optional reducing conditions, and separated by preparative HPLC to obtain the compound of general formula (P6);
- PG can be the protecting group of common hydroxyl
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- the first step the compound of general formula (P1) reacts with the compound of general formula (Y1) under optional condensation conditions to obtain the compound of general formula (P2);
- the second step the compound of the general formula (P2) is optionally deprotected under acidic or basic conditions to obtain the compound of the general formula (P3).
- the third step the compound of general formula (P3) reacts with the compound of general formula (Y2) under optional condensation conditions to obtain the compound of general formula (P4);
- the fourth step the compound of the general formula (P4) is optionally under acidic or basic conditions, and the protecting group PG 1 is removed to obtain the compound of the general formula (P5);
- the fifth step the compound of general formula (P5) reacts with the compound of general formula (Y3) under optional condensation conditions to obtain the compound of general formula (P6);
- Step 6 The compound of the general formula (P6) is optionally removed from the protecting group PG 1 under acidic or basic conditions to obtain the compound of the general formula (P7);
- the seventh step the compound of the general formula (P7) is reacted with the compound of the general formula (Y3) under optional condensation conditions, and separated by preparative HPLC to obtain the compound of the general formula (P8).
- Ring B is optionally substituted aryl or heteroaryl
- W does not exist or W is any group
- X is -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 - or
- Y is hydrogen, hydroxy, fluorine, chlorine, methyl, hydroxy or methoxy
- R 1 , R 2 and R 3 can be defined as R 1 , R 2 and R 3 shown in any formula (I), formula (II), formula ( III ) or formula (IV) of this application, respectively;
- LG 1 , LG 2 , LG 3 and LG 4 can be hydroxyl groups of common activated esters or carboxyl groups;
- PG 1 , PG 2 and PG 3 can be common amino protecting groups
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- Tr does not exist or Tr is any group
- L3 is selected from polypeptide fragments
- L2 is absent or selected from a linking fragment
- L 1 is selected from coupling units.
- the first step the compound of general formula (P1) is reacted with the compound of general formula (Y1) under optional condensation conditions, and separated by preparative HPLC to obtain the compound of general formula (P2).
- Ring B is optionally substituted aryl or heteroaryl
- W does not exist or W is any group
- X is -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 - or
- Y is -O-, -S- or -NH-;
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- LG 1 can be a hydroxyl group of a common activated ester or a carboxyl group
- Tr does not exist or Tr is any group
- L3 is selected from polypeptide fragments
- L2 is absent or selected from a linking fragment
- L 1 is selected from coupling units.
- the first step the compound of general formula (P1) reacts with the compound of general formula (Y1) under optional condensation conditions to obtain the compound of general formula (P2);
- the second step the compound of the general formula (P2) is optionally deprotected under acidic or basic conditions to obtain the compound of the general formula (P3).
- the third step the compound of general formula (P3) reacts with the compound of general formula (Y2) under optional condensation conditions to obtain the compound of general formula (P4);
- the fourth step the compound of the general formula (P4) is optionally under acidic or basic conditions, and the protecting group PG 1 is removed to obtain the compound of the general formula (P5);
- the fifth step the compound of the general formula (P5) is reacted with the compound of the general formula (Y3) under optional condensation conditions, and separated by preparative HPLC to obtain the compound of the general formula (P6).
- Ring B is optionally substituted aryl or heteroaryl
- W does not exist or W is any group
- X is -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 - or
- Y is -O-, -S- or -NH-;
- LG 1 , LG 2 and LG 3 can be hydroxyl groups of common activated esters or carboxyl groups;
- PG 1 , PG 2 and PG 3 can be common amino protecting groups
- R 1 , R 2 and R 3 can be shown in any formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) respectively in this application defined by R 1 , R 2 and R 3 ;
- Tr does not exist or Tr is any group
- L3 is selected from polypeptide fragments
- L2 is absent or selected from a linking fragment
- L 1 is selected from coupling units.
- Ligand Ab reacts with any compound represented by formula (IVa) or formula (IVb) in this application in an acidic, neutral or alkaline buffer to obtain a compound represented by formula (Va) or formula (Vb);
- Ab is a ligand containing at least one free sulfhydryl group (-SH), wherein the free sulfhydryl group can be obtained by reducing the ligand through a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl)phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, can reduce the disulfide bond (-S-S-) between ligand chains to form free sulfhydryl groups; wherein formula (I-C) or formula ( The S atom in the compound shown in II-C) and the sulfhydryl group that can be derived from Ab;
- Tr, L 1 , L 2 , L 3 can be defined as Tr, L 1 , L 2 , L 3 in the compound shown in any formula (IVa) or formula (IVb) of this application respectively;
- Ab, N aI can be respectively as follows In the compound shown by any formula (Va) or formula (Vb) in the present application, Ab and N a- I are defined;
- L 1x represents the structure after coupling with L 1 coupled with thiol.
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, dibasic phosphate Potassium Hydrogen-Dipotassium Phosphate Buffer, Succinic Acid-Sodium Succinate Buffer, Acetic Acid-Sodium Acetate Buffer, Boric Acid-Borax Buffer, Boric Acid-Potassium Borate Buffer, Borax-Sodium Hydroxide Buffer, Histidine - HCl buffer, Glycine-NaOH buffer, Arginine-HCl buffer, Sodium bicarbonate-Sodium carbonate buffer, Potassium bicarbonate-Potassium carbonate buffer, Tris-HCl buffer, Ammonia-Ammonium chloride Buffer, barbital sodium-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer,
- the ligand Ab reacts with the compound shown in any formula (IVa) or formula (IVb) of the present application in an acidic, neutral or alkaline buffer to obtain the compound shown in formula (Va) or formula (Vb).
- Ab is a ligand containing at least one free sulfhydryl group (-SH), wherein the free sulfhydryl group can be obtained by reducing the ligand through a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl)phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, can reduce the disulfide bond (-S-S-) between ligand chains to form free sulfhydryl groups; wherein formula (Va) or formula ( The S atom in the compound shown in Vb) and the mercapto group that can be derived from Ab;
- the compound shown in any formula (Va) or formula (Vb) of the present application is incubated for a certain period of time in an alkaline buffer at a selected temperature to obtain another compound of any formula (Va) of the present application. ) or a compound shown in formula (Vb);
- Tr, L 2 , L 3 can be defined as Tr, L 2 , L 3 in the compound shown in any formula (IVa) or formula (IVb) of the present application;
- Ab, NaI can be defined as in any formula (Va ) or the compounds represented by formula (Vb) as defined by Ab and NaI .
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, dibasic phosphate Potassium Hydrogen-Dipotassium Phosphate Buffer, Succinic Acid-Sodium Succinate Buffer, Acetic Acid-Sodium Acetate Buffer, Boric Acid-Borax Buffer, Boric Acid-Potassium Borate Buffer, Borax-Sodium Hydroxide Buffer, Histidine - HCl buffer, Glycine-NaOH buffer, Arginine-HCl buffer, Sodium bicarbonate-Sodium carbonate buffer, Potassium bicarbonate-Potassium carbonate buffer, Tris-HCl buffer, Ammonia-Ammonium chloride Buffer, barbital sodium-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer,
- Ligand Ab reacts with any compound shown in formula (IVa) or formula (IVb) of this application that can be coupled with two sulfhydryl groups in an acidic, neutral or alkaline buffer to obtain formula (Va) Or the compound shown in formula (Vb);
- Ab is a ligand containing at least 2 free sulfhydryl groups (-SH), wherein the free sulfhydryl groups can be obtained by reducing the ligand through a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl)phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, can reduce the disulfide bond (-S-S-) between ligand chains to form free sulfhydryl groups; wherein formula (Va) or formula ( The S atom in the compound shown in Vb) and the mercapto group that can be derived from Ab;
- Tr, L 1 , L 2 , L 3 can be defined as Tr, L 1 , L 2 , L 3 in the compound shown in any formula (IVa) or formula (IVb) of this application respectively;
- Ab, N aI can be respectively as follows In the compound shown in any formula (Va) or formula (Vb) of the present application, Ab and N a- I are defined;
- L 1y represents the structure after coupling with L 1 coupled with 2 sulfhydryl groups.
- the compound shown by formula (Va) or formula (Vb) having a group capable of coupling with 2 mercapto groups may comprise a L 1y group selected from the group consisting of: Wherein each R L1a , R L1b and R L1c are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O )H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C( O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, alkyl, alkenyl, alkynyl, alicyclic, heterocyclic, aryl, and heteroaryl .
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, dibasic phosphate Potassium Hydrogen-Dipotassium Phosphate Buffer, Succinic Acid-Sodium Succinate Buffer, Acetic Acid-Sodium Acetate Buffer, Boric Acid-Borax Buffer, Boric Acid-Potassium Borate Buffer, Borax-Sodium Hydroxide Buffer, Histidine - HCl buffer, Glycine-NaOH buffer, Arginine-HCl buffer, Sodium bicarbonate-Sodium carbonate buffer, Potassium bicarbonate-Potassium carbonate buffer, Tris-HCl buffer, Ammonia-Ammonium chloride Buffer, barbital sodium-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer,
- Ligand Ab reacts with any compound shown in formula (IVa) or formula (IVb) of this application that can be coupled with two sulfhydryl groups in an acidic, neutral or alkaline buffer to obtain formula (Va) Or the compound shown in formula (Vb);
- Ab is a ligand containing at least one free sulfhydryl group (-SH), wherein the free sulfhydryl group can be obtained by reducing the ligand through a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl)phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, can reduce the disulfide bond (-S-S-) between ligand chains to form free sulfhydryl groups; wherein formula (Va) or formula ( The S atom in the compound shown in Vb) and the mercapto group that can be derived from Ab;
- Tr, L 1 , L 2 , L 3 can be defined as Tr, L 1 , L 2 , L 3 in the compound shown in any formula (IVa) or formula (IVb) of this application respectively;
- Ab, N aI can be respectively as follows In the compound shown by any formula (Va) or formula (Vb) in the present application, Ab and N a- I are defined;
- L 1x represents the structure after coupling with L 1 coupled with thiol.
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, dibasic phosphate Potassium Hydrogen-Dipotassium Phosphate Buffer, Succinic Acid-Sodium Succinate Buffer, Acetic Acid-Sodium Acetate Buffer, Boric Acid-Borax Buffer, Boric Acid-Potassium Borate Buffer, Borax-Sodium Hydroxide Buffer, Histidine - HCl buffer, Glycine-NaOH buffer, Arginine-HCl buffer, Sodium bicarbonate-Sodium carbonate buffer, Potassium bicarbonate-Potassium carbonate buffer, Tris-HCl buffer, Ammonia-Ammonium chloride Buffer, barbital sodium-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer,
- the ligand Ab reacts with the compound shown in any formula (IVa) or formula (IVb) of the present application in an acidic, neutral or alkaline buffer to obtain the compound shown in formula (Va) or formula (Vb).
- Ab is a ligand containing at least one free sulfhydryl group (-SH), wherein the free sulfhydryl group can be obtained by reducing the ligand through a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl)phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, can reduce the disulfide bond (-S-S-) between ligand chains to form free sulfhydryl groups; wherein formula (Va) or formula ( The S atom in the compound shown in Vb) and the mercapto group that can be derived from Ab;
- the compound shown in any formula (Va) or formula (Vb) of the present application is incubated for a certain period of time in an alkaline buffer at a selected temperature to obtain another compound of any formula (Va) of the present application. ) or a compound shown in formula (Vb);
- Tr, L 2 , L 3 can be defined as Tr, L 2 , L 3 in the compound shown in any formula (IVa) or formula (IVb) of the present application;
- Ab, NaI can be defined as in any formula (Va ) or the compounds represented by formula (Vb) as defined by Ab and NaI .
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, dibasic phosphate Potassium Hydrogen-Dipotassium Phosphate Buffer, Succinic Acid-Sodium Succinate Buffer, Acetic Acid-Sodium Acetate Buffer, Boric Acid-Borax Buffer, Boric Acid-Potassium Borate Buffer, Borax-Sodium Hydroxide Buffer, Histidine - HCl buffer, Glycine-NaOH buffer, Arginine-HCl buffer, Sodium bicarbonate-Sodium carbonate buffer, Potassium bicarbonate-Potassium carbonate buffer, Tris-HCl buffer, Ammonia-Ammonium chloride Buffer, barbital sodium-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer,
- Ligand Ab reacts with any compound shown in formula (IVa) or formula (IVb) of this application that can be coupled with two sulfhydryl groups in an acidic, neutral or alkaline buffer to obtain formula (Va) Or the compound shown in formula (Vb);
- Ab is a ligand containing at least 2 free sulfhydryl groups (-SH), wherein the free sulfhydryl groups can be obtained by reducing the ligand through a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl)phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, can reduce the disulfide bond (-S-S-) between ligand chains to form free sulfhydryl groups; wherein formula (Va) or formula ( The S atom in the compound shown in Vb) and the mercapto group that can be derived from Ab;
- Tr, L 1 , L 2 , L 3 can be defined as Tr, L 1 , L 2 , L 3 in the compound shown in any formula (IVa) or formula (IVb) of this application respectively;
- Ab, N aI can be respectively as follows In the compound shown in any formula (Va) or formula (Vb) of the present application, Ab and N a- I are defined;
- L 1y represents the structure after coupling with L 1 coupled with 2 sulfhydryl groups.
- the compound shown by formula (Va) or formula (Vb) having a group capable of coupling with 2 mercapto groups may comprise a L 1y group selected from the group consisting of: Wherein each R L1a , R L1b and R L1c are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O )H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C( O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, alkyl, alkenyl, alkynyl, alicyclic, heterocyclic, aryl, and heteroaryl .
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, dibasic phosphate Potassium Hydrogen-Dipotassium Phosphate Buffer, Succinic Acid-Sodium Succinate Buffer, Acetic Acid-Sodium Acetate Buffer, Boric Acid-Borax Buffer, Boric Acid-Potassium Borate Buffer, Borax-Sodium Hydroxide Buffer, Histidine - HCl buffer, Glycine-NaOH buffer, Arginine-HCl buffer, Sodium bicarbonate-Sodium carbonate buffer, Potassium bicarbonate-Potassium carbonate buffer, Tris-HCl buffer, Ammonia-Ammonium chloride Buffer, barbital sodium-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer,
- Step 2 Dissolve compound 2B (1.0 g, 3.2 mmol) in THF (10 mL), replace with N 2 and cool down to 0° C., add BH 3 /THF (6.4 mL, 6.4 mmol), and LCMS shows that the reaction is complete after 17 hours.
- the reaction solution was added into methanol (40 mL) (kept in an ice bath at 0° C.), quenched BH 3 and then spin-dried to obtain 500 mg of colorless oil 2C, yield: 52%.
- MS-ESI m/z 298.1 [M+H] + .
- Step 3 Dissolve compound 2C (500mg, 1.68mmol) in dichloromethane (8mL). After cooling down to 0°C, add Dess-Martin reagent (1.43g, 3.36mmol). After 1.5 hours, LCMS showed that the reaction was complete. The reaction solution was diluted with water (100 mL), extracted twice with ethyl acetate (100 mL+50 mL), combined the organic phases and washed with saturated brine, dried over anhydrous sodium sulfate and spin-dried to obtain 250 mg of white solid 2D, yield: 50% . MS-ESI: m/z 296.0 [M+H] + .
- Step 5 Take compound 2E (100mg, 0.18mmol), iron powder (100mg, 1.8mmol), add it to ethanol (4mL), dissolve NH 4 Cl (96mg, 1.8mmol) in water, add it to ethanol, replace with N 2 and raise the temperature The reaction was carried out at 60° C. for 2 hours, and LCMS showed that the reaction was complete. The reaction solution was filtered with diatomaceous earth, the filter cake was rinsed with ethanol three times, and the mother liquor was spin-dried for preparation. After preparation, 40 mg of white solid powder 2 and 5 mg of white solid powder 2S were obtained, with yields of 42% and 5%, respectively.
Abstract
一种甾体化合物及其缀合物,具体涉及化合物及其缀合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐;以及该化合物及其缀合物的制备方法及应用。
Description
本申请涉及生物医药领域,具体的涉及一种甾体化合物及其缀合物。
炎症是多种伤害刺激和状态触发的适应性反应,其成为许多人类免疫系统相关疾病的基础。甾体化合物是一类抗炎症药物,可以具有影响免疫系统功能、治疗或预防与糖皮质激素受体信号转导相关的疾病和/或症状的潜力,然而现有的一些甾体化合物抗炎症效果不强,另一些甾体化合物可能具有许多不希望的副作用。因此目前急需进一步开发多种甾体形成的抗体偶联药物以及甾体类化合物,以作为可以发挥更好的疗效或可以具有更好的安全性的药物。
发明内容
本申请提供了一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其可以具有选自以下组的一种或多种效果:(1)具有影响免疫细胞活性的能力;(2)其偶联物具有靶向作用;(3)具有血浆稳定性;(4)具有生物安全性;(5)具有影响免疫细胞的细胞因子释放的能力;(6)具有影响IFN信号途径应答基因转录的能力;(7)具有影响皮肤纤维化程度的能力;(8)具有影响树突状细胞数量和/或比例的能力;(9)具有影响皮肤胶原含量的能力;(10)具有影响GRE表达水平的能力;(11)具有影响单核细胞细胞因子释放的能力;(12)具有影响接触性超敏反应的能力;(13)具有影响皮肤肿胀的能力和(14)具有影响关节炎症状的能力。
本申请提供了含有与蛋白质(例如,抗体或其抗原结合片段和可溶性受体蛋白)连接的糖皮质激素受体激动剂的免疫偶联物。在一些实施例中,抗体或其抗原结合片段是人的、人源化的、嵌合的或鼠的。在一些实施例中,蛋白质(例如,抗体、其抗原结合片段或可溶性受体蛋白)可以与细胞表面上的靶标结合并变得内化。
一方面,本申请提供一种式I的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,
R
1、R
2、R
3、R
4和R
5各自独立地为任意基团;
B不存在或B为任意基团;
W不存在或W为任意基团;
A1为取代的苯环;
CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O)
2-、-C(=O)-、-C=C-和-C≡C-,其中R
4和R
5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;
X选自:-O-,-S-,-NR-;
Y
1为任意基团,m为0至4中的任意整数;
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
另一方面,本发明提供了下式所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述化合物选自:
另一方面,本申请提供一种式IIa或IIb的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,
R
1、R
2、R
3、R
4和R
5各自独立地为任意基团;
B不存在或B为任意基团;
W不存在或W为任意基团;
A2为取代的苯环;
CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O)
2-、-C(=O)-、-C=C-和-C≡C-,其中R
4和R
5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;
X选自:-O-,-S-,-NR-;
Y
1为任意基团,m为0至4中的任意整数;
Y
2选自-O-,-S-和-NR-;
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基;其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
另一方面,本申请提供一种偶联物,包含前述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐。
另一方面,本申请提供一种药物组合物,其包含前述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐和/或前述的偶联物,以及任选地药学上可接受的载体。
另一方面,本申请提供一种影响免疫系统功能的方法,包括向受试者施用前述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐、前述的偶联物和/或前述的药物组合物。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的说明书中的描述仅仅是示例性的,而非为限制性的。
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中,术语“糖皮质激素”通常是指与糖皮质激素受体相互作用的天然存在的类固醇激素或合成的类固醇激素。
在本申请中,术语“卤素”通常是指氟、氯、溴、碘,例如可以是氟、氯。
在本申请中,术语“烷基”通常是指烷除去氢原子所衍生的残基。烷基可以是取代的或非取代的,替代或者非替代的。术语“烷基”通常指饱和的直链或支链脂肪族烃基,其具有从母体烷的相同碳原子或两个不同的碳原子上除去氢原子所衍生的残基,其可以为包含1至20个碳原子的直链或支链基团,例如含有1至12个碳原子,例如含有1至6个碳原子的链烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丙基、丁基等。烷基可以是取代的或非取代的,替代或者非替代的,例如当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基可以独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代,例如可以是氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H或C
1-6脂肪族基团。
在本申请中,术语“亚烷基”通常指饱和的直链或支链脂肪族烃基,其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基,其可以为包含1至20个碳原子的直链或支链基团,例如,术语“亚甲基”可以是指1个碳原子的基团除去两个氢原子所衍生的残基。亚甲基可以是取代的或非取代的,替代或者非替代的;例如含有1至12个碳原子,例如含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH
2-)、1,1-亚乙基(-CH(CH
3)-)、1,2-亚乙基(-CH
2CH
2)-、1,1-亚丙基(-CH(CH
2CH
3)-)、1,2-亚丙基(-CH
2CH(CH
3)-)、1,3-亚丙基(-CH
2CH
2CH
2-)、1,4-亚丁基(-CH
2CH
2CH
2CH
2-)和1,5-亚丁基(-CH
2CH
2CH
2CH
2CH
2-)等。亚烷基可以是取代的或非取代的,替代或者非替代的,例如当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基可以独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代,例如可以是氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H或C
1-6脂肪族基团。亚甲基或亚烷基可以是取代的或非取代的。
在本申请中,术语“烯基”通常是指含有一个或多个双键的直链或支链烃基。烯基的示例性实例包括烯丙基、高烯丙基、乙烯基、巴豆基、丁烯基、戊烯基和己烯基等。具有一个以上双键的C2-6链烯基的示例性实例包括丁二烯基、戊二烯基、己二烯基和己三烯基以及它 们的支化形式。不饱和键(双键)的位置可以是在碳链的任何一个位置。烯基可以是取代的或非取代的。
在本申请中,术语“亚烯基”通常是指具有从烯烃的碳原子上除去两个氢原子所衍生的残基。例如,可以是亚烯丙基、亚乙烯基、亚丁烯基、亚戊烯基和亚己烯基等。亚烯基可以是取代的或非取代的。
在本申请中,术语“炔基”通常是指不饱和直链或支链炔基,例如乙炔基、1-丙炔基、炔丙基、丁炔基等。炔基可以是取代的或非取代的。
在本申请中,术语“亚炔基”通常是指具有从炔烃的碳原子上除去两个氢原子所衍生的残基。例如,可以是亚乙炔基、亚丙炔基、亚炔丙基、亚丁炔基等。亚炔基可以是取代的或非取代的。
在本申请中,术语“芳基”通常是指具有芳环上除去一个氢原子所衍生的残基。术语“芳环”可以指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环),可以为6至10元,例如苯和萘。所述芳环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环。芳基可以是取代的或非取代的,当被取代时,取代基可以为一个或多个以下基团,其独立地选自以下组:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、和杂环烷硫基。芳基可以是取代的或非取代的。
在本申请中,术语“亚芳基”通常是指具有从芳环的碳原子上除去两个氢原子所衍生的残基。例如,可以是亚苯基和亚萘基。亚芳基可以是取代的或非取代的。
在本申请中,术语“杂芳基”通常是指具有从杂芳环的碳原子上除去一个氢原子所衍生的残基。术语“杂芳环”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子可以选自以下组:氧、硫和氮。杂芳基可以为5至10元,可以为5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或非取代的,当被取代时,取代基可以为一个或多个以下基团,其独立地选自以下组:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、和杂环烷硫基。杂芳基可以是取代的或非取代的。
在本申请中,术语“亚杂芳基”通常是指具有从杂芳环的碳原子上除去两个氢原子所衍生的残基。例如,可以是亚呋喃基、亚噻吩基、亚吡啶基、亚吡咯基、亚嘧啶基、亚吡嗪基、亚 咪唑基、亚四唑基等。亚杂芳基可以是取代的或非取代的。
在本申请中,术语“脂环基”与“环烷基”可以互换使用,术语“脂环基”通常是指具有从脂肪环的相同碳原子或多个不同的碳原子上除去氢原子所衍生的残基。术语“环烷”通常指饱和或部分不饱和单环或多环环状烃,碳环包含3至20个碳原子,可以包含3至12个碳原子,可以包含3至10个碳原子,可以包含3至8个碳原子。脂环基的非限制性实例包括环丙烷基、环丁烷基、环戊烷基、环戊烯基、环己烷基、环己烯基、环己二烯基、环庚烷基、环庚三烯基、环辛烷基等;多环碳环可以包括螺环、稠环和桥环的碳环。脂环基可以是取代的或非取代的。在本申请中,术语“碳环基”通常是指具有碳环的碳原子上除去一个氢原子所衍生的残基。术语“碳环”通常指饱和或部分不饱和单环或多环环状烃,碳环包含3至20个碳原子,可以包含3至12个碳原子,可以包含3至10个碳原子,可以包含3至8个碳原子。单环碳环的非限制性实例包括环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己烯、环己二烯、环庚烷、环庚三烯、环辛烷等;多环碳环可以包括螺环、稠环和桥环的碳环。碳环基可以是取代的或非取代的。在某些情形下,脂环和碳环可以相互替代使用。
在本申请中,术语“部分不饱和的”通常是指环状结构中环分子间至少含一个双键或三键。术语“部分不饱和”涵盖带有多处不饱和的环状结构,但并非意在包括本申请所定义的芳环或杂芳环。术语"不饱和的"表示部分具有一个或多个不饱和度。
在本申请中,术语“亚脂环基”与“亚环烷基”可以互换使用,术语“亚脂环基”通常是指具有从脂环的碳原子上除去两个氢原子所衍生的残基。例如,可以是亚环丙烷基、亚环丁烷基、亚环戊烷基、亚环戊烯基、亚环己烷基、亚环己烯基、亚环己二烯基、亚环庚烷基、亚环庚三烯基、亚环辛烷基等;多环碳环可以包括螺环、稠环和桥环的碳环。亚脂环基可以是取代的或非取代的。
在本申请中,术语“脂杂环基”与“杂环基”可以互换使用,术语“脂杂环基”通常是指稳定的不具有芳香性的3元-7元单环碳环结构,融合的7元-10元双环杂环结构或桥联的6元-10元双环杂环结构,这些环状结构即可以是饱和的,也可以是部分饱和的,除碳原子外,这些环状结构中还含有一个或多个杂原子,其中杂原子可以选自以下组:氧、硫和氮。例如是含有1-4个上述定义的杂原子。当用来表示脂杂环环状结构上的原子时,术语“氮”可以包括发生过取代反应的氮。例如,脂杂环基可以包含“杂环烷基”,杂环烷基可以指稳定的不具有芳香性的3元-7元单环烷结构,融合的7元-10元双环杂环结构或桥联的6元-10元双环杂环结构,除碳原子外,这些环状结构中还含有一个或多个杂原子,其中杂原子可以选自以下组:氧、硫和氮。例如是含有1-4个上述定义的杂原子。杂环烷基可以是取代的或非取代的。脂杂 环基可以是取代的或非取代的。
在本申请中,术语“亚脂杂环基”与“亚杂环基”可以互换使用,术语“亚脂杂环基”通常是指具有从脂杂环的碳原子上除去两个氢原子所衍生的残基。亚脂杂环基可以是取代的或非取代的。
在本申请中,在描述环烷基、亚环烷基、杂环基、亚杂环基、芳基、亚芳基、杂芳基、亚杂芳基等环状结构时,前缀(例如,C
3-C
20,C
3-C
7,C
5-C
6等)通常是指环原子的数目,或环原子数的范围,无论是碳原子或是杂原子。例如,如本申请中所用的术语“C
5-C
6杂环基”,涉及具有5或6个环原子的杂环基基团。又例如,本申请中所述的术语“C
5-C
10杂芳基”涉及具有5至10个环原子的杂芳基基团。
在本申请中,术语“成环原子”或“环原子”通常是指环状结构上包含的原子。例如,成环原子可以是苯环上的碳原子,可以是吡啶环上的氮原子。当成环原子上连接氢原子时,成环原子可以是取代的或非取代的。
在本申请中,术语“各自独立地”通常是指变量适用于任何一种情况,而不考虑在相同化合物中具有相同或不同定义的变量存在与否。例如其中的变量可以是指化合物的取代基种类、数量或化合物中原子的种类等。例如,在化合物中出现2次R并且R被定义为“独立地碳或氮”时,两个R可以均为碳,两个R可以均为氮,或一个R可以为碳而另一个R为氮。
在本申请中,术语“任选”或“任选地”通常意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明可以包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
在本申请中,术语“取代的”通常指基团中的一个或多个氢原子,例如为最多5个,例如为1~3个氢原子彼此独立地被相应数目的取代基取代。取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
当被取代时,“任选取代的”基团的取代基可以包括但不限于一个或多个独立地选自单独或组合的以下基团或特别指定的一组基团的取代基:低级烷基、低级烯基、低级炔基、低级烷酰基、低级杂烷基、低级杂环烷基、低级卤代烷基、低级卤代烯基、低级卤代炔基、低级全卤代烷基、低级全卤代烷氧基、低级环烷基、苯基、芳基、芳氧基、低级烷氧基、低级卤代烷氧基、氧代、低级酰氧基、羰基、羧基、低级烷基羰基、低级羧基酯、低级甲酰氨基、氰 基、卤素、羟基、氨基、低级烷基氨基、芳基氨基、酰氨基、硝基、硫醇、低级烷硫基、低级卤代烷硫基、低级全卤代烷硫基、芳硫基、磺酸酯、磺酸、三取代甲硅烷基、N3、SH、SCH3、C(O)CH3、CO2CH3、CO2H、腈、CF3、环烷基、吡啶基、噻吩、呋喃基、低级氨基甲酸酯、卤代苯基、羟基苯基、卤代烷基和羟烷基。两个取代基可以连接在一起以形成含有一至三个杂原子的五、六或七元芳族或非芳族碳环或杂环,例如形成亚甲二氧基或亚乙二氧基。任选取代的基团可以是未完全取代的(例如-CH
2CH
3),完全取代的(例如-CF
2CF
3),单取代的(-CH
2CH
2F)或在完全取代和单取代之间的任何水平取代(例如-CH
2CF
3)。当取代基被列出而没有关于取代的资格时,包括取代和未取代的形式。当取代基被认定为“取代的”时,取代的形式是特别意图的。另外,可以根据需要限定特定部分的不同组的任选取代基;在这些情况下,任选的取代被定义,通常紧随短语“任选被...取代”之后。术语“低级”与有机基团或化合物连用时意指化合物或基团可以是分支的或不分支的,具有不超过且包括7个碳原子,例如1-4个碳原子。低级烷基代表,例如,甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和分支的戊基、正己基和分支的己基。
在本申请中,术语0个或多个(例如,0个或1个以上、0个或1个、0个)亚甲基单元被“替代”通常指当所述结构包含1个或多个亚甲基单元时,所述一个或多个亚甲基单元可以不被替代,或被一个或多个不是亚甲基的基团(例如-NHC(O)-、-C(O)NH-、-C(O)-、-OC(O)-、-C(O)O-、-NH-、-O-、-S-、-SO-、-SO
2-、-PH-、-P(=O)H-、-NHSO
2-、-SO
2NH-、-C(=S)-、-C(=NH)-、-N=N-、-C=N-、-N=C-或-C(=N
2)-)所替代。
在本申请中,如本领域技术人员可知的,“烷基”、“烯基”、“环烷基”等之类的术语可以在名称前加一个标识表示在特定情况下基团中存在的原子数,例如,C
1-C
4烷基,C
3-C
7环烷氧基,C
1-C
4烷基羰基氨基等,“C”后所跟下标数字表示在基团中存在的碳原子数。例如,C
3烷基是指具有三个碳原子的烷基(例如,正丙基,异丙基);C
1-10中,基团的成员可具有落入1-10范围内的任何数目的碳原子。
基团中的一个或多个氢原子,例如为最多5个,例如为1~3个氢原子彼此独立地被相应数目的取代基取代。取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
在本申请中,术语“化合物”通常指具有两种或两种以上不同元素的物质。例如,本申请的化合物可以是有机化合物,例如本申请的化合物可以是分子量500以下的化合物,可以是分子量1000以下的化合物,也可以是分子量1000以上的化合物,也可以是10000以上、 100000以上的化合物。在本申请中,化合物还可以是指通过化学键相连的化合物,例如可以是一个或多个分子量1000以下的分子通过化学键与生物大分子相连的化合物,所述生物大分子可以是高聚糖、蛋白、核酸、多肽等。例如本申请的化合物可以包括蛋白质与一个或多个分子量1000以下的分子相连的化合物,可以是包括蛋白质与一个或多个分子量10000以下的分子相连的化合物,可以是包括蛋白质与一个或多个分子量100000以下的分子相连的化合物.
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液,例如1,3-丁二醇中制备的溶液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。例如,可使用包括合成甘油单或二酯在内的任何调和固定油。此外,脂肪酸例如油酸也可以制备注射剂。
在本申请中,本申请的化合物包含化合物的其互变异构体、内消旋体、外消旋体、对映异构体、和/或非对映异构体。在本申请中,术语“非对映异构体”通常是指具有两个或更多个手性中心并且其分子不是彼此的镜像的立体异构体。非对映异构体可以具有不同的物理性质,例如、熔点、沸点、波谱性质和反应性。在本申请中,术语“互变异构体”或“互变异构形式”可互换使用,通常是指可通过低能垒(low energy barrier)互相转化的不同能量的结构异构体。例如,质子互变异构体(protontautomer)(也称为质子移变互变异构体(prototropic tautomer))包括通过质子迁移进行的互相转化,诸如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组进行的互相转化。在本申请中,术语“内消旋体”通常是指分子内含有不对称性的原子,但具有对称因素而使分子内总旋光度为零。术语"外消旋体"或"外消旋混合物"是指由等摩尔量的两种对映异构体物质构成的组合物。
在本申请中,本申请的化合物的某些原子可能以一种以上的同位素形式出现。例如,氢可能以氕(
1H)、氘(
2H)和氚(
3H)的形式存在,碳可能以三种不同的同位素(
12C、
13C和
14C)自然存在。可并入本申请化合物中的同位素示例还包括但不限于
15N、
18O、
17O、
18F、
32P、
33P、
129I、
131I、
123I、
124I、
125I,或者类似的同位素。因此,相对于这些同位素的自然丰度,本申请的化合物可富集在一种或多种这些同位素中。如本领域技术人员所知,此类同位素富集化合物可用于多种用途。例如,用重同位素如氘(
2H)替代可能会提供某些治疗优势,这可以是由于更高的代谢稳定性。例如,氘(
2H)的自然丰度约为0.015%。因此,自然界中大约每6500个氢原子,就有一个氘原子。因此,本发明的含氘化合物在一个或多个位置(视情况而定)的氘丰度大于0.015%。除非另有指明,否则本申请所述的结构还可以包括仅在是 否存在一个或多个同位素富集原子方面存在差别的化合物。举例而言,除了氢原子被氘或氚所取代,或碳原子被碳13或碳14所取代之外,其余部分均与本申请结构一致的化合物均在本申请的范围之内。
在本申请中,“异构体”通常是指具有相同分子式的不同的化合物。“立体异构体”通常是指仅原子的空间排列方式不同的异构体。在本申请中,术语“异构体”包括任何以及所有几何异构体和立体异构体。例如,“异构体”包括几何双键顺式和反式异构体,也称为E–和Z–异构体;R–和S–对映异构体;非对映异构体、(d)–异构体和(l)–异构体、其外消旋混合物;及其落入本公开范围内的其他混合物。
在本申请中,“对映异构体”通常是指一对彼此的不可重叠的镜像的立体异构体。一对对映异构体的1:1混合物为“外消旋”混合物。适宜时,术语“(±)”用于表示外消旋混合物。“非对映异构体”是具有至少两个不对称原子,但不为彼此的镜像的立体异构体。绝对立体化学是根据Cahn-Ingold-Prelog R-S系统规定的。当化合物为纯对映异构体时,每个手性碳处的立体化学可以由R或S来指定。绝对构型未知的拆分的化合物可以根据其在钠D线的波长下使平面偏振光旋转的方向(右旋或左旋)来指定为(+)或(-)。本申请描述的某些化合物含有一个或多个不对称中心,因此可产生对映异构体、非对映异构体和其他可以根据绝对立体化学定义的立体异构形式,如(R)-或(S)-。本申请的化学实体、药物组合物和方法旨在包括所有这样的可能的异构体,包括外消旋混合物、光学纯形式和中间混合物。光学活性的(R)-和(S)-异构体可以使用手性合成子或手性试剂制备,或使用常规技术拆分。当本申请所述的化合物包含烯属双键或其他几何不对称中心时,并且除非另有说明,否则所述化合物旨在包括E和Z几何异构体二者。
在本申请中,术语“对映异构体纯度”通常是指特定对映异构体相对于另一种对映异构体的存在的相对量,以百分比表示。例如,如果可能具有(R)-或(S)-异构构型的化合物作为外消旋混合物存在,则就(R)-或(S)-异构体中的任一种而言,对映异构体纯度为约50%。如果该化合物的一种构形式优于另一种,例如,80%(S)-和20%(R)-,则该化合物就(S)-异构形式而言的对映体纯度为80%。化合物的对映异构体纯度可以通过本领域已知的多种方式测定,包括但不限于使用手性载体的色谱法,偏振光旋转的偏振测量,使用手性位移试剂(包括但不限于含有镧系元素的手性配合物或Pirkle醇)的核磁共振光谱法,或使用手性化合物如Mosher酸对化合物进行衍生化,然后进行色谱或核磁共振光谱。
在本申请中,术语“互变异构体”通常是指一种类型的异构体,其包括由氢原子的至少一种形式迁移及化合价的至少一种变化(例如,单键到双键、三键到双键或三键到单键,反之 亦然)产生的两种或多种可相互转化的化合物。“互变异构”包括质子移变或质子移动互变异构,其视为酸碱化学的一个子集。“质子移变互变异构”或“质子移动互变异构”涉及质子的迁移,伴随键级的变化。互变异构体的确切比例取决于多种因素,包括温度、溶剂和pH。当互变异构化可能存在(例如,在溶液中)时,可以达到互变异构体的化学平衡。互变异构(即,提供互变异构体对的反应)可以由酸或碱催化,或可以在没有外部试剂的作用或存在下发生。示例性的互变异构包括但不限于,酮-烯醇;酰胺-酰亚胺;内酰胺-内酰亚胺;烯胺-亚胺;和烯胺-(不同的)烯胺互变异构。酮-烯醇互变异构的具体的实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮互变异构体的相互转化。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的具体实例为吡啶-4-醇和吡啶-4(1H)-酮互变异构体的相互转化。
在本申请中,术语“药物组合物”通常是指含有一种或多种本申请所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物可以是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。常规的药物组合物的制备可以见中国药典。
在本申请中,术语“药学上可接受的盐”或“可药用的盐”通常是指本申请化合物或配体-药物偶联物的盐,或本申请中所述的化合物的盐,这类盐用于哺乳动物体内时可以具有安全性和/或有效性,且可以具有应有的生物活性,本申请抗体-抗体药物偶联化合物可以与酸形成盐,药学上可接受的盐的非限制性实例包括:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、柠檬酸盐、乙酸盐、琥珀酸盐、抗坏血酸盐、草酸盐、硝酸盐、梨酸盐、磷酸氢盐、磷酸二氢盐、水杨酸盐、柠檬酸氢盐、酒石酸盐、马来酸盐、富马酸盐、甲酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐。
在本申请中,术语“免疫偶联物”、“偶联物”、“抗体-药物偶联物”或“ADC”通常是指与蛋白质如细胞结合剂(例如,抗TNF-α抗体或其片段)连接并由以下通式定义的化合物或其衍生物:(SM-L-Q)n-A,其中SM=衍生自小分子糖皮质激素受体激动剂(例如,糖皮质激素)的基团,L=接头,Q=异双官能团、异三官能团或不存在,并且A=蛋白质(例如,抗体或其抗原结合片段、抗TNF蛋白、抗TNF-α抗体或其片段、可溶性受体或可溶性TNF受体),并且n=1-10。免疫偶联物也可以由相反顺序的以下通式定义:A-(Q-L-SM)n。
在本申请中,术语“接头”通常是指能够将蛋白质(例如,抗体、抗体片段(例如,抗原结合片段)或功能等效物)与糖皮质激素连接的任何化学部分。接头可能对切割敏感(“可切割接头”),从而促进糖皮质激素的释放。例如,在糖皮质激素和/或抗体保持活性的条件下, 此类可切割接头可能对酸诱导的切割、光诱导的切割、肽酶诱导的切割、酯酶诱导的切割和二硫键切割敏感。可替代地,接头可以基本上抗切割(“不可切割接头”)。
在本申请中,术语“药物抗体比”或“DAR”是指与A(即蛋白质,例如抗体或其抗原结合片段、抗TNF蛋白、抗TNF-α抗体或其片段、可溶性受体或可溶性TNF受体)连接的SM(即衍生自小分子糖皮质激素受体激动剂(例如,糖皮质激素)的基团)的数量。因此,在具有通式(SM-L-Q)n-A的免疫偶联物中,DAR由变量“n”限定。
当提及代表单独的免疫偶联物的具有式(SM-L-Q)n-A的化合物时,DAR通常是指与单独的A连接的SM的数量(例如,n是1至10的整数)。
当提及代表多种免疫偶联物的具有式(SM-L-Q)n-A的化合物时,DAR通常是指与A连接的SM的平均数量(例如,n是1至10的整数或分数)。因此,通过实例的方式,包含每个A含有3个SM的第一免疫偶联物和每个A含有4个SM的第二免疫偶联物的具有式(SM-L-Q)n-A的化合物的DAR(即,“n”)为3.5。
在本申请中,不可切割接头通常是能够以稳定的共价方式将糖皮质激素与抗体连接的任何化学部分,并且在上文针对可切割接头列出的类别下不会脱落。因此,不可切割接头基本上抗酸诱导的切割、光诱导的切割、肽酶诱导的切割、酯酶诱导的切割和二硫键切割。此外,不可切割是指在糖皮质激素和/或抗体不丧失其活性的条件下,接头中或与接头相邻的化学键承受由酸、光不稳定切割剂、肽酶、酯酶或者切割二硫键的化学或生理化合物诱导的切割的能力。
一些可切割接头被肽酶切割(“肽酶可切割接头”)。只有某些肽易于在细胞内部或外部切割,参见例如Trout等人,Proc.Natl.Acad.Sci.USA[美国国家科学院院刊],626-629(1982)和Umemoto等人Int.J.Cancer[国际癌症杂志],677-684(1989)。此外,肽由α-氨基酸单元和肽键组成,肽键在化学上是一个氨基酸的羧酸和第二个氨基酸的氨基之间的酰胺键。其他酰胺键(如赖氨酸的羧酸和α-氨基酸基团之间的键)应理解为不是肽键并且被认为是不可切割。
一些接头被酯酶切割(“酯酶可切割接头”)。只有某些酯可以被存在于细胞内部或外部的酯酶切割。酯通过羧酸和醇的缩合形成。简单酯是用简单醇(如脂族醇)和小环状醇和小芳香醇产生的酯。
在一些实施例中,可切割接头组分可以包含含有1至10个氨基酸残基的肽。在这些实施例中,肽允许蛋白酶切割接头,从而在暴露于细胞内蛋白酶(如溶酶体酶)时促进糖皮质激素的释放(Doronina等人(2003)Nat.Biotechnol.[自然生物技术]21:778-784)。示例性肽包括但 不限于二肽、三肽、四肽和五肽。示例性二肽包括但不限于丙氨酸-丙氨酸(ala-ala);缬氨酸-瓜氨酸(vc或val-cit);丙氨酸-苯丙氨酸(af或ala-phe);苯丙氨酸-赖氨酸(fk或phe-lys);苯丙氨酸-高赖氨酸(phe-homolys);和N-甲基-缬氨酸-瓜氨酸(Me-val-cit)。示例性三肽包括但不限于甘氨酸-缬氨酸-瓜氨酸(glv-val-cit)和甘氨酸-甘氨酸-甘氨酸(gly-gly-gly)。
肽可以包含天然存在的氨基酸残基和/或非天然氨基酸残基。术语“天然存在的氨基酸”通常是指Ala、Asp、Cys、Glu、Phe、Gly、His、He、Lys、Leu、Met、Asn、Pro、Gin、Arg、Ser、Thr、Val、Trp和Tyr。通过非限制性实例的方式,“非天然氨基酸”(即,天然不存在的氨基酸)包括高丝氨酸、高精氨酸、瓜氨酸、苯基甘氨酸、牛磺酸、碘酪氨酸、硒代半胱氨酸、正亮氨酸(“Nle”)、正缬氨酸(“Nva”)、β-丙氨酸、L-萘基丙氨酸或D-萘基丙氨酸、鸟氨酸(“Orn”)等。可以设计和优化肽以用于被特定酶(例如,肿瘤相关蛋白酶、组织蛋白酶B、C和D或纤溶酶蛋白酶)酶促切割。
氨基酸还可以包括D-形式的天然氨基酸和非天然氨基酸。“D-”表示具有“D”(右旋)构型的氨基酸,与天然存在的(“L-”)氨基酸中的构型相反。天然氨基酸和非天然氨基酸可以是可商购的(西格玛化工有限公司(Sigma Chemical Co.)、先进化学技术公司(AdvancedChemtech))或可以使用本领域已知的方法合成。
在本申请中,术语“药学上可接受的载体”通常是指给予治疗剂,例如抗体或多肽、基因和其它治疗剂的载体。该术语指本身不诱导对接受组合物的个体有害的抗体产生并且可以给予而不产生过度毒性的任何药物载体。合适的载体可以是大的、代谢缓慢的大分子,例如蛋白质、多糖、聚乳酸、聚乙醇酸、多聚氨基酸、氨基酸共聚物、脂质聚集物和灭活的病毒颗粒。本领域技术人员熟知这些载体。治疗组合物中药学上可接受的载体可包括液体,例如水、盐水、甘油和乙醇。这些载体中也可存在辅助物质,例如润湿剂或乳化剂、pH缓冲物质等。
在本申请中,术语“抗TNFα蛋白”通常是指能够(i)与TNFα结合并且(ii)抑制可溶性TNF-α与细胞表面TNF受体(p55和/或p75)结合和/或在补体存在下在体外裂解表达表面TNFα或TNFα受体的细胞的蛋白质。抗TNFα蛋白包括例如抗TNF抗体或其抗原结合片段(例如,阿达木单抗或英利昔单抗)以及可溶性TNF受体(例如,依那西普)。
在本申请中,术语“抗体”通常是指对指定蛋白质或肽或其片段有反应性的免疫球蛋白。抗体可以是来自任何类的抗体,包括但不限于IgG、IgA、IgM、IgD和IgE,及来自任何亚类(例如IgG1、IgG2、IgG3、和IgG4)的抗体。抗体可具有选自例如IgG1、IgG2、IgG3、或IgG4的重链恒定区。抗体还可具有选自例如kappa(κ)或lambda(λ)的轻链。本申请的抗体可衍生自任何物种。术语“抗体”可包括完整的多克隆抗体、完整的单克隆抗体、嵌 合抗体、人源化抗体、人抗体、包含抗体的融合蛋白和任何其他经修饰的免疫球蛋白分子,只要这些抗体展示出所需的生物活性即可。
在本申请中,术语“抗原结合片段”通常是指抗体分子的一部分,其包含负责抗体与抗原之间的特异性结合的氨基酸。抗原中由抗体特异性地识别和结合的部分是称作如上文所述的“表位”。如上文所述,抗原结合结构域可典型地包含抗体轻链可变区(VL)和抗体重链可变区(VH);然而,其并非必须包含两者。Fd片段例如具有两个VH区并且通常保留完整抗原结合结构域的一些抗原结合功能。抗体的抗原结合片段的实例包括(1)Fab片段,具有VL、VH、恒定轻链(CL)和CH1结构域的单价片段;(2)F(ab′)2片段,具有由铰链区的二硫桥连接的两个Fab片段的二价片段;(3)具有两个VH和CH1结构域的Fd片段;(4)具有抗体单臂的VL和VH结构域的Fv片段,(5)dAb片段(Ward等人,“Binding Activities of a Repertoire of Single Immunoglobulin Variable DomainsSecreted From Escherichia coli,”Nature 341:544-546(1989),其以引用的方式整体并入本申请),其具有VH结构域;(6)分离的互补决定区(CDR);(7)单链Fv(scFv),例如源于scFV-文库。尽管Fv片段的两个结构域VL和VH是由独立基因编码,但其可通过合成连接子使用重组方法接合,合成连接子使得其被制备为其中VL和VH区配对以形成单价分子的单一蛋白链(称为单链Fv(scFv))(可参见例如Huston等人,“Protein Engineering of AntibodyBinding Sites:Recovery of Specific Activity in an Anti-Digoxin Single-ChainFv Analogue Produced in Escherichia coli,”Proc.Natl.Acad.Sci.USA 85:5879-5883(1988));(8)“VHH”涉及来自骆驼科(骆驼、单峰骆驼、美洲驼、羊驼等)重链抗体的可变抗原结合结构域(参见Nguyen V.K.等人,2000,The EMBO Journal,19,921-930;Muyldermans S.,2001,J Biotechnol.,74,277-302以及综述Vanlandschoot P.等人,2011,Antiviral Research 92,389-407)。VHH也可称为纳米抗体(Nanobody)(Nb)。
在本申请中,术语“可变区”或“可变结构域”通常是指参与抗体与抗原的结合的抗体重链或轻链的结构域。在本申请中,术语“可变”通常是指,抗体的可变结构域的序列的某些部分变化强烈,形成各种特定抗体对其特定抗原的结合和特异性。变异性并非均匀地分布在抗体的整个可变区中。它集中在轻链可变区和重链可变区中的三个区段,被称为互补决定区(CDR)或高变区(HVR),分别为LCDR1、LCDR2、LCDR3、HCDR1、HCDR2和HCDR3。可变域中更高度保守的部分被称为框架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区(H-FR1,H-FR2,H-FR3,H-FR4,L-FR1,L-FR2,L-FR3,L-FR4),大部分采用β-折叠构型,通过三个CDR结构环区连接。每条链中的CDR通过FR区紧密靠近在一起,并与来自另一条链的CDR一起形成抗体的抗原结合位点。
在本领域中,可以通过多种方法来编码抗体的可变区或划分抗体的CDR,例如基于序列可变性的Kabat编号方案和定义规则(参见,Kabat等人,免疫学的蛋白质序列,第五版,美国国立卫生研究院,贝塞斯达,马里兰州(1991)),基于结构环区域位置的Chothia编号方案和定义规则(参见,A1-Lazikani等人,JMol Biol 273:927-48,1997),efranc等人的基于种系V基因的氨基酸序列比对的IMGT编号方案和定义规则,还有Honneger’s编号方案(AHo’s),Martin编号方案,Gelfand编号方案等,可参见Mathieu Dondelinger等人,Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition,Front.Immunol.,16 October 2018.
在本申请中,术语“百分比(%)序列同一性”通常是指两个或更多个经比对的氨基酸序列与组成这些氨基酸序列的总长度的氨基酸残基数相比而言一致的氨基酸的匹配(“命中”)数。换言之,使用比对,对于两个或更多个序列,当将这些序列针对最大对应(如使用本领域已知的序列比较算法测量的)进行比较和比对时,或者当手动比对和视觉检查时,可以确定相同的氨基酸残基的百分比(例如70%、75%、80%、85%、90%、95%、96%、97%、98%或99%序列同一性)。因此,进行比较以确定序列一致性的序列可以通过一个或多个氨基酸取代、添加或缺失来区分。用于比对蛋白序列的适合程序是本领域技术人员已知的。蛋白序列的百分比序列一致性可以例如用程序如CLUSTALW、Clustal Omega、FASTA或BLAST来确定,例如使用NCBI BLAST算法(AltschulSF等人(1997),Nucleic Acids Res.[核酸研究]25:3389-3402)。
在本申请中,术语“抗体类似物”通常以最广意义使用并且特别地涵盖以单特异性特异地结合靶分子并且结构上与天然抗体不同的分子。例如,在描述抗PD-1抗体或抗PD-L1抗体的上下文中,术语“抗体类似物”是指包含与氨基酸序列的部分具有大体上的同一性的区段并且具有至少一个下列性质的抗体:(1)在适当的结合条件下特异性结合PD-1或PD-L1,(2)抑制PD-1或PD-L1的至少一个生物活性的能力。通常,抗体类似物包含相对于天然序列的保守氨基酸置换(或插入或缺失)。类似物通常为至少20或25个氨基酸长,至少50、60、70、80、90、100、150或200个氨基酸长或更长,并且通常可与抗体的全长重链或轻链一样长。一些例子包括与种系氨基酸序列相比具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16或17个置换的抗体类似物。
在本申请中,术语“有效量”或“治疗有效量”通常是指足以实现下文说明的预期应用的本申请所述的化合物或药物组合物的量,所述预期应用包括但不限于疾病治疗。治疗有效量可根据以下变化:预期应用(体内或体外);或所治疗的对象及疾病状况,例如,对象的体重和年龄、疾病状况的严重程度;给药方式等,其可以由本领域普通技术人员容易地确定。术语 还适用于将在靶细胞中诱导特定应答的剂量,所述应答为例如血小板粘附和/或细胞迁移。具体剂量将根据例如以下变化:选择的具体化合物、遵循的给药方案、是否与其他药剂组合施用、施用时间、施用的组织,和运送其的实体递送系统。
在本申请中,术语“体内”通常是指发生在对象体内的事件。
在本申请中,术语“体外”通常是指在对象体外发生的事件。例如,体外分析包括任何在对象外部进行的分析。体外分析包括基于细胞的分析,其中采用活细胞或死细胞。体外分析还包括无细胞分析,其中不采用完整的细胞。
在本申请中,术语“治疗(treatment)”和“治疗(treating)”通常是指获得有益或希望的结果的方法,所述有益或希望的结果包括但不限于治疗益处。治疗益处包括但不限于根除、抑制、减少或改善所治疗的潜在障碍。另外,治疗益处是通过根除抑制、减少或改善与潜在的障碍相关的一种或多种生理症状实现的,从而在患者中观察到改善,但是患者仍然可能患有潜在障碍。
在本申请中,术语“预防(prevention)”和“预防(preventing)”通常是指获得有益或希望的结果的方法,所述有益或希望的结果包括但不限于预防益处。为了预防益处,可以向处于患上特定疾病的风险的患者或向报告具有疾病的一种或多种生理症状的患者施用药物组合物,即使尚未诊断出该疾病。
在本申请中,术语“受试者”或“患者”通常是指人类(即,任何年龄组的男性或女性,例如,小儿对象(例如,婴儿、儿童、青少年)或成人对象(例如,年轻人、中年人或老年人))和/或其他灵长类动物(例如,食蟹猴、恒河猴);哺乳动物,包括商业上相关的哺乳动物,如牛、猪、马、绵羊、山羊、猫和/或犬;和/或鸟类,包括商业上相关的鸟类,如鸡、鸭、鹅、鹌鹑和/或火鸡。
在本申请中,术语“约”或“大约”通常是指本领域普通技术人员测定的具体值的可接受的误差,其部分取决于测量或测定值的方式。在某些实施方式中,术语“约”或“大约”通常是指1、2、3或4个标准偏差。在某些实施方式中,术语“约”或“大约”通常是指在给定值或范围50%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.05%内。
在本申请中,术语“包含”和其变形形式,包括“含有”、“包括”等其它形式,通常是指包含其它组分、元素、数值、步骤等。
图1:本发明药物偶联物对R848诱导的人外周血单核细胞IFNα、TNFα、IL-6和IL-8 的抑制作用。1a:R848诱导PBMC中的IFNα释放;1b:R848诱导PBMC中的TNFα释放;1c:R848诱导PBMC中的IL6释放;1d:R848诱导PBMC中的IL8释放。
图2:异硫氰酸荧光素(FITC)诱导的迟发型IV型超敏反应小鼠模型中的生物活性测定。
图3:II型牛胶原混合佐剂诱导的DBA/1小鼠关节炎模型中的关节炎评分。3a:关节炎评分;3b:关节炎评分的AUC。
发明详述
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,
R
1、R
2、R
3、R
4和R
5各自独立地为任意基团;
B不存在或B为任意基团;
W不存在或W为任意基团;
A1为取代的苯环;
CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O)
2-、-C(=O)-、-C=C-和-C≡C-,其中R
4和R
5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;
X选自:-O-,-S-,-NR-;
Y
1为任意基团,m为0至4中的任意整数;
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂 芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,所述的式I的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐选自:
其中,
R
1、R
2、R
3、R
4和R
5各自独立地为任意基团;
B不存在或B为任意基团;
W不存在或W为任意基团;
A1为取代的苯环;
CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O)
2-、-C(=O)-、-C=C-和-C≡C-,其中R
4和R
5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代 的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;
X选自:-O-,-S-,-NR-;
Y
1为任意基团,m为0或1;
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在本发明某些优选实施方案中,所述的如式(I)、(Ia)、(Ib)、(Ic)所示的化合物或其药学上可接受的盐中的某些基团如下定义,未提及的基团同本申请任一方案所述(简称“在某些实施方式中”)。
在某些实施方式中,其中所述X为-O-、-S-或-NH-。
在某些实施方式中,其中所述CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-和-C(=O)-。
在某些实施方式中,其中所述R
4和R
5一起形成任选取代的环烷基或任选取代的杂环基。
在某些实施方式中,其中所述R
4和R
5各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中,当R
4和R
5包含亚甲基单元时,所述R
4和R
5的所述亚甲基单元各自独立地不被替代、或所述R
4和R
5的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,其中所述R
4和R
5各自独立地选自以下组:氢、氕、氘、氚、卤素、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的 芳基和任选取代的杂芳基;其中,当R
4和R
5包含亚甲基单元时,所述R
4和R
5的所述亚甲基单元各自独立地不被替代、或所述R
4和R
5的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R
4和R
5各自独立地选自:H、F、Cl、-OH、-NH
2、C
1-C
6烷基,或所述R
4和R
5一起形成C
3-C
6环烷基或3-6元杂环基;所述n选自1、2或3。
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述-(CR
4R
5)
n-各自独立地选自:-CH
2-、-CH
2CH
2-、
在某些实施方式中,其中所述Y
1不存在或选自:氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,其中所述Y
1不存在或选自:氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、任选取代的C
1-C
6烷基、任选取代的C
1-C
6烷氧基;其中各R独立选自氢、氕、氘、氚、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,其中所述Y
1不存在或选自:羟基、巯基、氨基和任选取代的C
1-C
6烷基。
在某些实施方式中,其中所述R
1、R
2和R
3各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中,当R
1、R
2和R
3包含亚甲基单元时,所述R
1、R
2和R
3的所述亚甲基单元各自独立地不被替代、或所述R
1、R
2和R
3的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,其中所述R
1,R
2各自独立的选自:H,F,Cl,Br和任选取代的C
1-C
6烷基。
例如,其中所述R
1,R
2可以各自独立的选自:H,F,Cl,Br和任选取代的甲基。
在某些实施方式中,其中所述R
3选自:氢、任选取代的-OH、任选取代的-SH和任选取代的C
1-C
6烷基。
在某些实施方式中,当所述R
3为任选取代的甲基时,所述R
3被R
31取代,所述R
31选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
31包含亚甲基单元时,所述R
31的所述亚甲基单元各自独立地不被替代、或所述R
31的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
31选自以下组:氢、卤素、任选取代的-OH、和任选取代的-SH。
在某些实施方式中,当所述R
31为任选取代的-OH时,所述R
31被R
311取代,所述R
311选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
311包含亚甲基单元时,所述R
311的所述亚甲基单元各自独立地不被替代、或所述R
311的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
311选自以下组:氢、任选取代的-P(=O)H
2、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的C
1-C
6烷基和任选取代的C
2-C
9亚杂环基;其中,当R
311包含亚甲基单元时,所述R
311的所述亚甲基单元各自独立地不被替代、或所述R
311的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的- PH-、任选取代的-P(=O)H
2-和任选取代的-NH-;其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-N
+(R)
3、-PHR、-P(R)
2、-P(=O)R
2、-OP(=O)R
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,所述R
311选自以下组:氢、任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
在某些实施方式中,当所述R
3为任选取代的-OH时,所述R
3被R
32取代,所述R
32选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
32包含亚甲基单元时,所述R
32的所述亚甲基单元各自独立地不被替代、或所述R
32的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
32选自以下组:氢、和任选取代的C
1-C
6烷基。
在某些实施方式中,当所述R
32为任选取代的甲基或任选取代的乙基时,所述R
32被R
321取代,所述R
321选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
321包含亚甲基单元时,所述R
321的所述亚甲基单元各自独立地不被替代、或所述R
321的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
321选自以下组:氢、卤素、-CN、和任选取代的C
1-C
6烷基。
在某些实施方式中,所述R
321选自以下组:氢、F、Cl、-CN、和任选取代的甲基。
在某些实施方式中,当所述R
3为任选取代的-SH时,所述R
3被R
33取代,所述R
33选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
33包含亚甲基单元时,所述R
33的所述亚甲基单元各自独立地不被替代、或所述R
33的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
33选自以下组:氢和任选取代的C
1-C
6烷基。
在某些实施方式中,所述R
33为任选取代的甲基。
在某些实施方式中,当所述R
33为任选取代的甲基时,所述R
33被R
331取代,所述R
331选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
331包含亚甲基单元时,所述R
331的所述亚甲基单元各自独立地不被替代、或所述R
331的所述亚 甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
331选自以下组:氢、氯、氟和-CN。
例如,其中所述R
3可以选自:任选取代的-CH
2Cl、任选取代的-CH
2SH、任选取代的-CH
2OH、任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的-OH、任选取代的-OCH
3、任选取代的-OCH
2F、任选取代的-OCH
2Cl、任选取代的-OCH
2CN、任选取代的-OCH
2CH
3、任选取代的巯基、任选取代的-SCH
2F、任选取代的-SCH
2Cl、任选取代的-SCH
2CF
3、和任选取代的-SCH
2CN。
在某些实施方式中,本发明所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R
1和R
2各自独立地选自氢、氟、氯和甲基,所述R
3选自:-CH
2Cl、-CH
2SH、-CH
2OH、
-OCH
3、-OCH
2F、-OCH
2Cl、-OCH
2CN、-OCH
2CH
3、-SH、-SCH
2F、-SCH
2Cl、-SCH
2CF
3、和-SCH
2CN。
在某些实施方式中,其中所述B不存在或B选自:任选取代的C
1-C
6烷基、任选取代的C
3-C
8环烷基,任选取代的C
3-C
8杂环基、任选取代的C
6-C
10芳基、任选取代的C
5-C
10杂芳基,其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,当所述X
1为任选取代的CH时,所述X
1被R
6取代,所述R
6选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
6包含亚甲基单元时,所述R
6的所述亚甲基单元各自独立地不被替代、或所述R
6的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代 的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
6选自以下组:氢和任选取代的-OH。
在某些实施方式中,当所述R
6为任选取代的-OH时,所述R
6被R
61取代,所述R
61选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
61包含亚甲基单元时,所述R
61的所述亚甲基单元各自独立地不被替代、或所述R
61的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
61选自以下组:H和任选取代的C
1-C
6烷基。
在某些实施方式中,所述X
1选自以下组:CH、C(-O-CH
3)、和N。
在某些实施方式中,其中所述B选自:
任选取代的
任选取代的
任选取代的
任选取代的任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
X
2和X
3各自独立地选自以下组:O,S和任选取代的NH。
在某些实施方式中,当所述X
2或X
3为任选取代的NH时,所述X
2或X
3被R
7取代,所述R
7选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔 基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
7包含亚甲基单元时,所述R
7的所述亚甲基单元各自独立地不被替代、或所述R
7的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
7选自以下组:氢和任选取代的C
1-C
6烷基;其中,当R
7包含亚甲基单元时,所述R
7的所述亚甲基单元各自独立地不被替代、或所述R
7的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,当所述R
7为任选取代的C
1-C
6烷基时,所述R
7被R
71取代,所述R
71选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
71包含亚甲基单元时,所述R
71的所述亚甲基单元各自独立地不被替代、或所述R
71的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
71选自以下组:H和任选取代的C
1-C
6烷基。
在某些实施方式中,所述X
2或X
3选自以下组:NH、N(CH
3)、O和S。
例如,其中所述B可以选自:
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选 取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,其中所述W不存在或W选自:-S(=O)-、-S(=O)
2-、-O-、-S-、任选取代的-NHC(=O)-、任选取代的-C(=O)NH-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基;其中,当W包含亚甲基单元时,所述W的所述亚甲基单元各自独立地不被替代、或所述W的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的 亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,当所述W为任选取代的C
1-C
6亚烷基时,所述W被R
8取代,所述R
8选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
8包含亚甲基单元时,所述R
8的所述亚甲基单元各自独立地不被替代、或所述R
8的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
8选自以下组:氢、=O、任选取代的C
1-C
6烷基和任选取代的环烷基。
在某些实施方式中,所述R
8为任选取代的甲基。
在某些实施方式中,当所述R
8为任选取代的甲基时,所述R
8被R
81取代,所述R
81选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基。
在某些实施方式中,所述R
81选自以下组:卤素和任选取代的环烷基。
在某些实施方式中,所述R
81选自以下组:F和任选取代的环丙基。
在某些实施方式中,其中所述W不存在或W选自:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-CH
2NHC(=O)-、任选取代的-NHC(=O)CH
2-、任选取代的-C(=O)NH-、任选取代的-NH-、任选取代的-CH=CH-、-C≡C-、任选取代的C
1-C
6亚烷基、任选取代的-OCH
2-、任选取代的-CH
2O-、任选取代的-SCH
2-、任选取代的-CH
2S-、任选取代的-NHC(=O)-、任选取代的-C(=O)CH
2-、任选取代的-CH
2NH-、任选取代的-NHCH
2-、任选取代的
任选 取代的
任选取代的
任选取代的
和任选取代的
例如,所述W可以不存在或W选自:
所述A1可以选自:
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其选自
其中,
所述X选自-O-,-S-和-NH-;
R
4和R
5各自独立地选自以下组:H、F、Cl、-OH、-NH
2和C
1-C
6烷基;
所述n选自1、2或3;
所述Y
1不存在或选自:羟基、巯基、氨基和C
1-C
6烷基;
所述R
1和R
2各自独立地选自氢、氟、氯和甲基;
所述R
3选自:-CH
2Cl、-CH
2SH、-CH
2OH、
-OCH
3、-OCH
2F、-OCH
2Cl、-OCH
2CN、-OCH
2CH
3、-SH、-SCH
2F、-SCH
2Cl、-SCH
2CF
3和-SCH
2CN。
例如,其中所述式I的化合物可以选自以下结构:
另一方面,本发明提供了下式所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述化合物选自:
另一方面,本申请提供一种式IIa或IIb的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,
R
1、R
2、R
3、R
4和R
5各自独立地为任意基团;
B不存在或B为任意基团;
W不存在或W为任意基团;
A2为取代的苯环;
CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O)
2-、-C(=O)-、-C=C-和-C≡C-,其中R
4和R
5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;
X选自:-O-,-S-,-NR-;
Y
1为任意基团,m为0至4中的任意整数;
Y
2选自-O-,-S-和-NR-;
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基; 其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在本发明某些优选实施方案中,所述的如式(IIa)、(IIb)所示的化合物或其药学上可接受的盐中的某些基团如下定义,未提及的基团同本申请任一方案所述(简称“在某些实施方式中”)。
在某些实施方式中,其中所述CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-和-C(=O)-。
在某些实施方式中,其中所述R
4和R
5一起形成任选取代的环烷基或任选取代的杂环基。例如,所述R
4和R
5可以一起形成环丙基或环丁基。
在某些实施方式中,其中所述R
4和R
5各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中,当R
4和R
5包含亚甲基单元时,所述R
4和R
5的所述亚甲基单元各自独立地不被替代、或所述R
4和R
5的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,其中所述R
4和R
5各自独立地选自以下组:氢、氕、氘、氚、卤素、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中,当R
4和R
5包含亚甲基单元时,所述R
4和R
5的所述亚甲基单元各自独立地不被替代、或所述R
4和R
5的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、 非对映异构体、或其混合物形式,或其可药用的盐,其中所述R
4和R
5各自独立地选自以下组:H、F、Cl、-OH、-NH
2和C
1-C
6烷基;所述n选自1、2或3。
在某些实施方式中,其中所述Y
1选自:氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,其中所述Y
1选自:氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、任选取代的C
1-C
6烷基、任选取代的C
1-C
6烷氧基;其中各R独立选自氢、氕、氘、氚、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,所述Y
1不存在或选自:-OR、-SR、-N(R)
2和任选取代的C
1-C
6烷基;其中各R独立选自氢、氕、氘、氚、C
1-C
6烷基、C
1-C
6烷氧基。
在某些实施方式中,所述Y
1不存在或选自:羟基、巯基、氨基和C
1-C
6烷基。
在某些实施方式中,所述Y
2包括-NR-;其中各R独立选自氢、氕、氘、氚、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,其中所述R
1、R
2和R
3各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中,当R
1、R
2和R
3包含亚甲基单元时,所述R
1、R
2和R
3的所述亚甲基单元各自独立地不被替代、或所述R
1、R
2和R
3的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,其中所述R
1,R
2各自独立的选自:H,F,Cl,Br和任选取代的C
1-C
6烷基。
在某些实施方式中,其中所述R
1,R
2各自独立的选自:H,F,Cl,Br和任选取代的甲基。
在某些实施方式中,其中所述R
3选自:氢、任选取代的-OH、任选取代的-SH、和任选取代的C
1-C
6烷基。
在某些实施方式中,当所述R
3为任选取代的甲基时,所述R
3被R
31取代,所述R
31选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
31包含亚甲基单元时,所述R
31的所述亚甲基单元各自独立地不被替代、或所述R
31的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
31选自以下组:氢、卤素、任选取代的-OH、和任选取代的-SH。
在某些实施方式中,当所述R
31为任选取代的-OH时,所述R
31被R
311取代,所述R
311选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
311包含亚甲基单元时,所述R
311的所述亚甲基单元各自独立地不被替代、或所述R
311的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
311选自以下组:氢、任选取代的-P(=O)H
2、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的C
1-C
6烷基和任选取代的C
2-C
9亚杂环基;其中,当R
311包 含亚甲基单元时,所述R
311的所述亚甲基单元各自独立地不被替代、或所述R
311的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H
2-和任选取代的-NH-;其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-N
+(R)
3、-PHR、-P(R)
2、-P(=O)R
2、-OP(=O)R
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,所述R
311选自以下组:氢、任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
在某些实施方式中,当所述R
3为任选取代的-OH时,所述R
3被R
32取代,所述R
32选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
32包含亚甲基单元时,所述R
32的所述亚甲基单元各自独立地不被替代、或所述R
32的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代 的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
32选自以下组:氢、和任选取代的C
1-C
6烷基。
在某些实施方式中,当所述R
32为任选取代的甲基或任选取代的乙基时,所述R
32被R
321取代,所述R
321选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
321包含亚甲基单元时,所述R
321的所述亚甲基单元各自独立地不被替代、或所述R
321的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
321选自以下组:氢、卤素、-CN、和任选取代的C
1-C
6烷基。
在某些实施方式中,所述R
321选自以下组:氢、F、Cl、-CN、和任选取代的甲基。
在某些实施方式中,当所述R
3为任选取代的-SH时,所述R
3被R
33取代,所述R
33选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
33包含亚甲基单元时,所述R
33的所述亚甲基单元各自独立地不被替代、或所述R
33的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
33选自以下组:氢、和任选取代的C
1-C
6烷基。
在某些实施方式中,当所述R
33为任选取代的甲基或任选取代的乙基时,所述R
33被R
331取代,所述R
331选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、 任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
331包含亚甲基单元时,所述R
331的所述亚甲基单元各自独立地不被替代、或所述R
331的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R331选自以下组:氢、氯、氟和-CN。
例如,其中所述R
3可以选自:任选取代的-CH
2Cl、任选取代的-CH
2SH、任选取代的-CH
2OH、任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的-OH、任选取代的-OCH
3、任选取代的-OCH
2F、任选取代的-OCH
2Cl、任选取代的-OCH
2CN、任选取代的-OCH
2CH
3、任选取代的巯基、任选取代的-SCH
2F、任选取代的-SCH
2Cl、任选取代的-SCH
2CF
3、和任选取代的-SCH
2CN。
在某些实施方式中,本发明所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R
3选自:-CH
2Cl、-CH
2SH、-CH
2OH、
-OCH
3、-OCH
2F、-OCH
2Cl、-OCH
2CN、-OCH
2CH
3、-SH、-SCH
2F、-SCH
2Cl、-SCH
2CF
3和-SCH
2CN。
在某些实施方式中,其中所述B不存在或B选自:任选取代的C
1-C
6烷基、任选取代的C
3-C
8环烷基,任选取代的C
3-C
8杂环基、任选取代的C
6-C
10芳基、任选取代的C
5-C
10杂芳基,其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,当所述X
1为任选取代的CH时,所述X
1被R
6取代,所述R
6选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
6包含亚甲基单元时,所述R
6的所述亚甲基单元各自独立地不被替代、或所述R
6的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
6选自以下组:氢和任选取代的-OH。
在某些实施方式中,当所述R
6为任选取代的-OH时,所述R
6被R
61取代,所述R
61选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
61包含亚甲基单元时,所述R
61的所述亚甲基单元各自独立地不被替代、或所述R
61的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
61选自以下组:H和任选取代的C
1-C
6烷基。
在某些实施方式中,所述X
1选自以下组:CH、C(-O-CH
3)和N。
在某些实施方式中,其中所述B可以选自:任选取代的
任选取代的
任选取代的
任选取代的任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
X
2和X
3各自独立地选自以下组:O,S和任选取代的NH。
在某些实施方式中,当所述X
2或X
3为任选取代的NH时,所述X
2或X
3被R
7取代,所述R
7选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
7包含亚甲基单元时,所述R
7的所述亚甲基单元各自独立地不被替代、或所述R
7的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代 的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
7选自以下组:氢和任选取代的C
1-C
6烷基。
在某些实施方式中,当所述R
7为任选取代的C
1-C
6烷基时,所述R
7被R
71取代,所述R
71选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
71包含亚甲基单元时,所述R
71的所述亚甲基单元各自独立地不被替代、或所述R
71的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
71选自以下组:H和任选取代的C
1-C
6烷基。
在某些实施方式中,所述X
2或X
3选自以下组:NH、N(CH
3)、O和S。
在某些实施方式中,其中所述B选自:
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在某些实施方式中,其中所述W不存在或W选自:-S(=O)-、-S(=O)
2-、-O-、-S-、-NHC(=O)-、-C(=O)NH-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基;其中,当W包含亚甲基单元时,所述W的所述亚甲基单元各自独立地不被替代、或所述W的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,当所述W为任选取代的C
1-C
6亚烷基时,所述W被R
8取代,所述R
8选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环基、任选取代的芳基和任选取代的杂芳基;其中,当R
8包含亚甲基单元时,所述R
8的所述亚甲基单元各自独立地不被替代、或所述R
8的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的- PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环基、任选取代的亚芳基和任选取代的亚杂芳基。
在某些实施方式中,所述R
8选自以下组:氢、=O、任选取代的C
1-C
6烷基和任选取代的环烷基。
在某些实施方式中,所述R
8为任选取代的甲基。
在某些实施方式中,当所述R
8为任选取代的甲基时,所述R
8被R
81取代,所述R
81选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、任选取代的-S(=O)H、任选取代的-S(=O)
2H、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-PH
2、任选取代的-P(=O)H
2、任选取代的-NH
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基。
在某些实施方式中,所述R
81选自以下组:卤素和任选取代的环烷基。
在某些实施方式中,所述R
81选自以下组:F和任选取代的环丙基。
在某些实施方式中,其中所述W不存在或W选自:-S(=O)-、-S(=O)
2-、-O-、-S-、-C(=O)-、任选取代的-CH
2NHC(=O)-、任选取代的-NHC(=O)CH
2-、任选取代的-C(=O)NH-、任选取代的-NH-、任选取代的-CH=CH-、-C≡C-、任选取代的C
1-C
6亚烷基、任选取代的-OCH
2-、任选取代的-CH
2O-、任选取代的-SCH
2-、任选取代的-CH
2S-、任选取代的-NHC(=O)-、任选取代的-COCH
2-、任选取代的-CH
2NH-、任选取代的-NHCH
2-、任选取代的-CH(CH
3)-、任选取代的
任选取代的
任选取代的
任选取代的
和任选取代的
例如,其中所述W可以不存在或W选自:
所述A2可以选自:
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其选自
其中,
所述X选自-O-,-S-和-NH-;
R
4和R
5各自独立地选自以下组:H、F、Cl、-OH、-NH
2和C
1-C
6烷基;
所述n选自1、2或3;
所述Y
1不存在或选自:羟基、巯基、氨基和C
1-C
6烷基;
所述R
1和R
2各自独立地选自氢、氟、氯和甲基;
所述R
3选自:-CH
2Cl、-CH
2SH、-CH
2OH、
-OCH
3、-OCH
2F、-OCH
2Cl、-OCH
2CN、-OCH
2CH
3、-SH、-SCH
2F、-SCH
2Cl、-SCH
2CF
3和-SCH
2CN。
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述化合物选自:
在某些实施方式中,所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋 体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,还包括Trigger片段(Tr),所述化合物包括如下结构:
其中所述Tr选自以下结构:
R
1、R
2、R
3、R
4和R
5各自独立地为任意基团;
B不存在或B为任意基团;
W不存在或W为任意基团;
CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O)
2-、-C(=O)-、-C=C-和-C≡C-,其中R
4和R
5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;
X选自:-O-,-S-,-NR-;
Y
1为任意基团,m为0至4中的任意整数;
Y
2选自-O-,-S-和-NR-;
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基;其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
例如,其中所述R
1,R
2可以各自独立的选自:H,F,Cl,Br和任选取代的甲基。
例如,其中所述R
3可以选自:任选取代的-CH
2Cl、任选取代的-CH
2SH、任选取代的-CH
2OH、任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的-OH、任选取代的-OCH
3、任选取代的-OCH
2F、任选取代的-OCH
2Cl、任选取代的-OCH
2CN、任选取代的-OCH
2CH
3、任选取代的巯基、任选取代的-SCH
2F、任选取代的-SCH
2Cl、任选取代的-SCH
2CF
3、和任选取代的-SCH
2CN。
例如,其中所述B可以选自:
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基和卤素取代的C
1-C
6烷氧基。
例如,所述W可以不存在或W选自:
在某些实施方式中,所述Linker片段包括L
1片段、L
2片段和/或L
3片段,所述化合物具有以下结构:
其中,
Tr不存在或Tr为任意基团;
L
3选自多肽片段;
L
2不存在或选自连接片段;
L
1选自偶联单元;
R
1、R
2、R
3、R
4和R
5各自独立地为任意基团;
B不存在或B为任意基团;
W不存在或W为任意基团;
CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O)
2-、-C(=O)-、-C=C-和-C≡C-,其中R
4和R
5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;
X选自:-O-,-S-,-NR-;
Y
1为任意基团,m为0至4中的任意整数;
Y
2选自-O-,-S-和-NR-;
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基;其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
在本发明某些优选实施方案中,所述的如式(Ⅳa)、(Ⅳb)所示的化合物或其药学上可接受的盐中的某些基团如下定义,未提及的基团同本申请任一方案所述(简称“在某些实施方式中”)。
在某些实施方式中,其中所述L3选自二肽、三肽和四肽。
在某些实施方式中,其中所述二肽选自:GA、GG、AG、EG、EA、GE、DG、DA、GD、VC、VA、AA和VK。
在某些实施方式中,其中所述三肽选自:EAG、EGG、GEG、GEA、DAG、DGG、GDG、GDA、GGA、GAG、GFG、AAG、AAA、VAG、VCG、VKG。
在某些实施方式中,其中所述四肽选自:GGFG、GGAG、GGGG、GEGG、GEAG、GDGG、GDAG、AAAG和EAGG。
在某些实施方式中,其中所述L3选自以下组:甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)、丙氨酸-丙氨酸-丙氨酸-甘氨酸(AAAG)、甘氨酸-甘氨酸-甘氨酸-甘氨酸(GGGG)、缬氨酸-丙氨酸-甘氨酸(VAG)、缬氨酸-瓜氨酸-甘氨酸(VCG)、丙氨酸-丙氨酸-甘氨酸(AAG)、丙氨酸-丙氨酸-丙氨酸(AAA)、缬氨酸-丙氨酸(VA)、缬氨酸-瓜氨酸(VC)、丙氨酸-丙氨酸(AA)、谷氨酸-丙氨酸-甘氨酸-甘氨酸(EAGG)、甘氨酸-谷氨酸-丙氨酸-甘氨酸(GEAG)、甘氨酸-谷氨酸-甘氨酸-甘氨酸(GEGG)、谷氨酸-甘氨酸-甘氨酸(EGG)、谷氨酸-丙氨酸-甘氨酸(EAG)、缬氨酸-赖氨酸-甘氨酸(VKG)、甘氨酸-谷氨酸-甘氨酸(GEG)、谷氨酸-丙氨酸(EA)、谷氨酸-甘氨酸(EG)和甘氨酸-谷氨酸(GE)。
在某些实施方式中,其中所述L
2不存在。
在某些实施方式中,其中所述L
2包含或不包含PEG支链或PEG直链。
在某些实施方式中,当所述L
2不包含PEG时,所述L
2选自:
在某些实施方式中,当所述L
2包含PEG直链时,所述L
2选自:
其中p为1至20中的任意整数。
在某些实施方式中,当所述L
2包含PEG直链时,所述L
2选自:
在某些实施方式中,当所述L
2包含PEG支链时,所述L
2选自:
在某些实施方式中,当所述L
2包含PEG支链时,所述L
2选自:
在某些实施方式中,当L
1通过与配体的巯基偶联时,所述L
1选自:
其中,所述R
L1a、R
L1b、R
L1c各自独立的选自:氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基。
在某些实施方式中,所述R
L1a、R
L1b、R
L1c各自独立的选自:氢、任选取代的甲基、任选取代的乙基、任选取代的芳基和任选取代的苄基。
在某些实施方式中,当L
1通过氨基与配体偶联时,所述L
1选自:
在某些实施方式中,当L
1通过点击化学偶联时,所述L
1选自:
例如,其中所述的式IVa或IVb的化合物可以选自以下结构:
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述的式IVa或IVb的化合物选自以下结构:
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述的化合物还包括Linker片段,所述的式IIa或IIb的化合物能够通过Linker片段与配体偶联,所述化合物具有以下结构:
其中,
Tr不存在或Tr为任意基团;
L
3选自多肽片段;
L
2不存在或选自连接片段;
L
1选自偶联单元;通式IVa-1和IVb-1中L
1为连接形式;
R
1、R
2、R
3、R
4、R
5、B、W、CR
4R
5、n、X、Y
1和Y
2分别如本发明任一项所述;
在某些实施方式中,本发明化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述的结构单元-Tr-L
3-L
2-L
1-选自:
另一方面,本申请提供一种偶联物,包含前述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐。
在某些实施方式中,其包含配体-药物偶联物。例如,所述偶联物可以包括抗体-药物偶联物。
在某些实施方式中,其中所述配体包括抗体或其抗原结合片段。
在某些实施方式中,其中所述抗体选自:人抗体、人源化抗体、嵌合抗体、多特异性抗体、单克隆抗体和多克隆抗体。
在某些实施方式中,其中所述抗原结合片段选自:Fab、Fab’、F(ab’)2、Fv、scFv、双抗体、Fd、dAb、VHH、大抗体和互补决定区(CDR)片段。
在某些实施方式中,其中所述配体特异性结合选自下组的抗原:AXL,BAFFR,BCMA,BCR–列表组分(BCR–list components),BDCA2,BDCA4,BTLA,BTNL2BTNL3,BTNL8,BTNL9,C10orf54,CCR1,CCR3,CCR4,CCR5,CCR6,CCR7,CCR9,CCR10,CD11c,CD137,CD138,CD14,CD163,CD168,CD 177,CD19,CD20,CD209,CD209L,CD22,CD226,CD248,CD25,CD27,CD274,CD276,CD28,CD30,CD300A,CD33,CD37,CD38,CD4,分化抗原簇40(CD40),CD44,CD45,CD46,CD47,CD48,CD5,CD52,CD55,CD56,CD59,CD62E,CD68,CD69,CD70,CD74,CD79a,CD79b,CD8,CD80,CD86,CD90.2,CD96,CLEC12A,CLEC12B,CLEC7A,CLEC9A,CR1,CR3,CRTAM,CSF1R,CTLA4,CXCR1/2,CXCR4,CXCR5,DDR1,DDR2,DEC-205,DLL4,DR6,FAP,FCamR,FCMR,FcR’s,Fire,GITR,HHLA2,II型HLA(HLA class II),HVEM,ICOSLG,IFNAR,I型干扰素受体亚基(IFNAR1),IFNLR1,IL10R1,IL10R2,IL12R,IL13RA1,IL13RA2,IL15R,IL17RA,IL17RB,IL17RC,IL17RE,IL20R1,IL20R2,IL21R,IL22R1,IL22RA,IL23R,IL27R,IL29R,IL2Rg,IL31R,IL36R,IL3RA,IL4R,IL6R,IL5R,IL7R,IL9R,整合素(Integrins),LAG3,LIFR,MAG/Siglec-4(唾液酸结合性免疫球蛋白样凝集素-4),MMR,MSR1,NCR3LG1,NKG2D,NKp30,NKp46,OX40(CD134),PDCD1,PROKR1,PVR,PVRIG,PVRL2,PVRL3,RELT,SIGIRR,Siglec-1(唾液酸结合性免疫球蛋白样凝集素-1), Siglec-10,Siglec-5,Siglec-6,Siglec-7,Siglec-8,Siglec-9,SIRPA,SLAMF7,TACI,TCR–列表组分/assoc(TCR-listcomponents/assoc),PTCRA,TCRb,CD3z,CD3,TEK,TGFBR1,TGFBR2,TGFBR3,TIGIT,TLR2,TLR4,肿瘤坏死因子α(TNFα),TROY,TSLPR,TYRO,VLDLR,VSIG4,IL2R-y和VTCN1。
在某些实施方式中,其中所述配体特异性结合:TNFα,CD40,和/或IFNAR1。
在某些实施方式中,其中所述配体选自:抗TNFα抗体或其抗原结合片段,抗CD40抗体或其抗原结合片段,和抗IFNAR1抗体或其抗原结合片段。在某些实施方式中,其中所述配体选自:抗TNFα抗体或其抗原结合片段,抗CD40抗体或其抗原结合片段,抗BDCA2抗体或其抗原结合片段和抗IFNAR1抗体或其抗原结合片段。
例如,其中所述配体可以选自:抗TNFα单克隆抗体,抗CD40单克隆抗体,和抗IFNAR1单克隆抗体。
本披露还提供了含有与抗TNFα蛋白连接的糖皮质激素受体激动剂的免疫偶联物。在某些实施例中,抗TNFα蛋白是抗体或其抗原结合片段。在某些实施例中,抗TNFα蛋白是结合TNFα(例如,可溶性TNFα和/或膜结合TNFα)的抗体或其抗原结合片段。在某些实施例中,抗TNFα蛋白是可溶性TNF受体蛋白,例如与重链恒定结构域或其片段(如Fc)融合的可溶性TNF受体蛋白。在一些实施例中,抗TNFα蛋白(例如,抗TNF抗体、其抗原结合片段或可溶性TNF受体)可以与细胞表面上的TNFα结合并变得内化。例如,US2014/0294813(将其通过引用以其整体并入本文)披露了在与细胞表面人TNF结合后展示出内化的抗TNF蛋白。在某些实施例中,抗体或其抗原结合片段与人和/或小鼠TNF-α结合。结合TNF-α的抗体和抗原结合片段是本领域已知的。
抗TNF-α抗体及其抗原结合片段包括例如阿达木单抗、英利昔单抗、赛妥珠单抗(certolizumab pegol)、阿非莫单抗、奈瑞莫单抗(nerelimomab)、奥左拉珠单抗(ozoralizumab)、普拉库鲁单抗(placulumab)、戈利木单抗(golimumab)和抗鼠TNFαmIgG2a。另外的抗TNF-α抗体和抗原结合片段提供在例如WO 2013/087912、WO 2014/152247和WO 2015/073884中,将其各自通过引用以其整体并入本文。
阿达木单抗描述于美国专利号6,258,562中,将其通过引用以其整体并入本文。英利昔单抗描述于美国专利号5,656,272中,将其通过引用以其整体并入本文。赛妥珠单抗在WO01/94585中进行了讨论,将其通过引用以其整体并入本文。阿非莫单抗(也称为MAK195)在Vincent,Int.J.Clin.Pract.[国际临床实践杂志]54:190-193(2000)中进行了讨论,将其通过引用以其整体并入本文。奥左拉珠单抗(也称为ATN-103)是纳米抗体。它含有由GlySer接头融合 的三个重链可变区。可变区1和3是相同的,并且奥左拉珠单抗不含重链。奥左拉珠单抗在WO 2012/131053中进行了讨论,将其通过引用以其整体并入本文。普拉库鲁单抗(也称为CEP-37247)是由VL-pCH1-CH2-CH3或[V-κ]2-Fc的二聚体组成的结构域抗体,并且在Gay等人,Mabs 2:625-638(2010)中进行了讨论,将其通过引用以其整体并入本文。戈利木单抗(也称为CNTO 148)在WO2013/087912中进行了讨论,并且序列提供在GenBank:DI496971.1和GenBank DI 496970.1中,将其各自通过引用以其整体并入本文。抗鼠TNFαmIgG2a,记载于文献:McRae BL et al.J Crohns Colitis 10(1):69-76(2016),将其各自通过引用以其整体并入本文。
抗TNF-α抗体及其抗原结合片段还包括竞争性抑制阿达木单抗、英利昔单抗、赛妥珠单抗、阿非莫单抗、奈瑞莫单抗、奥左拉珠单抗、普拉库鲁单抗或戈利木单抗与TNF-α的结合的抗体及其抗原结合片段。抗TNF-α抗体及其抗原结合片段还包括与阿达木单抗、英利昔单抗、赛妥珠单抗、阿非莫单抗、奈瑞莫单抗、奥左拉珠单抗、普拉库鲁单抗或戈利木单抗结合相同TNF-α表位的抗体和抗原结合片段。
在某些实施例中,抗TNF-α抗体或其抗原结合片段竞争性抑制阿达木单抗与TNF-α的结合。在某些实施例中,抗TNF-α抗体或其抗原结合片段与阿达木单抗结合相同的TNF-α表位。在某些实施例中,抗TNF-α抗体或其抗原结合片段是阿达木单抗或其抗原结合片段。在某些实施例中,抗TNF-α抗体或其抗原结合片段是阿达木单抗。
在某些实施例中,抗TNF-α抗体或其抗原结合片段包含阿达木单抗、英利昔单抗、赛妥珠单抗、阿非莫单抗、奈瑞莫单抗、奥左拉珠单抗、普拉库鲁单抗或戈利木单抗的序列,例如互补决定区(CDR)、可变重链结构域(VH)和/或可变轻链结构域(VL)。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链可变区(VH),其中所述重链可变区包含HCDR1,HCDR2,HCDR3,它们各自分别与以下分子的HCDR1,HCDR2,HCDR3具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab)或戈利木单抗(golimumab)。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区分别与以下分子的重链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab)或戈利木单抗(golimumab)。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链,其中所 述重链分别与以下分子的重链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab)或戈利木单抗(golimumab)。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的轻链可变区(VL),其中所述轻链可变区包含LCDR1,LCDR2,LCDR3,它们各自分别与以下分子的LCDR1,LCDR2,LCDR3具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab)或戈利木单抗(golimumab)。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的轻链可变区,其中所述轻链可变区分别与以下分子的轻链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab)或戈利木单抗(golimumab)。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的轻链,其中所述轻链分别与以下分子的轻链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab)或戈利木单抗(golimumab)。
在某些实施方式中,本申请提供了抗体或其抗原结合片段,其可以特异性结合TNF-α并且包含阿达木单抗、英利昔单抗、赛妥珠单抗、阿非莫单抗、奈瑞莫单抗、奥左拉珠单抗、普拉库鲁单抗或戈利木单抗的VL的Chothia VL CDR。在某些方面,本文提供了抗体或其抗原结合片段,其特异性结合TNF-α并且包含阿达木单抗、英利昔单抗、赛妥珠单抗、阿非莫单抗、奈瑞莫单抗、奥左拉珠单抗、普拉库鲁单抗或戈利木单抗的VH的Chothia VH CDR。在某些方面,本文提供了抗体或其抗原结合片段,其特异性结合TNF-α并且包含阿达木单抗、英利昔单抗、赛妥珠单抗、阿非莫单抗、奈瑞莫单抗、奥左拉珠单抗、普拉库鲁单抗或戈利木单抗的VL的Chothia VL CDR并且包含阿达木单抗、英利昔单抗、赛妥珠单抗、阿非莫单抗、奈瑞莫单抗、奥左拉珠单抗、普拉库鲁单抗或戈利木单抗的VH的Chothia VH CDR。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链可变区(VH),其中所述重链可变区包含HCDR1,HCDR2,HCDR3,它们各自分别与以下分子的HCDR1,HCDR2,HCDR3具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区分别与以下分子的重链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链,其中所述重链分别与以下分子的重链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的轻链可变区(VL),其中所述轻链可变区包含LCDR1,LCDR2,LCDR3,它们各自分别与以下分子的LCDR1,LCDR2,LCDR3具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
例如,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链可变区(VH)和轻链可变区(VL),其中所述重链可变区包含HCDR1,HCDR2,HCDR3,所述轻链可变区包含LCDR1,LCDR2,LCDR3,它们各自分别与以下分子的HCDR1,HCDR2,HCDR3,LCDR1,LCDR2,LCDR3具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的轻链可变区,其中所述轻链可变区分别与以下分子的轻链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链可变区和轻链可变区,其中所述重链可变区和所述轻链可变区分别与以下分子的轻链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
在某些实施方式中,其中所述抗TNFα抗体或其抗原结合片段包含抗体的轻链,其中所述轻链分别与以下分子的轻链具有至少约80%、约85%、约90%、约95%、约96%、约97%、 约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
例如,其中所述抗TNFα抗体或其抗原结合片段包含抗体的重链和轻链,其中所述重链和轻链分别与以下分子的轻链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:阿达木单抗(Adalimumab)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab),戈利木单抗(golimumab)或抗鼠TNFαmIgG2a 8c11。
示例性抗TNF-α抗体或其抗原结合片段的序列提供在表1-2中。
表1:阿达木单抗氨基酸序列
表2:抗鼠TNFαmIgG2a 8c11氨基酸序列
在一个实施例中,抗体或其抗原结合部分是拮抗剂抗体或其抗原结合部分,其引起与在不存在所述抗体或其抗原结合部分的情况下的CD40活性或功能相比,CD40活性或功能降低。在具体实施例中,抗体或其抗原结合部分基本上不含激动剂活性,即,抗体或其抗原结合部分不会引起与在不存在所述抗体或其抗原结合部分的情况下的CD40活性或功能相比,CD40活性或功能的量值增加。在某些实施例中,抗CD40抗体是多克隆抗体、单克隆抗体、嵌合抗体、人类化抗体、人类抗体或其抗原结合部分。
在某些实施例中,抗CD40抗体是Iscalimab(CFZ533)(Novartis;如美国专利案第8828396 和9221913号中所描述);抗CD40抗体是鲁卡木单抗(lucatumumab)(Novartis;如美国专利案第8277810号中所描述);抗体5D12、3A8和3C6,或其人类化版本(Novartis;如美国专利案第5874082号中所描述);抗体15B8(Novartis;如美国专利案第7445780号中所描述);抗体4 D1 1(Kyowa Hakko Kirin;如美国专利案第7193064号中所描述);特立西单抗(temeliximab)(Bristol Myers Squibb;如美国专利案第6051228号中所描述);抗体PG102(PanGenetics;如美国专利案第8669352号中所描述);抗体2C10(Primatope;美国专利申请公开案第20140093497号);美国专利案第8591900号和第8778345号中描述的抗CD40抗体(Boehringer Ingelheim);美国专利案第5801227号中描述的抗CD40抗体(Amgen);或APX005(Boehringer Ingelheim;如美国专利案申请公开案第20120301488号中所描述。
在某些实施方式中,其中所述抗CD40抗体或其抗原结合片段包含抗体的重链可变区(VH),其中所述重链可变区包含HCDR1,HCDR2,HCDR3,它们各自分别与以下分子的HCDR1,HCDR2,HCDR3具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Iscalimab(CFZ533)。
在某些实施方式中,其中所述抗CD40抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区分别与以下分子的重链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Iscalimab(CFZ533)。
在某些实施方式中,其中所述抗CD40抗体或其抗原结合片段包含抗体的重链,其中所述重链分别与以下分子的重链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性Iscalimab(CFZ533)。
在某些实施方式中,其中所述抗CD40抗体或其抗原结合片段包含抗体的轻链可变区(VL),其中所述轻链可变区包含LCDR1,LCDR2,LCDR3,它们各自分别与以下分子的LCDR1,LCDR2,LCDR3具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Iscalimab(CFZ533)。
在某些实施方式中,其中所述抗CD40抗体或其抗原结合片段包含抗体的轻链可变区,其中所述轻链可变区分别与以下分子的轻链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Iscalimab(CFZ533)。
在某些实施方式中,其中所述抗CD40抗体或其抗原结合片段包含抗体的轻链,其中所述轻链分别与以下分子的轻链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Iscalimab(CFZ533)。
示例性抗CD40抗体或其抗原结合片段的序列提供在表3中。
表3:CFZ533单抗氨基酸序列(Kabat)
在一实施方案中,本发明的抗体对IFNAR1具有特异性(即特异性结合)。此类抗体在本文中也可以称为“本发明的抗IFNAR1抗体”。在另一个实施方案中,本发明的抗体对人 IFNAR1具有特异性。在另一个实施方案中,本发明的抗IFNAR1抗体可以与人以外的物种或与人IFNAR1在结构上相关的其他蛋白质(例如,人IFNAR1同源物)的IFNAR1交叉反应。在其他实施方案中,本发明的抗IFNAR1抗体可以仅对人IFNAR1具有特异性,并且不表现出物种或其他类型的交叉反应性。
抗IFNAR1抗体的选择序列可以在美国专利No.5,235,038,美国专利申请No.5,919,453中找到。美国专利第10831,459号,第10/182,058号,第11157,494号和第11521,102号的全部内容为了所有目的通过引用整体并入本文。
在某些实施方式中,其中所述抗IFNAR1抗体或其抗原结合片段包含抗体的重链可变区(VH),其中所述重链可变区包含HCDR1,HCDR2,HCDR3,它们各自分别与以下分子的HCDR1,HCDR2,HCDR3具有至少约80%的序列同一性:Anifrolumab(MEDI-546)。
在某些实施方式中,其中所述抗IFNAR1抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区分别与以下分子的重链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Anifrolumab(MEDI-546)。
在某些实施方式中,其中所述抗IFNAR1抗体或其抗原结合片段包含抗体的重链,其中所述重链分别与以下分子的重链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性Anifrolumab(MEDI-546)。
在某些实施方式中,其中所述抗IFNAR1抗体或其抗原结合片段包含抗体的轻链可变区(VL),其中所述轻链可变区包含LCDR1,LCDR2,LCDR3,它们各自分别与以下分子的LCDR1,LCDR2,LCDR3具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Anifrolumab(MEDI-546)。
在某些实施方式中,其中所述抗IFNAR1抗体或其抗原结合片段包含抗体的轻链可变区,其中所述轻链可变区分别与以下分子的轻链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Anifrolumab(MEDI-546)。
在某些实施方式中,其中所述抗IFNAR1抗体或其抗原结合片段包含抗体的轻链,其中所述轻链分别与以下分子的轻链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Anifrolumab(MEDI-546)。
示例性抗IFNAR1抗体或其抗原结合片段的序列提供在表4中。
表4:Anifrolumab单抗氨基酸序列(Kabat)
在某些实施方式中,其中所述抗BDCA2抗体或其抗原结合片段包含抗体的重链可变区,其中所述重链可变区分别与以下分子的重链可变区具有至少约80%的序列同一性:Litifilimab(BIIB059)。在某些实施方式中,其中所述抗BDCA2抗体或其抗原结合片段包含抗体的轻链可变区,其中所述轻链可变区分别与以下分子的轻链可变区具有至少约80%的序列同一性:Litifilimab(BIIB059)。
在某些实施方式中,其中所述抗BDCA2抗体或其抗原结合片段包含抗体的重链,其中所述重链分别与以下分子的重链具有至少约80%的序列同一性:Litifilimab(BIIB059)。在某些实施方式中,其中所述抗BDCA2抗体或其抗原结合片段包含抗体的轻链,其中所述轻链分别与以下分子的轻链具有至少约80%的序列同一性:Litifilimab(BIIB059)。
在某些实施方式中,其中所述抗BDCA2抗体或其抗原结合片段包含抗体的重链可变区(VH),其中所述重链可变区分别与以下分子的重链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Litifilimab(BIIB059)。
在某些实施方式中,其中所述抗BDCA2抗体或其抗原结合片段包含抗体的轻链可变区(VL),其中所述轻链可变区分别与以下分子的轻链可变区具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Litifilimab(BIIB059)。
在某些实施方式中,其中所述抗BDCA2抗体或其抗原结合片段包含抗体的重链,其中所述重链分别与以下分子的重链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Litifilimab(BIIB059)。
在某些实施方式中,其中所述抗BDCA2抗体或其抗原结合片段包含抗体的轻链,其中所述轻链分别与以下分子的轻链具有至少约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%的序列同一性:Litifilimab(BIIB059)。
示例性抗BDCA2抗体或其抗原结合片段的序列提供在表5中。
表5:Litifilimab(BIIB059)单抗氨基酸序列
本申请还涵盖与本文中阐述的抗TNF-α抗体、抗CD40抗体或抗IFNAR1抗体基本上同源的变体和等效物。这些变体和等效物可以含有例如保守性取代突变,即,一个或多个氨基酸被类似氨基酸取代。举例来说,保守性取代是指氨基酸被相同一般类别内的另一种氨基酸取代,例如一种酸性氨基酸被另一种酸性氨基酸取代、一种碱性氨基酸被另一种碱性氨基酸取代或一种中性氨基酸被另一种中性氨基酸取代。保守性氨基酸取代的目的是所属领域中众所周知的。抗体可以是抗体的重组多肽、天然多肽或合成多肽。所属领域中将了解,可以改变本申请的一些氨基酸序列而不显著影响蛋白质的结构或功能。因此,本申请进一步包括多肽的变化形式,其展示显著活性或其包括抗体的区域。这类突变体包括缺失、插入、倒位、重复和类型取代。
在某些实施方式中,其中所述配体选自:阿达木单抗(Adalimumab)、Iscalimab(CFZ533)、Anifrolumab(MEDI-546)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab)、戈利木单抗(golimumab)、抗鼠TNFαmIgG2a 8c11、Litifilimab(BIIB059)、其衍生物、其生物类似物。
例如,所述配体选自:阿达木单抗(Adalimumab)、Iscalimab(CFZ533)和Anifrolumab(MEDI-546)。
在某些实施方式中,其中所述配体-药物偶联物具有以下结构:
其中,
Ab代表能够与靶标结合的配体,包括但不限于抗体及其抗原结合片段;
N
a-I为1至10中的任意数字;
Tr不存在或Tr为任意基团;
L
3选自多肽片段;
L
2不存在或选自连接片段;
L
1选自偶联单元;
R
1、R
2、R
3、R
4和R
5各自独立地为任意基团;
B不存在或B为任意基团;
W不存在或W为任意基团;
CR
4R
5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O)
2-、-C(=O)-、-C=C-和-C≡C-,其中R
4和R
5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为 1-20中的任意整数;
X选自:-O-,-S-,-NR-;
Y
1为任意基团,m为0至4中的任意整数;
Y
2选自-O-,-S-和-NR-;
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基;其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
术语“配体”一般意指能够特异性结合和或以反应方式结合或复合靶分子,例如靶细胞或组织上的受体,底物,抗原决定簇或其它结合位点的任意分子。配体的实例包括抗体及其片段(例如单克隆抗体或其片段),酶(例如纤维蛋白分解酶),生物反应调节剂(例如白细胞介素,干扰素,红细胞生成素(erythropeoitin)或集落刺激因子),肽激素及其抗原结合片段,多糖,脂质,寡核苷酸,多核苷酸,合成分子,无机分子,有机分子及其任何组合。
术语“靶标”或“靶分子”可包括非常多种物质和分子,其范围为简单的分子到复杂的靶。靶分子可以是蛋白、核酸、脂质、碳水化合物或能被多肽域识别的任何其它分子。例如,靶分子可以包括化合物(即,非生物的化合物,例如,有机分子、无机分子或具有有机和无机原子的分子,但是不包括多核苷酸和蛋白)、化合物的混合物、空间上定位的化合物的阵列、生物大分子、噬菌体肽展示文库、多核糖体肽展示文库、从生物材料(例如细菌、植物、真菌或动物(例如,哺乳动物)细胞或组织)制成的提取物、蛋白、毒素、肽激素、细胞、病毒等。其它靶分子包括,例如,整个细胞、整个组织、相关的或不相关的蛋白的混合物、病毒或细菌菌株的混合物等。
术语“特异性结合”或“特异性的”通常指可测量的和可再现的相互作用,例如靶标和抗体之间的结合,可在分子(包括生物分子)的异质群体存在的情况决定靶标的存在。例如,特异性结合靶标(其可以为表位)的抗体可以是以比它结合其它靶标更大的亲和性、亲合力、更容易、和/或以更大的持续时间结合该靶标的抗体。在某些实施方案中,抗体特异性结合蛋白质上的表位,所述表位在不同种属的蛋白质中是保守的。在某些实施方案中,特异性结合可以包括但不要求排他性地结合。
偶联单元L
1在与配体偶联前后结构可以发生改变,即在Linker-Payload结构(如式IVa或式IVb)和药物-配体偶联物结构(如式Va或式Vb)中,L
1的结构会有所改变,这种改变可以由本领域普通技术人员容易地确定。
例如,当L
1通过巯基与配体偶联时,L
1的结构变化如下:
其中,巯基可以来自配体,所述R
L1a、R
L1b、R
L1c各自独立的选自:氢、任选取代的烷基和任选取代的芳基;例如,所述R
L1a、R
L1b、R
L1c可以各自独立的选自:氢、任选取代的甲基、任选取代的乙基、任选取代的芳基和任选取代的苄基。
例如,当L
1通过氨基与配体偶联时,L
1的结构变化如下:
其中氨基可以来自配体。
例如,当L
1通过点击化学与配体偶联时,L
1的结构变化如下:
例如,其中所述R
1,R
2可以各自独立的选自:H,F,Cl,Br和任选取代的甲基。
例如,其中所述R
3可以选自:任选取代的-CH
2Cl、任选取代的-CH
2SH、任选取代的-CH
2OH、任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的-OH、任选取代的-OCH
3、任选取代的-OCH
2F、任选取代的-OCH
2Cl、任选取代的-OCH
2CN、任选取代的-OCH
2CH
3、任选取代的巯基、任选取代的-SCH
2F、任选取代的-SCH
2Cl、任选取代的-SCH
2CF
3、和任选取代的-SCH
2CN。
例如,其中所述B可以选自:
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选 取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
任选取代的
其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR
2、-OC(O)NHR、-OC(O)NR
2、-SR、-S(O)R、-S(O)
2R、-NHR、-N(R)
2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O)
2NHR、-S(O)
2N(R)
2、-NHS(O)
2NR
2、-NRS(O)
2NR
2、-NHS(O)
2R、-NRS(O)
2R、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基和卤素取代的C
1-C
6烷氧基。
例如,所述W可以不存在或W选自:
例如,所述偶联物可以选自以下结构:
;其中N
a-I为1至10中的任意数字。
在某些实施方式中,本发明所述的偶联物,其中所述配体-药物偶联物具有以下结构:
其中,
Ab代表能够与靶标结合的配体,优选为抗体或其抗原结合片段;
N
a-I为1至10中的任意数字;
所述X选自-O-,-S-和-NH-;
R
4和R
5各自独立地选自以下组:H、F、Cl、-OH、-NH
2和C
1-C
6烷基;
所述n选自1、2或3;
所述Y
1不存在或选自:羟基、巯基、氨基和C
1-C
6烷基;
所述R
1和R
2各自独立地选自氢、氟、氯和甲基;
所述R
3选自:-CH
2Cl、-CH
2SH、-CH
2OH、
-OCH
3、-OCH
2F、-OCH
2Cl、-OCH
2CN、-OCH
2CH
3、-SH、-SCH
2F、-SCH
2Cl、-SCH
2CF
3和-SCH
2CN。
在某些实施方式中,本发明所述的偶联物,所述偶联物选自以下结构:
;其中N
a-I为1至10中的任意数字,Ab选自抗体或其抗原结合片段。
在某些实施方式中,本发明所述的偶联物,所述偶联物选自以下结构:
在某些实施方式中,所述偶联物的活性代谢物包含前述的化合物。
另一方面,本申请提供一种药物组合物,其包含前述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐和/或前述的偶联物,以及任选地药学上可接受的载体。
另一方面,本申请提供一种影响免疫系统功能的方法,包括向受试者施用前述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐、前述的偶联物和/或前述的药物组合物。
在某些实施方式中,所述影响免疫系统功能包含影响免疫细胞的功能。
在某些实施方式中,所述免疫细胞选自以下组:颗粒白细胞和无颗粒白细胞。
在某些实施方式中,所述免疫细胞选自以下组:中性粒细胞、嗜酸性粒细胞、和嗜碱性粒细胞。
在某些实施方式中,所述免疫细胞选自以下组:淋巴细胞和吞噬细胞。
在某些实施方式中,所述免疫细胞选自以下组:B细胞、T细胞、自然杀伤细胞、单核细胞、巨噬细胞、肥大细胞和树突状细胞。
另一方面,本申请提供前述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐、前述的偶联物和/或前述的药物组合物在制备药物中的用途,所述药物用于预防和/或治疗疾病和/或症状。
在某些实施方式中,所述疾病和/或症状包含与糖皮质激素受体信号转导相关的疾病和/或症状。
在某些实施方式中,所述疾病和/或症状选自以下组:增生性疾病和/或症状、代谢性疾病和/或症状、炎症疾病和/或症状和神经退行性疾病和/或症状。
在某些实施方式中,所述疾病和/或症状选自以下组:系统性自身免疫疾病和/或症状、血液系统相关疾病和/或症状、神经肌肉系统相关疾病和/或症状、消化系统相关疾病和/或症状、泌尿系统相关疾病和/或症状、内分泌腺系统相关疾病和/或症状、皮肤肌肉系统相关疾病和/或症状、和呼吸系统系统相关疾病和/或症状。
在某些实施方式中,所述疾病和/或症状选自以下组:类风湿关节炎、系统性红斑狼疮、硬皮病、干燥综合症、强直性脊柱炎、韦格纳肉芽肿病和系统性硬化。
在某些实施方式中,所述疾病和/或症状选自以下组:自身免疫性溶血性贫血、恶性贫血、特发性血小板减少性紫癜、特发性血小板减少症和血管炎。
在某些实施方式中,所述疾病和/或症状选自以下组:多发性硬化、重症肌无力和古兰巴雷综症。
在某些实施方式中,所述疾病和/或症状选自以下组:溃疡性结肠炎、克罗恩病、自身免疫性肝病和萎缩性胃炎。
在某些实施方式中,所述疾病和/或症状选自以下组:IgA肾病、原发性肾病综合征、自身免疫性肾小球肾炎、肺肾出血综合征和狼疮肾炎。
在某些实施方式中,所述疾病和/或症状选自以下组:I型糖尿病、Grave's病、桥本甲状腺炎、原发性肾上腺皮质萎缩和慢性甲状腺炎。
在某些实施方式中,所述疾病和/或症状选自以下组:银屑病、寻常型天孢疹、皮肤红斑狼疮、皮肌炎和风湿性多肌痛。
在某些实施方式中,所述疾病和/或症状为哮喘。
另一方面,本申请提供一种预防和/或治疗疾病和/或症状的方法,所述方法包括向有此需 要的受试者施用前述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐、前述的偶联物和/或前述的药物组合物。
在某些实施方式中,所述疾病和/或症状包含与糖皮质激素受体信号转导相关的疾病和/或症状。
在某些实施方式中,所述疾病和/或症状选自以下组:增生性疾病和/或症状、代谢性疾病和/或症状、炎症疾病和/或症状和神经退行性疾病和/或症状。
在某些实施方式中,所述疾病和/或症状选自以下组:系统性自身免疫疾病和/或症状、血液系统相关疾病和/或症状、神经肌肉系统相关疾病和/或症状、消化系统相关疾病和/或症状、泌尿系统相关疾病和/或症状、内分泌腺系统相关疾病和/或症状、皮肤肌肉系统相关疾病和/或症状、和呼吸系统系统相关疾病和/或症状。
在某些实施方式中,所述疾病和/或症状选自以下组:类风湿关节炎、系统性红斑狼疮、硬皮病、干燥综合症、强直性脊柱炎、韦格纳肉芽肿病和系统性硬化。
在某些实施方式中,所述疾病和/或症状选自以下组:自身免疫性溶血性贫血、恶性贫血、特发性血小板减少性紫癜、特发性血小板减少症和血管炎。
在某些实施方式中,所述疾病和/或症状选自以下组:多发性硬化、重症肌无力和古兰巴雷综症。
在某些实施方式中,所述疾病和/或症状选自以下组:溃疡性结肠炎、克罗恩病、自身免疫性肝病和萎缩性胃炎。
在某些实施方式中,所述疾病和/或症状选自以下组:IgA肾病、原发性肾病综合征、自身免疫性肾小球肾炎、肺肾出血综合征和狼疮肾炎。
在某些实施方式中,所述疾病和/或症状选自以下组:I型糖尿病、Grave's病、桥本甲状腺炎、原发性肾上腺皮质萎缩和慢性甲状腺炎。
在某些实施方式中,所述疾病和/或症状选自以下组:银屑病、寻常型天孢疹、皮肤红斑狼疮、皮肌炎和风湿性多肌痛。
在某些实施方式中,所述疾病和/或症状为哮喘。不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的化合物、制备方法和用途等,而不用于限制本申请发明的范围。
实施例
在本申请中,
提供溴代条件的试剂包括但不限于溴水,N-溴代琥珀酰亚胺,二溴海因,三溴化磷,液溴,液溴/三苯基磷,氢溴酸,四溴化碳;
钛催化剂包括但不限于钛酸四异丙酯,三异丙氧基氯化钛,四氯化钛,三异丙醇甲基钛;
钯催化剂包括但不限于四三苯基膦钯,醋酸钯,氯化钯,双(三苯基膦)二氯化钯,三(二亚苄基丙酮)二钯,双(二亚苄基丙酮)二钯,双(乙腈)二氯化钯,[1,1’-双{二苯基膦基}二茂铁]二氯化钯,[1,1’-双{二苯基膦基}二茂铁]二氯化钯二氯甲烷复合物,二苯腈二氯化钯,1,4-双(二苯基膦)丁烷-氯化钯,烯丙基氯化钯二聚物,烯丙基环戊二烯基钯;
硼酸酯二聚体包括但不限于联硼酸频那醇酯,联硼酸新戊二醇酯,双联(2-甲基-2,4-戊二醇)硼酸酯,双联邻苯二酚硼酸酯,双(二异丙基-L-酒石酸二乙酯)二硼酸酯,双[(-)蒎烷二醇]二硼酯,双(1S,2S,3R,5S)(+)-蒎烷二醇二硼酯,四次甲氨基乙硼烷,双(N,N,N’,N’-四甲基-D-酒石酰胺二醇酸根)二硼,四羟基二硼,双(N,N,N’,N’-四甲基-L-酒石酰胺二醇酸根)二硼,双(二异丙基-D-酒石酸甘醇酸)二硼酸酯,双联(D-酒石酸二乙酯)硼酸酯,双联(2,4-二甲基-2,4-戊二醇)硼酸酯,双联(L-酒石酸二乙酯)硼酸酯,4,4,5,5-四甲基-1,3,2-二氧杂硼环戊烷-2-基硼酸;
金属铜盐包括但不限于硫酸铜,五水硫酸铜,硫酸亚铜,氯化铜,氯化亚铜,碳酸铜,磷酸铜,乙酸铜及其水合物,草酸铜,氟硼酸铜及其水合物,二甲醇铜,酒石酸铜,甲酸铜,碘化亚铜,三氟乙酸铜,三氟甲磺酸铜,碱式碳酸铜,溴化铜,溴化亚铜,氧化亚铜;
配体可选自任意Ullmann反应常用的配体,包括但不限于L-脯氨酸,酪氨酸,苯基丙氨酸,1,10-菲洛啉,N,N’-二甲基乙二胺,乙二醇,1,1’-联萘-2,2’二酚,2-羰基环己基羧酸乙酯,水杨醛腙;
缩合剂可以选自4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉盐、1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑))-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鑰六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷,优选4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉盐或1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;
提供碱性条件的试剂包括有机碱和无机碱,所述的有机碱包括但不限于三乙胺,二乙胺,N-甲基吗啉,吡啶,六氢吡啶,N,N-二异丙基乙胺,正丁基锂,二异丙基氨基锂,醋酸钾,叔丁醇钠,叔丁醇钾等;所述无机碱包括但不限于氢化钠,碳酸钾,碳酸钠,碳酸铯,氢氧化钠,氢氧化锂,磷酸钠,磷酸钾;
提供酸性条件的试剂包括质子酸和路易斯酸,所述质子酸包括但不限于盐酸,硫酸,硝酸,亚硝酸,亚硫酸,磷酸,亚磷酸,甲酸、乙酸、丙酸、丁酸、柠檬酸、苯甲酸,对甲基苯磺 酸,对硝基苯甲酸,甲磺酸,三氟甲磺酸,三氟乙酸;所述路易斯酸包括但不限于三氟化硼,氯化锌,氯化镁,氯化铝,氯化锡,氯化铁;
氢化条件包括但不限于:Pb/C/氢气,Pt/C/氢气,氯化钯/氢气,兰尼镍/氢气,氢氧化钯碳/氢气,氢氧化钯/氢气;
提供氧化条件的试剂包括但不限于戴斯马丁氧化剂、双氧水、亚氯酸钠、次氯酸钠、高氯酸钾;
提供还原条件的试剂包括但不限于氢化钠,氢化钙,氢化锂,氢化铝锂,硼氢化钠,硼氢化锂,三乙基硼氢化钠,三乙酰氧基硼氢化钠,氰基硼氢化钠;
提供氧化条件的试剂包括但不限于戴斯马丁氧化剂、双氧水、亚氯酸钠、次氯酸钠、高氯酸钾。
此外,在本申请中
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Quan tum-I核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-D)、氘代氯仿(CDC13)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),化学位移是以10_6(ppm)作为单位给出。
MS的测定用Angilent 6230 ESI-TOF质谱仪(生产商:安捷伦,c型号:6230)。
UPLC的测定用Waters AcquityUPLCSQD液质联用仪(Poroshell 120 EC-C18,2.1mm x 50mm,1.9微米色谱柱)。
HPLC的测定使用安捷伦1260高压液相色谱仪(TOSOH G3000 SW SEC色谱柱)。
UV的测定使用Thermonanodrop2000紫外分光光度计。
酶联免疫测定用EnVision酶标仪(PerkinElmer公司)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm0.2mm,薄层层析分离纯化产品采用的规格是0.4mm0.5mm娃胶板。
柱层析一般使用烟台黄海200~300目硅胶为载体。
本申请的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCRGmbH&Co.KG,AcrosOrgannics,AldrichChemicalCompany,韶远化学科技(AccelaChemBioInc)、达瑞化学品等公司。
实施例中如无特殊说明,反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
实施例中如无特殊说明,反应中的溶液是指水溶液。
实施例中如无特殊说明,反应的温度为室温。室温为最适宜的反应温度,温度范围是20℃~30℃。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括:A:二氯甲烷和异丙醇体系,B:二氯甲烷和甲醇体系,C:石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
本公开部分化合物是通过TOF-LC/MS来表征的。TOF-LC/MS使用安捷伦6230飞行时间质谱仪和安捷伦1290-Infinity超高效液相色谱仪。
本申请的示例性制备路线如下:
一、payload及linker-payload的制备
制备路线1
第一步:通式(P1)化合物在任选溴代条件下,于苯环上引入溴原子;
第二步:通式(P2)化合物在任选钯试剂催化条件下与硼酸酯二聚体作用反应,得到通式(P3)化合物;
第三步:通式(P3)化合物上与通式(Y1)化合物在任选钯试剂催化条件下反应,得到通式(P4)化合物;
第四步:通式(P4)化合物在任选酸性或碱性条件下与通式(Y2)化合物反应,得到通式(P5)化合物;
第五步:通式(P5)化合物在任选酸性或碱性条件下,脱除保护基PG,并经制备HPLC分离,得到通式(P6)化合物。
其中:
PG可以为常见羟基的保护基;
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;
B环为任选取代的芳基或杂芳基;
-B(OR)
2为硼酸酯基单体,其中两个R可以连接形成杂环、杂桥环或杂螺环,且环上可任选被C
1-C
6烷基、芳基、杂芳基、羧基或酰氧基C
1-C
6烷基取代;
X为氯、溴或碘;
其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基;
R、R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R、R
1、R
2和R
3所定义。
制备路线2
第一步:通式(Y1)化合物与化合物(P1)在任选金属铜盐及任选配体催化下,在任选碱性条件下反应,得到通式(P2)化合物;
第二步:通式(P2)化合物在任选还原条件下反应,得到通式(P3);
第三步:通式(P3)化合物在任选氧化条件下,得到通式(P4);
第四步:通式(P4)化合物与通式(Y2)化合物在任选酸性或碱性条件下反应,得到通 式化合物(P5);
第五步:通式(P5)化合物在任选酸性或碱性条件下,脱除保护基PG,并经制备HPLC分离,得到通式(P6)化合物。
其中:
PG可以为常见羟基的保护基;
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;
B环为任选取代的芳基或杂芳基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义。
制备路线3
第一步:通式(P1)化合物在在任选钯试剂催化条件下发生羰基插入反应,得到通式(P2)化合物;
第二步:通式(P2)化合物在任选还原条件下反应,得到通式(P3);
第三步:通式(P3)化合物在任选溴代条件下,得到通式(P4)化合物;
第四步:通式(P4)化合物在任选碱性条件下与通式(Y1)化合物反应,得到通式(P5)化合物;
第五步:通式(P5)化合物在任选还原条件下反应,得到通式(P6);
第六步:通式(P6)化合物在任选氧化条件下,得到通式(P7);
第七步:通式(P7)化合物与通式(Y2)化合物在任选酸性或碱性条件下反应,得到通式化合物(P8);
第八步:通式(P8)化合物在任选酸性或碱性条件下,脱除保护基PG,并经制备HPLC分离,得到通式(P9)化合物。
其中:
PG
1和PG
2可以为常见羟基或酯基的保护基;
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基;
R可以为任选取代的C
1-C
6烷基;
B环为任选取代的芳基或杂芳基;
R、R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R、R
1、R
2和R
3所定义。
制备路线4
第一步:通式(P1)化合物在任选溴代条件下,于甲基处引入溴原子,得到通式(P2)化合物;
第二步:通式(P2)化合物上与通式(Y1)化合物在任选钯试剂催化条件下反应,得到通式(P3)化合物;
第三步:通式(P3)化合物在任选酸性或碱性条件下与通式(Y2)化合物反应,得到通式(P4)化合物;
第四步:通式(P4)化合物在任选酸性或碱性条件下,脱除保护基PG,并经制备HPLC分离,得到通式(P5)化合物。
其中:
PG
1可以为常见羟基的保护基;
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
B环为任选取代的芳基或杂芳基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
制备路线5
第一步:通式(P1)化合物在任选还原条件下反应,得到通式(P2);
第二步:通式(P2)化合物在任选酸性或碱性条件下,上保护基PG,得到通式(P3);
第三步:通式(P3)化合物在任选碱性条件下与通式(Y1)化合物反应,得到通式(P4)化合物;
第四步:通式(P4)化合物在任选还原条件下反应,得到通式(P5);
第五步:通式(P5)化合物在任选氧化条件下,得到通式(P6);
第六步:通式(P6)化合物与通式(Y2)化合物在任选酸性或碱性条件下反应,得到通式化合物(P7);
第七步:通式(P7)化合物在任选酸性或碱性条件下,脱除保护基PG,并经制备HPLC分离,得到通式(P8)化合物。
其中:
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
B环为任选取代的芳基或杂芳基;
PG
1和PG
2可以为常见羟基或羟基的保护基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
制备路线6
第一步:通式(P1)化合物上与通式(Y1)化合物在任选缩合条件下反应,得到通式(P2)化合物
第二步:通式(P2)化合物在任选还原条件下反应,得到通式(P3)化合物;
第三步:通式(P3)化合物在任选氧化条件下反应,得到通式(P4)化合物;
第四部:通式(P4)化合物与通式(Y2)在任选酸性或碱性条件下反应,得到通式(P5)化合物;
第五步:通式(P5)化合物在任选还原条件下反应,得到通式(P6)化合物;
其中:
PG
1和PG
2可以为常见羟基或酯基的保护基;
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
B环为任选取代的芳基或杂芳基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
制备路线7
第一步:通式(P1)化合物在硝化条件下,于苯环上引入硝基,得到通式(P2)化合物;
第二步:通式(P2)化合物在任选钯试剂催化条件下与硼酸酯二聚体作用反应,得到通式(P3)化合物;
第三步:通式(P3)化合物上与通式(Y1)化合物在任选钯试剂催化条件下反应,得到通式(P4)化合物;
第四步:通式(P4)化合物在任选酸性或碱性条件下与通式(Y2)化合物反应,得到通式(P5)化合物;
第五步:通式(P5)化合物在任选氢化条件下,得到通式(P6)化合物;
第六步:通式(P6)化合物在任选酸性或碱性条件下,脱除保护基PG,并经制备HPLC分离,得到通式(P7)化合物。
其中:
PG可以为常见羟基的保护基;
-B(OR)
2为硼酸酯基单体,其中两个R可以连接形成杂环、杂桥环或杂螺环,且环上可任选被C
1-C
6烷基、芳基、杂芳基、羧基或酰氧基C
1-C
6烷基取代;
其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基;
B环为任选取代的芳基或杂芳基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
制备路线8
第一步:通式(P1)化合物在硝化条件下,于苯环上引入硝基,得到通式(P2)化合物;
第二步:通式(P2)化合物在任选钛催化条件下,与乙基格氏试剂反应,得到通式(P3)化合物;
第三步:通式(P2)化合物在任选钯试剂催化条件下与硼酸酯二聚体作用反应,得到通式(P3)化合物;
第四步:通式(P3)化合物上与通式(Y1)化合物在任选钯试剂催化条件下反应,得到通式(P4)化合物;
第五步:通式(P4)化合物在任选酸性或碱性条件下与通式(Y2)化合物反应,得到通式(P5)化合物;
第六步:通式(P5)化合物在任选氢化条件下,将硝基还原,并经制备HPLC分离,得到通式(P6)化合物。
其中:
B环为任选取代的芳基或杂芳基;
-B(OR)
2为硼酸酯基单体,其中两个R可以连接形成杂环、杂桥环或杂螺环,且环上可任选被C
1-C
6烷基、芳基、杂芳基、羧基或酰氧基C
1-C
6烷基取代;
其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
制备路线9
第一步:通式(P1)化合物在任选碱性条件下与通式(Y1)化合物反应,得到通式(P2)化合物;
第二步:通式(P2)化合物在任选还原条件下反应,得到通式(P3);
第三步:通式(P3)化合物在任选氧化条件下,得到通式(P4);
第四步:通式(P4)化合物与通式(Y2)化合物在任选酸性或碱性条件下反应,得到通式化合物(P5)
第五步:通式(P5)化合物在任选酸性或碱性条件下,脱除保护基PG,并经制备HPLC分离,得到通式(P6)化合物。
其中:
PG可以为常见羟基的保护基;
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
B环为任选取代的芳基或杂芳基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
制备路线10
第一步:通式(P1)化合物在任选钯催化条件下与通式(Y1)化合物反应,得到通式(P2)化合物;
第二步:通式(P2)化合物在任选还原条件下反应,得到通式(P3);
第三步:通式(P3)化合物在任选氧化条件下,得到通式(P4);
第四步:通式(P4)化合物与通式(Y2)化合物在任选酸性或碱性条件下反应,得到通式化合物(P5)
第五步:通式(P5)化合物在任选酸性或碱性条件下,脱除保护基PG,并经制备HPLC分离,得到通式(P6)化合物。
其中:
X为N-R或-O-,R为任选取代的C
1-C
6烷基;
PG可以为常见羟基的保护基;
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自 氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
B环为任选取代的芳基或杂芳基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
制备路线11
第一步:通式(P1)化合物上与通式(Y1)化合物在任选缩合条件下反应,得到通式(P2)化合物
第二步:通式(P2)化合物在任选还原条件下反应,得到通式(P3)化合物;
第三步:通式(P3)化合物在任选氧化条件下反应,得到通式(P4)化合物;
第四部:通式(P4)化合物与通式(Y2)在任选酸性或碱性条件下反应,得到通式(P5)化合物;
第五步:通式(P5)化合物在任选还原条件下反应,并经制备HPLC分离,得到通式(P6)化合物;
其中:
PG可以为常见羟基的保护基;
Y选自:氢、氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R)
2、-PHR、-P(R)
2、-P(=O)HR、-P(=O)R
2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C
1-C
6烷基、C
1-C
6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C
1-C
6烷基、和卤素取代的C
1-C
6烷氧基。
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
制备路线12
第一步:通式(P1)化合物上与通式(Y1)化合物在任选缩合条件下反应,得到通式(P2)化合物;
第二步:通式(P2)化合物在任选酸性或碱性条件下,脱除保护基PG
1,得到通式(P3)化合物。
第三步:通式(P3)化合物上与通式(Y2)化合物在任选缩合条件下反应,得到通式(P4)化合物;
第四步:通式(P4)化合物在任选酸性或碱性条件下,脱除保护基PG
1,得到通式(P5)化合物;
第五步:通式(P5)化合物上与通式(Y3)化合物在任选缩合条件下反应,得到通式(P6)化合物;
第六步:通式(P6)化合物在任选酸性或碱性条件下,脱除保护基PG
1,得到通式(P7)化合物;
第七步:通式(P7)化合物上与通式(Y3)化合物在任选缩合条件下反应,并经制备HPLC分离,得到通式(P8)化合物。
其中:
B环为任选取代的芳基或杂芳基;
W不存在或W为任意基团;
Y
1为氢、羟基、氟、氯、甲基、羟基或甲氧基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(II)、式(III)或式(IV)所示R
1、R
2和R
3所定义;
LG
1、LG
2、LG
3和LG
4可以为常见活化酯或羧基的羟基;
PG
1、PG
2和PG
3可以为常见氨基的保护基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
Tr不存在或Tr为任意基团;
L
3选自多肽片段;
L
2不存在或选自连接片段;
L
1选自偶联单元。
制备路线13
第一步:通式(P1)化合物上与通式(Y1)化合物在任选缩合条件下反应,并经制备HPLC分离,得到通式(P2)化合物。
其中:
B环为任选取代的芳基或杂芳基;
W不存在或W为任意基团;
Y为-O-,-S-或-NH-;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
LG
1可以为常见活化酯或羧基的羟基;
Tr不存在或Tr为任意基团;
L
3选自多肽片段;
L
2不存在或选自连接片段;
L
1选自偶联单元。
制备路线14
第一步:通式(P1)化合物上与通式(Y1)化合物在任选缩合条件下反应,得到通式(P2)化合物;
第二步:通式(P2)化合物在任选酸性或碱性条件下,脱除保护基PG
1,得到通式(P3)化合物。
第三步:通式(P3)化合物上与通式(Y2)化合物在任选缩合条件下反应,得到通式(P4)化合物;
第四步:通式(P4)化合物在任选酸性或碱性条件下,脱除保护基PG
1,得到通式(P5)化合物;
第五步:通式(P5)化合物上与通式(Y3)化合物在任选缩合条件下反应,并经制备HPLC分离,得到通式(P6)化合物。
其中:
B环为任选取代的芳基或杂芳基;
W不存在或W为任意基团;
Y为-O-,-S-或-NH-;
LG
1、LG
2和LG
3可以为常见活化酯或羧基的羟基;
PG
1、PG
2和PG
3可以为常见氨基的保护基;
R
1、R
2和R
3可以分别如本申请任一式(I)、式(IIa)、式(IIb)、式(IIIa)、式(IIIb)、式(IVa)或式(IVb)所示R
1、R
2和R
3所定义;
Tr不存在或Tr为任意基团;
L
3选自多肽片段;
L
2不存在或选自连接片段;
L
1选自偶联单元。
二、抗体偶联药物(antibody drug conjugates,ADCs)的制备
制备路线15
配体Ab和本申请任一式(IVa)或式(IVb)所示的化合物在酸性、中性或碱性的缓冲液中反应可以得到式(Va)或式(Vb)所示的化合物;
其中:Ab为含有至少1个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(I-C)或式(II-C)所示的化合物中的S原子与可以来源于Ab的巯基;
Tr、L
1、L
2、L
3可以分别如本申请任一式(IVa)或式(IVb)所示的化合物中Tr、L
1、L
2、L
3所定义;Ab、N
a-I可以分别如本申请任一式(Va)或式(Vb)所示的化合物中Ab、N
a-
I所定义;L
1x代表与巯基偶联的L
1偶联后的结构。
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸-琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合。
制备路线16
第一步,配体Ab和本申请任一式(IVa)或式(IVb)所示的化合物在酸性、中性或碱性的缓冲液中反应可以得到式(Va)或式(Vb)所示的化合物;
其中:Ab为含有至少1个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(Va)或式(Vb)所示的化合物中的S原子与可以来源于Ab的巯基;
第二步,本申请任一式(Va)或式(Vb)所示的化合物在碱性的缓冲液中,与选定的温度下,孵育一定的时间,得到另一种本申请任一式(Va)或式(Vb)所示的化合物;
Tr、L
2、L
3可以分别如本申请任一式(IVa)或式(IVb)所示的化合物中Tr、L
2、L
3所定义;Ab、N
a-I可以分别如本申请任一式(Va)或式(Vb)所示的化合物中Ab、N
a-I所定义。
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸-琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸 缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合;选定的温度可以为5~60℃;孵育的时间可以为0~72小时。
制备路线17
配体Ab和本申请任一式(IVa)或式(IVb)所示的具有能够与2个巯基偶联的基团的化合物在酸性、中性或碱性的缓冲液中反应得到式(Va)或式(Vb)所示的化合物;
其中:Ab为含有至少2个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(Va)或式(Vb)所示的化合物中的S原子与可以来源于Ab的巯基;
Tr、L
1、L
2、L
3可以分别如本申请任一式(IVa)或式(IVb)所示的化合物中Tr、L
1、L
2、L
3所定义;Ab、N
a-I可以分别如本申请任一式(Va)或式(Vb)所示的化合物中Ab、N
a-
I所定义;L
1y代表与2个巯基偶联的L
1偶联后的结构。
式(Va)或式(Vb)所示的具有能够与2个巯基偶联的基团的化合物可以包含选自以下组的L
1y基团:
其中每一个R
L1a,R
L1b和R
L1c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基。
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸- 琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合。
制备路线18
配体Ab和本申请任一式(IVa)或式(IVb)所示的具有能够与2个巯基偶联的基团的化合物在酸性、中性或碱性的缓冲液中反应得到式(Va)或式(Vb)所示的化合物;
其中:Ab为含有至少1个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(Va)或式(Vb)所示的化合物中的S原子与可以来源于Ab的巯基;
Tr、L
1、L
2、L
3可以分别如本申请任一式(IVa)或式(IVb)所示的化合物中Tr、L
1、L
2、L
3所定义;Ab、N
a-I可以分别如本申请任一式(Va)或式(Vb)所示的化合物中Ab、N
a-
I所定义;L
1x代表与巯基偶联的L
1偶联后的结构。
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸-琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合。
制备路线19
第一步,配体Ab和本申请任一式(IVa)或式(IVb)所示的化合物在酸性、中性或碱性的缓冲液中反应可以得到式(Va)或式(Vb)所示的化合物;
其中:Ab为含有至少1个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(Va)或式(Vb)所示的化合物中的S原子与可以来源于Ab的巯基;
第二步,本申请任一式(Va)或式(Vb)所示的化合物在碱性的缓冲液中,与选定的温度下,孵育一定的时间,得到另一种本申请任一式(Va)或式(Vb)所示的化合物;
Tr、L
2、L
3可以分别如本申请任一式(IVa)或式(IVb)所示的化合物中Tr、L
2、L
3所定义;Ab、N
a-I可以分别如本申请任一式(Va)或式(Vb)所示的化合物中Ab、N
a-I所定义。
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸- 琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合;选定的温度可以为5~60℃;孵育的时间可以为0~72小时。
制备路线20
配体Ab和本申请任一式(IVa)或式(IVb)所示的具有能够与2个巯基偶联的基团的化合物在酸性、中性或碱性的缓冲液中反应得到式(Va)或式(Vb)所示的化合物;
其中:Ab为含有至少2个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(Va)或式(Vb)所示的化合物中的S原子与可以来源于Ab的巯基;
Tr、L
1、L
2、L
3可以分别如本申请任一式(IVa)或式(IVb)所示的化合物中Tr、L
1、L
2、L
3所定义;Ab、N
a-I可以分别如本申请任一式(Va)或式(Vb)所示的化合物中Ab、N
a-
I所定义;L
1y代表与2个巯基偶联的L
1偶联后的结构。
式(Va)或式(Vb)所示的具有能够与2个巯基偶联的基团的化合物可以包含选自以下组的L
1y基团:
其中每一个R
L1a, R
L1b和R
L1c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基。
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸-琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合。
实施例1
化合物1
步骤1将化合物1A(500mg,3.67mmol)溶于二氯甲烷(10mL)中,加入DIEA(1.42g,10.99mmol),另取TBSCl(830mg,5.51mmol)的二氯甲烷(5mL)加入上述反应液中,搅拌过夜17小时。TLC(PE/EA=20/1)显示反应结束。将反应液直接减压旋干,经(PE:EA=100:0-100:1)过柱得到800mg乳白色油状液体1B,收率:87%。
步骤2将化合物1B(125mg,0.50mmol)和化合物1C(188mg,0.50mmol)投料于超干乙腈(8mL)中溶解,氮气置换,降温0℃,用注射器加入甲烷磺酸(48mg,0.50mmol)与MeCN(2mL)混溶,搅拌过夜16小时。TLC(PE/EA=3/1)显示反应结束。加入碳酸氢钠,过滤,旋干,得到粗品送制备纯化得62mg白色粉末化合物1和7mg白色粉末1S,收率分别为25%和3%。
化合物1:
MS-ESI:m/z 495.3[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ7.41(d,J=8.1Hz,2H),7.34-7.28(m,3H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.43(s,1H),4.93(d,J=4.9Hz,1H),4.79(brs,1H),4.52(d,J=19.5Hz, 1H),4.48(s,2H),4.34-4.25(m,1H),4.19(d,J=19.5Hz,1H),2.61-2.52(m,1H),2.35-2.27(m,1H),2.19-1.98(m,2H),1.84-1.58(m,5H),1.39(s,3H),1.13-0.95(m,2H),0.87(s,3H).
化合物1S:
MS-ESI:m/z 495.3[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ7.35-7.27(m,3H),7.22(d,J=8.1Hz,2H),6.17(dd,J=10.1,1.9Hz,1H),6.09(s,1H),5.95(s,1H),5.30(d,J=6.8Hz,1H),4.81-4.76(m,1H),4.48(s,2H),4.30(s,1H),4.25(d,J=19.2Hz,1H),4.01(d,J=19.2Hz,1H),2.59-2.53(m,1H),2.36-2.28(m,1H),2.12-1.97(m,2H),1.90-1.69(m,5H),1.39(s,3H),1.26-1.13(m,1H),1.06(dd,J=11.0,3.4Hz,1H),0.89(s,3H).
化合物2
步骤1取化合物2A(5.0g,25.4mmol),咪唑(2.59g,38.0mmol)溶于二氯甲烷(50mL)中,加入TBSCl(4.9g,32.5mmol),25℃下反应2小时后TLC显示反应结束。加100mL水,100mL二氯甲烷×2萃取两次后合并二氯甲烷并用无水硫酸钠干燥旋干直接拌样过柱,经(PE:EA=20:1)得3g黄色固体2B,收率:38%。MS-ESI:m/z 312.2[M+H]
+。
步骤2取化合物2B(1.0g,3.2mmol)溶于THF(10mL)中,N
2置换后降温至0℃,加入BH
3/THF(6.4mL,6.4mmol),17小时后LCMS显示反应结束。将反应液加入甲醇(40mL)中(冰浴保持0℃),淬灭BH
3后旋干得500mg无色油状物2C,收率:52%。MS-ESI:m/z 298.1[M+H]
+。
步骤3取化合物2C(500mg,1.68mmol)溶于二氯甲烷(8mL)中,降温至0℃后加入Dess-Martin试剂(1.43g,3.36mmol),1.5小时后LCMS显示反应结束。将反应液加 水(100mL)稀释,用乙酸乙酯(100mL+50mL)萃取两次后合并有机相并用饱和食盐水洗涤,无水硫酸钠干燥后旋干得250mg白色固体2D,收率:50%。MS-ESI:m/z 296.0[M+H]
+。
步骤4取化合物2D(100mg,0.34mmol),化合物1C(127mg,0.34mmol),MgSO
4(250mg,2.08mmol)溶于乙腈(10mL)中,降温至0℃并氮气置换后加入三氟甲磺酸(150mg,1.0mmol),加完后保持冰浴反应2小时,LCMS显示反应结束。将反应液直接过滤,用乙腈润洗滤饼三次后母液旋干,经柱层析(DCM:MeOH=30:1)得100mg白色固体2E,收率:55%。MS-ESI:m/z 540.0[M+H]
+。
步骤5取化合物2E(100mg,0.18mmol),铁粉(100mg,1.8mmol),加入乙醇(4mL)中,NH
4Cl(96mg,1.8mmol)溶于水中后加入乙醇中,N
2置换并升温至60℃反应2小时,LCMS显示反应结束。将反应液垫硅藻土过滤,用乙醇润洗滤饼三次后母液旋干送制备,经制备冻干得40mg白色固体粉末2和5mg白色固体粉末2S,收率分别为42%和5%。
化合物2:
MS-ESI:m/z 532.2[M+Na]
+。
1H NMR(400MHz,DMSO-d
6)δ7.32(d,J=10.1Hz,1H),7.20(d,J=7.7Hz,1H),6.94(s,1H),6.89(d,J=7.7Hz,1H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.34(s,1H),4.95-4.89(m,1H),4.80(brs,1H),4.49(d,J=19.4Hz,1H),4.44(s,2H),4.33-4.27(m,1H),4.18(d,J=19.4Hz,1H),2.62-2.52(m,1H),2.35-2.28(m,1H),2.19-2.07(m,1H),2.07-1.99(m,1H),1.80-1.60(m,5H),1.40(s,3H),1.15-1.02(m,1H),0.99(dd,J=11.2,3.6Hz,1H),0.86(s,3H).
化合物2S:
MS-ESI:m/z 532.3[M+Na]
+。
1H NMR(400MHz,DMSO-d
6)δ7.32(d,J=10.1Hz,1H),7.15-7.09(m,1H),6.70(s,1H),6.63(d,J=7.6Hz,1H),6.17(dd,J=10.0,1.9Hz,1H),5.99(s,1H),5.94(s,1H),5.25(d,J=6.8Hz,1H),4.78(brs,1H),4.40(s,2H),4.33-4.22(m,2H),4.02(d,J=19.2Hz,1H),2.60-2.53(m,1H),2.36-2.28(m,1H),2.11-1.97(m,2H),1.90-1.69(m,5H),1.39(s,3H),1.26-1.13(m,1H),1.09-1.02(m,1H),0.88(s,3H).
化合物3
步骤1将化合物3A(6.58g,33.08mmol,1.0eq),化合物3B(5.03g,33.08mmol,1.0eq)加入250mL三口瓶中,加入THF(50mL)、水(5mL)和K
2CO
3(13.71g,99.24mmol,3.0eq),氮气保护,加入Pd(dppf)Cl
2(1.21g,1.65mmol,0.05eq),氮气置换三次。加热至80℃回流,搅拌3-4小时后,TLC(PE/EA=5/1)显示反应完毕。将反应液冷却至室温,过滤,滤液倒入300mL水中,EA(200mL)萃取,水洗有机相(100mL×3),用饱和NaCl洗涤一次,无水Na
2SO
4干燥,旋干后硅胶拌样,柱层析(PE/EA=7/1)出产品,旋干得2.5g白色固体3C,收率:33%。
步骤2将化合物1D(3g,7.97mmol,1.0eq)、化合物3C(1.8g,7.97mmol,1.0eq)、MgSO
4(2.88g,23.91mmol,3.0eq),加入100mL三口瓶,加入乙腈(30mL),氮气保护,冰水浴下加入三氟甲磺酸(1.2g,7.97mmol,1.0eq),加完升至室温反应2小时。TLC(PE/EA=3/1)显示反应完毕,反应液过滤,滤液旋干,硅胶拌样柱层析(PE/EA=2/1)出产品,旋干得3.7g白色固体3,收率79%。
MS-ESI:m/z 585.3[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ7.36(d,J=7.8Hz,2H),7.30(d,J=10.1Hz,1H),7.24(d,J=7.7Hz,2H),7.20(d,J=7.5Hz,1H),7.15(s,1H),7.11(d,J=7.6Hz,1H),7.07(d,J=7.6Hz,1H),6.16(dd,J=10.1,1.9Hz,1H),5.92(s,1H),5.39(s,1H),4.91(d,J=4.8Hz,1H),4.78(brs,1H),4.49(d,J=19.4Hz,1H),4.43(s,2H),4.32-4.25(m,1H),4.17(d,J=19.5Hz,1H),3.90(s,2H),2.59-2.51(m,1H),2.35-2.26(m,1H),2.18-1.95(m,2H),1.82-1.56(m,5H),1.39(s,3H),1.11-0.96(m,4H),0.85(s,3H).
化合物4
步骤1将化合物4A(500mg,2.51mmol)溶于THF/H
2O(10/2mL)中,然后加入化合物4B(573mg,3.77mmol)和K
2CO
3(1.04g,7.53mmol)。置换氮气后加入Pd(dppf)Cl
2(367mg,0.50mmol),在氮气保护下加热至80℃反应2小时。反应液冷却至室温,加水(20mL)稀释,乙酸乙酯(20mLx3)萃取,有机相合并后用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,浓缩,过柱(PE/EA=1:0 to 3:1)得270mg黄色固体4C,收率:48%。
步骤2将化合物4C(150mg,0.66mmol)溶于MeCN(10mL)中,然后加入化合物1C(250mg,0.66mmol)和MgSO
4(160mg,1.32mmol),在氮气保护0℃下加入三氟甲磺酸(299mg,1.99mmol)。0℃继续反应1小时。反应液加水(20mL)稀释,用二氯甲烷(10mLx3)萃取,有机相合并后用饱和食盐水(10mL)洗涤,干燥后旋干得到粗产物,再通过制备得到120mg白色粉末状固体4和13mg白色粉末状固体4S,收率分别为31%和3%。
化合物4:
MS-ESI:m/z 585.4[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ7.35(d,J=8.0Hz,2H),7.30(d,J=10.1Hz,1H),7.24-7.16(m,4H),7.14(d,J=8.1Hz,2H),6.16(dd,J=10.1,1.9Hz,1H),5.92(s,1H),5.38(s,1H),4.90(d,J=4.8Hz,1H),4.48(d,J=19.4Hz,1H),4.42(s,2H),4.31-4.25(m,1H),4.16(d,J=19.4Hz,1H),3.89(s,2H),2.59-2.52(m,1H),2.36-2.25(m,1H),2.18-1.96(m,2H),1.82-1.55(m,5H),1.38(s,3H),1.10-0.94(m,2H),0.85(s,3H).
化合物4S:
MS-ESI:m/z 585.3[M+H]
+。
1H NMR(400MHz,Chloroform-d)δ7.31-7.26(m,3H),7.21-7.11(m,6H),6.31(dd,J=10.1,1.9Hz,1H),6.08(s,2H),5.43-5.38(m,1H),4.65(s,2H),4.52-4.45(m,1H),4.27(d,J=19.9Hz,1H),4.05(d,J=19.9Hz,1H),3.95(s,2H),2.66-2.54(m,1H),2.23-2.07(m,3H),1.95-1.83(m,2H),1.80-1.68(m,1H),1.63(dd,J=14.1,2.6Hz,1H),1.46(s,3H),1.31-1.13(m,2H),0.99(s,3H).
化合物5
步骤1将化合物5A(50g,216mmol,1.0eq)和咪唑(22g,323mmol,1.5eq)加入2L三口瓶中,加二氯甲烷(700mL)溶解后,将TBSCl(44g,292mmol,1.35eq)缓慢加入,TLC(PE/EA=9/1)跟踪原料反应完。反应液冷却至室温后过滤,用二氯甲烷(100mL),H
2O(90mL)分液萃取两次,有机相用无水硫酸钠干燥,旋干拌样过正相柱纯化(PE:EA=10:1)得65g白色固体5B,收率为87%。
步骤2将化合物5B(60g,173mmol,1.0eq),联硼酸频那醇酯(44g,173mmol,1.0eq),Pd(dppf)Cl
2(6.3g,8.6mmol,0.05eq),醋酸钾(51g,520mmol,3.0eq)加入2L的三口瓶中,加dioxane 1L溶解,N
2保护,110℃下搅拌12小时后TLC(PE:EA=9:1)显示反应结束。反应液冷却至室温后过滤,用(1L)乙酸乙酯,H
2O(1L)分液萃取两次,有机相用无水硫酸钠干燥,旋干拌样过正相柱纯化(PE:EA=10:1)得60g白色固体5C,收率:88%。
步骤3将化合物5C(30g,76mmol,1.0eq),化合物5D(15.2g,76mmol,1eq),Pd(dppf)Cl
2(3g,4mmol,0.05eq),加入到1L三口瓶中,然后加入600mL dioxane,Cs
2CO
3(74g,228mmol,3.0eq)溶于60mL水,氮气保护,110℃反应2小时,TLC(PE:EA=9:1)显示反应结束。反应液冷却至室温后过滤,用(1L)乙酸乙酯,H
2O(1L)分液萃取两次,有机相用无水硫酸钠干燥,旋干拌样过正相柱纯化(PE:EA=10:1)得20g白色固体5E,收率:68%。
步骤4将化合物5E(2.0g,5.2mmol,1.0eq),化合物1C(1.96g,5.2mmol,1.0eq),MgSO
4(1.88g,15.6mmol,3.0eq)放入250mL三口瓶中,加入乙腈50mL,干冰乙醇冷却到零下20℃,缓慢加入三氟甲磺酸(2.34g,15.6mmol,3.0eq),0℃下搅拌2小时,TLC(PE:EA=1:1)显示反应完全。反应液加入碳酸氢钠溶液调pH=7~8,把乙腈旋蒸完,萃取,用PE:EA=3:1打浆得到3.2g化合物5F的粗品,收率:98%,直接用于下一步 反应。MS-ESI:m/z 630.1[M+H]
+。
步骤5将化合物5F(3.2g,5.08mmol,1eq),Fe(2.84g,50.8mmol,10eq)放入250mL三口瓶中,加入80mL乙醇,NH
4Cl(2.72g,50.8mmol,10eq)溶于80mL水加入三口瓶中,60℃反应2小时,TLC(DCM:MOH=10:1)显示反应完全。把乙醇减压蒸发完,用碳酸氢钠水溶液调pH=8,用80mL二氯甲烷和水萃取两次,有机相用硫酸镁干燥过滤,把有机相旋干得到2.6g黄色固体,拿出其中400mg粗品过反相柱得到43.9mg 95%以上纯度化合物5。
MS-ESI:m/z 600.1[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ7.38(d,J=8.0Hz,2H),7.31(d,J=10.1Hz,1H),7.24(d,J=7.9Hz,2H),6.96(s,1H),6.90(s,1H),6.76(s,1H),6.16(dd,J=10.1,1.8Hz,1H),5.93(s,1H),5.40(s,1H),4.92(d,J=4.8Hz,1H),4.79(brs,1H),4.49(d,J=19.4Hz,1H),4.43(s,2H),4.32-4.26(m,1H),4.17(d,J=19.5Hz,1H),3.90(s,2H),2.62-2.52(m,1H),2.36-2.26(m,1H),2.18-1.97(m,2H),1.81-1.55(m,5H),1.39(s,3H),1.10-0.94(m,2H),0.86(s,3H).
化合物6
步骤1将化合物6A(10g,43.1mmol)、溶于二氯甲烷(100mL)中,加入DIEA(16.7g,129.3mmol),另取TBSCl(9.7g,64.6mmol)的二氯甲烷(100mL)加入上述反应液中,搅拌过夜3天。TLC(PE/EA=40/1)显示反应结束。将反应液直接减压旋干,用纯石油醚过柱得到12.0g淡黄色油状液体6B,收率:80%。
步骤2将化合物6B(1g,2.89mmol),联硼酸频那醇酯(883mg,3.48mmol),1,4-二氧六环(10mL),KOAc(853mg,8.69mmol),Pd(dppf)Cl
2(212mg,0.29mmol)于1,4-二氧六环(10mL)中,氮气置换,加热(110℃)搅拌过夜17小时。TLC(PE:EA=40:1)显 示反应结束。将反应液直接旋干,拌样过柱,由50:1的石油醚和乙酸乙酯得183mg淡黄色油状液体6C,收率:16%。MS-ESI:m/z 394.3[M+H]
+。
步骤3取化合物6C(180mg,0.46mmol),Pd(dppf)Cl
2(33.5mg,0.046mmol),化合物5D(90.6mg,0.46mg),Cs
2CO
3(298mg,0.92mmol),1,4-二氧六环(8mL),水(2mL)。置换N
2,加热(110℃),搅拌过夜(20小时)。TLC(PE/EA=10/1)显示反应结束。将反应液直接旋干,拌样过柱,由100:1的石油醚和乙酸乙酯得95.8mg淡黄色油状液体6D,收率54%。MS-ESI:m/z 386.1[M+H]
+。
步骤4将化合物6D(500mg,1.30mmol),化合物1C(488mg,1.30mmol),MeCN(10mL),MgSO
4(930mg,7.73mmol),加入三口瓶中,置换N
2,降至0℃,加入三氟甲磺酸(585mg,3.90mmol)用恒压地液漏斗加入,搅拌(3小时)。TLC(DCM/MeOH=10/1)显示反应结束。将反应液直接旋干,拌样过柱,由50:1的二氯甲烷和MeOH得300mg白色固体6E,收率37%。MS-ESI:m/z 630.1[M+H]
+。
步骤5将化合物6E(4g,6.35mmol),乙醇(100mL),加入单口瓶中,加入铁粉(2.36g,42.1mmol),NH
4Cl(3.4g,63.6mmol),溶于水(40mL)中后加入上述单口瓶中,置换N
2,60℃加热搅拌(2小时)。TLC(二氯甲烷/CH3OH=10/1)显示反应结束。加入NaHCO
3水溶液调至pH到7~8之间,搅拌10分钟,将其过滤,得到的滤液旋干,加入二氯甲烷溶解搅拌过柱。由30:1的二氯甲烷和甲醇得3.5g白色粉末固体6,收率:92%。取白色粉末固体50mg爬大板,经过滤,旋干,加入乙腈和水(纯净水)后冻干得到38mg产品6,纯度90.08%。
MS-ESI:m/z 622.3[M+Na]
+。
1H NMR(400MHz,DMSO-d
6)δ7.35(d,J=8.0Hz,2H),7.30(d,J=10.2Hz,1H),7.22-7.16(m,2H),6.93(d,J=7.6Hz,1H),6.45-6.40(m,1H),6.40-6.34(m,1H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.39(s,1H),5.14-5.04(m,1H),4.98-4.83(m,3H),4.78(d,J=3.4Hz,1H),4.54-4.45(m,1H),4.34-4.26(m,3H),4.22-4.12(m,1H),3.75(s,2H),2.60-2.53(m,1H),2.36-2.26(m,1H),2.17-1.96(m,2H),1.81-1.60(m,5H),1.39(s,3H),1.09-0.97(m,2H),0.85(s,3H).
化合物7
步骤1将化合物7A(65g,280mmol,1.0eq)和咪唑(29g,420mmol,1.5eq)加入2L三口瓶中,加二氯甲烷(700mL)溶解后,将TBSCl(59g,392mmol,1.4eq)缓慢加入,TLC(PE:EA=9:1)跟踪原料反应完。反应液冷却至室温后过滤,用二氯甲烷(100mL),H
2O(90mL)分液萃取两次,有机相用无水硫酸钠干燥,旋干拌样过正相柱纯化(PE:EA=10:1)得80g白色固体7B,收率:82%。
步骤2将化合物7B(70g,203mmol,1.0eq),联硼酸频那醇酯(51g,203mmol,1.0eq),Pd(dppf)Cl
2(7.4g,10.1mmol,0.05eq),醋酸钾(60g,609mmol,3.0eq)加入2L的三口瓶中,加dioxane 1L溶解,N
2保护,110℃下搅拌12小时后TLC(PE:EA=10:1)显示反应结束。反应液冷却至室温后过滤,用(1L)乙酸乙酯,H
2O(1L)分液萃取两次,有机相用无水硫酸钠干燥,旋干拌样过正相柱纯化(PE:EA=10:1)得60g白色固体7C,收率:75%。
步骤3将化合物7C(15g,38mmol,1.0eq),化合物5D(7.6g,38mmol,1eq),Pd(dppf)Cl
2(1.4g,1.9mmol,0.05eq),加入到1L三口瓶中,然后加入600mL dioxane,Cs
2CO
3(37g,114mmol,3.0eq)溶于50mL水,氮气保护,110℃反应2小时,TLC(PE:EA=10:1)显示反应结束。反应液冷却至室温后过滤,用(1L)乙酸乙酯,H
2O(1L)分液萃取两次,有机相用无水硫酸钠干燥,旋干拌样过正相柱纯化(PE:EA=10:1)得10g白色固体7D,收率:68%。
步骤4将化合物7D(1g,2.6mmol,1.0eq),化合物1C(0.98g,2.6mmol,1.0eq),MgSO
4(0.94g,7.8mmol,3.0eq)放入250mL三口瓶中,加入乙腈50mL,干冰乙醇冷却到零下20℃,缓慢加入三氟甲磺酸(1.17g,7.8mmol,3.0eq),0℃下搅拌2小时,TLC(二氯甲烷:MeOH=10:1)显示反应完全。反应液加入碳酸氢钠溶液调pH=7~8,把乙腈旋蒸完,萃取,用PE:EA=3:1打浆得到1.4g化合物7E,收率:86%。MS-ESI:m/z 630.1[M+H]
+。
步骤5将化合物7E(200mg,0.317mmol,1eq),铁粉(177mg,3.17mmol,10eq)放入25mL三口瓶中,加入6mL乙醇,NH
4Cl(170mg,3.17mmol,10eq)溶于6mL水加入三口瓶中,60℃反应2小时,TLC(DCM:MeOH=10:1)显示反应完全。把乙醇减压蒸发完,用碳酸氢钠水溶液调pH=8,用80mL二氯甲烷和水萃取两次,有机相用硫酸镁干燥过滤,把有机相旋干得到200mg黄色固体,过反相柱得到42.6mg化合物7,收率:22%。
MS-ESI:m/z 600.8[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ7.36(d,J=8.0Hz,2H),7.31(d,J=10.1Hz,1H),7.22(d,J=7.9Hz,2H),7.20-7.14(m,1H),7.07(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=4.7Hz,1H),4.79(s,1H),4.54-4.45(m,3H),4.31-4.26(m,1H),4.17(d,J=19.5Hz,1H),3.87(s,2H),2.60-2.53(m,1H),2.36-2.26(m,1H),2.18-1.96(m,2H),1.81-1.54(m,5H),1.39(s,3H),1.12-0.94(m,2H),0.86(s,3H).
化合物8
步骤1将化合物3(2g,3.42mmol,1.0eq)、化合物8A(2.52g,6.84mmol,2.0eq)加入反应瓶,加入THF(30mL)溶解,氮气保护,冰水浴下加入TsOH(0.63g,3.66mmol,1.07eq),5-10℃反应30-40分钟。TLC(PE/EA=1/2)显示反应完毕。将反应液加入水中,EA(100mL)萃取产品,水洗有机相(50mL×3),有机相用无水硫酸钠干燥,浓缩硅胶拌样,柱层析(PE/EA=2/1)过出产品,旋干得2.3g白色固体8B,收率:75%。MS- ESI:m/z 893.4[M+H]
+。
步骤2将化合物8B(2g,2.24mmol)溶于DCM(20mL),氮气保护,冰水浴下滴加DEA(6mL),加完室温反应2小时。TLC(PE/EA=1/2)显示反应完毕。将反应液旋干,DCM带三次,过反相柱,冻干得600mg类白色固体8C,收率:40%。MS-ESI:m/z 671.3[M+H]
+。
步骤3将化合物8C(300mg,0.447mmol,1.0eq)、化合物8D(230mg,0.492mmol,1.1eq),加入反应瓶,加入DMF(3.5mL)溶解,氮气保护,冰水浴,加入DIEA(173mg,1.341mmol,3.0eq),滴加HATU(221mg,0.581mmol,1.3eq)的1mL DMF溶液,加完0-5℃搅拌30分钟。LC-MS显示反应完毕。将反应液倒入冰水中,加入EA(100mL),萃取产物,水洗有机相(50mL×3),有机相无水硫酸钠干燥,旋干得430mg黄色固体8E,收率:86%。MS-ESI:m/z 1119.4[M+H]
+。
步骤4在氮气保护下,化合物8E(300mg,0.268mmol,1eq)、Pd(PPh
3)
4(62mg,0.0536mmol,0.2eq)、N-甲基吗啉(452mg,4.47mmol,16.7eq)加入反应瓶中,氮气保护,室温反应1小时。TLC显示反应完毕。将反应液直接过反相柱纯化得210mg白色固体8F,收率:72%。MS-ESI:m/z 1079.3[M+H]
+。
步骤5在氮气保护下,化合物8F(200mg,0.185mmol),溶于DCM(2.4mL)中,冰水浴,滴加DEA(0.8mL),加完升至室温反应2小时,LCMS显示反应完毕。将反应液用PE(60mL×3)直接萃洗三次,产物析出粘在瓶壁上,乙腈(3mL)溶解后过反相柱纯化得62mg白色固体8G,收率:39%。MS-ESI:m/z 857.6[M+H]
+。
步骤6将化合物8G(60mg,0.07mmol,1.0eq),溶于THF(3mL)中,加入(0.6mL)水溶清,冰水浴,加入TEA(414mg,4.1mmol,58eq),搅拌1分钟,加入溴乙酰溴(113mg,0.56mmol,8.0eq),0-5℃搅拌5分钟,LC-MS,显示反应完毕。将反应液用干冰乙醇保存送制备,冻干后得11mg白色固体8,收率:16%。
MS-ESI:m/z 977.3[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ8.62(t,J=6.6Hz,1H),8.47(t,J=5.6Hz,1H),8.24(t,J=5.9Hz,1H),8.18(d,J=7.7Hz,1H),7.40-7.34(m,2H),7.31(d,J=10.1Hz,1H),7.27-7.20(m,3H),7.16(brs,1H),7.14-7.07(m,2H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=5.1Hz,1H),4.77(brs,1H),4.65-4.55(m,2H),4.49(d,J=19.4Hz,1H),4.39(s,2H),4.33-4.25(m,2H),4.17(d,J=19.5Hz,1H),3.94-3.89(m,4H),3.80(d,J=5.6Hz,2H),3.72(d,J=5.8Hz,2H),2.57-2.52(m,2H),2.30-2.24(m,2H),2.18-2.06(m,1H),2.06-1.89(m,2H),1.83- 1.59(m,6H),1.39(s,3H),1.12-0.97(m,2H),0.85(s,3H).
化合物9
步骤1将化合物4(2.4g,4.1mmol,1.0eq)、化合物8A(4.5g,12.3mmol,3.0eq)加入反应瓶,加入THF(30mL)溶解,氮气保护,冰水浴下加入TsOH(1.1g,6.6mmol,1.6eq),5-10℃反应30-40分钟。TLC(PE/EA=1/2),显示反应完毕。将反应液加入水中,EA(100mL)萃取产品,水洗有机相(50mL×3),有机相无水硫酸钠干燥,浓缩硅胶拌样,柱层析(PE/EA=2/1)过出产品,旋干得1.5g白色固体9A,收率:41%。MS-ESI:m/z 893.4[M+H]
+。
步骤2将化合物9A(1.3g,1.46mmol)溶于DCM(13mL),氮气保护,冰水浴下滴加DEA(2.6mL),加完室温反应2小时。TLC(PE/EA=1/2)显示反应完毕。将反应液旋干,DCM带三次,过反相柱,冻干得350mg类白色固体9B,收率:36%。MS-ESI:m/z 670.8[M+H]
+。
步骤3将化合物9B(350mg,0.52mmol,1.0eq)、化合物8D(243mg,0.52mmol,1.0eq),加入反应瓶,加入DMF(3.5mL)溶解,氮气保护,冰水浴下加入DIEA(168mg,1.3mmol,2.5eq),滴加HATU(240mg,0.63mmol,1.21eq)的1mL DMF溶液,加完0-5℃搅拌30分钟。LC-MS显示反应完毕。将反应液倒入冰水中,加入EA(100mL),萃取产物,水洗有机相(50mL×3),有机相无水硫酸钠干燥,旋干得600mg发泡黄色固体9C,粗品超量不计收率。MS-ESI:m/z 1119.4[M+H]
+。
步骤4在氮气保护下,化合物9C(400mg,0.35mmol,1.0eq)、Pd(PPh
3)
4(82mg,0.071mmol,0.2eq)、N-甲基吗啉(353mg,3.5mmol,10.0eq)加入反应瓶中,氮气保护,室温反应1小时。LC-MS显示反应完毕。将反应液直接过反相柱纯化得150mg白色固体9D,收 率:39%。MS-ESI:m/z 1079.4[M+H]
+。
步骤5在氮气保护下,化合物9D(150mg,0.14mmol),溶于DCM(1.5mL)中,冰水浴,滴加DEA(0.3mL),加完升至室温反应2小时,LCMS显示反应完毕。将反应液直接旋干,DCM带三次,过反相柱纯化得60mg白色固体9E,收率:50%。MS-ESI:m/z 857.4[M+H]
+。
步骤6将化合物9E(50mg,0.058mmol,1.0eq),溶于THF(3mL)中,加入3滴水溶清,冰水浴,加入TEA(117mg,1.16mmol,20.0eq),搅拌1分钟,加入溴乙酰溴(93mg,0.46mmol,8.0eq),0-5℃搅拌5分钟,LC-MS显示反应完毕。将反应液用干冰保存送制备,冻干后得11mg白色固体9,收率:19%。
MS-ESI:m/z 977.3[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ8.62(t,J=6.6Hz,1H),8.49(t,J=5.6Hz,1H),8.26(t,J=5.8Hz,1H),8.19(d,J=7.5Hz,1H),7.36(d,J=7.9Hz,2H),7.30(d,J=10.1Hz,1H),7.26-7.14(m,6H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=4.9Hz,1H),4.79(brs,1H),4.61-4.54(m,2H),4.49(d,J=19.4Hz,1H),4.37(s,2H),4.32-4.24(m,2H),4.16(d,J=19.4Hz,1H),3.95-3.88(m,4H),3.79(d,J=5.5Hz,2H),3.72(d,J=5.8Hz,2H),2.58-2.52(m,2H),2.30-2.24(m,2H),2.17-2.05(m,1H),2.05-1.89(m,2H),1.82-1.58(m,6H),1.39(s,3H),1.11-0.96(m,2H),0.85(s,3H).
化合物10
步骤1将化合物5(1.9g,3.21mmol,1.0eq),化合物8D(1.5g,3.21mmol,1.0eq)和HATU(1.6g,4.24mmol,1.3eq)加入100mL三口瓶中,加DMF(45mL)溶解 后,将2,6-二甲基吡啶(1.4g,12.72mmol,4.0eq)缓慢加入,LCMS跟踪原料反应完。反应液缓慢地滴加到300mL水中,过滤得到产品,产品用油泵抽真空干燥得到3.3g黄色固体10A,收率94%。MS-ESI:m/z 1048.4[M+H]
+。
步骤2将化合物10A(1.8g,1.72mmol,1.0eq),Pd(PPh
3)
4(392mg,0.34mmol,0.2eq),加入50mL三口瓶中,加入二氯甲烷(30mL)溶解,氮气保护,缓慢加入N-甲基吗啉(868mg,8.6mmol,5.0eq),反应半小时,LCMS显示反应完。二乙胺(6mL)缓慢加入三口瓶中,常温下搅拌1小时,LCMS显示反应完毕。反应液加20mL DMF,在室温下真空旋蒸直到剩下20mL溶剂,停止旋蒸,过反相柱(ACN in water from 30%~70%),冻干得到455mg淡黄色固体10B,收率:34%。
步骤3将化合物10B(150mg,0.19mmol,1.0eq)溶于THF(5mL)和水(0.2mL)中,加入三乙胺(190mg,1.9mmol,10eq),冰水浴冷却至0℃,溴乙酰溴(153mg,0.76mmol,4.0eq)溶于1mL THF,然后缓慢加入反应液中,0℃下反应15分钟,然后LCMS显示反应完毕,制备得20mg白色固体10,收率:12%。
MS-ESI:m/z 906.3[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ9.87(s,1H),8.52(s,1H),8.22(d,J=7.6Hz,1H),7.43(s,1H),7.38(d,J=7.9Hz,2H),7.31(d,J=9.7Hz,2H),7.23(d,J=7.9Hz,2H),6.87(s,1H),6.16(d,J=10.3Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=5.1Hz,1H),4.78(s,1H),4.49(d,J=19.2Hz,1H),4.41(s,2H),4.39-4.32(m,1H),4.29(s,1H),4.17(d,J=19.5Hz,1H),3.93(s,2H),3.88(s,2H),3.82-3.77(m,2H),2.59-2.53(m,1H),2.35-2.21(m,4H),2.04-1.92(m,2H),1.84-1.63(m,6H),1.39(s,3H),1.09-0.99(m,2H),0.86(s,3H).
化合物11
步骤1将化合物6(300mg,0.5mmol,1.0eq),化合物8D(233mg,0.5mmol,1.0eq)和HATU(228mg,0.6mmol,1.2eq)加入25mL三口瓶中,加DMF(5mL)溶解 后,将2,6-二甲基吡啶(150mg,1.4mmol,2.8eq)缓慢加入,LCMS跟踪原料反应完。反应液缓慢地滴加到100mL水中,过滤得到产品,产品用油泵抽真空干燥得到450mg黄色固体11A,收率:86%。MS-ESI:m/z 1048.4[M+H]
+。
步骤2将化合物11A(450mg,0.43mmol,1.0eq),Pd(PPh
3)
4(92mg,0.08mmol,0.2eq),加入50mL三口瓶中,加入THF(10mL)溶解,氮气保护,缓慢加入N-甲基吗啉(200mg,1.98mmol,4.6eq),反应半小时,LCMS显示反应完毕。过反相柱(ACN in water from 30%~70%),冻干得到250mg淡黄色固体11B,收率:58%。MS-ESI:m/z 1008.3[M+H]
+。
步骤3将化合物11B(250mg,0.25mmol),加入25mL三口瓶中,加入DCM(10mL)溶解,氮气保护,加入2mL二乙胺,反应半小时,LCMS显示反应完毕。过反相柱(ACN in water from 20%~50%),冻干得到130mg淡黄色固体11C,收率:67%。MS-ESI:m/z 786.4[M+H]
+。
步骤4将化合物11C(120mg,0.153mmol,1.0eq)溶于THF(5mL)和水(0.2mL)中,加入三乙胺(155mg,1.53mmol,10.0eq),冰水浴冷却至0℃,溴乙酰溴(123mg,0.61mmol,4.0eq)溶于1mL THF,然后缓慢加入反应液中,0℃下反应15分钟,然后LCMS显示反应完。prep-HPLC得12.2mg白色固体11,收率:9%。
MS-ESI:m/z 906.3[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ9.51(s,1H),8.58-8.45(m,1H),8.37(d,J=7.6Hz,1H),7.51-7.46(m,1H),7.40-7.34(m,2H),7.31(d,J=10.0Hz,1H),7.28-7.19(m,3H),7.01-6.94(m,1H),6.16(dd,J=10.0,1.9Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=5.0Hz,1H),4.77(brs,1H),4.49(d,J=19.5Hz,1H),4.42(d,J=3.7Hz,1H),4.39-4.32(m,1H),4.29(brs,1H),4.17(d,J=19.5Hz,1H),3.98-3.77(m,6H),2.60-2.52(m,2H),2.34-2.28(m,2H),2.18-1.96(m,3H),1.88-1.55(m,6H),1.39(s,3H),1.13-0.98(m,2H),0.85(s,3H).
化合物12
步骤1在化合物4C(10.0g,44.2mmol)的DCM(70mL)溶液中加入TEA(8.94g,88.39mmol,12.30mL),降温至0℃,向反应中加入MsCl(6.08g,53.0mmol,4.10mL),于25℃搅拌12小时。LCMS显示原料已经消耗完毕。加入DCM(50mL)稀释反应液,加水(200mL)淬灭。用DCM(100mL×3)萃取,有机相合并,用饱和食盐水(100mL)洗,无水Na
2SO
4干燥。过滤,将滤液旋干得到黄色油状化合物12A(8.60g,粗品)。
步骤2向化合物12A(8.60g,31.58mmol)的DMF(51.6mL)溶液中加入巯基乙酸(7.21g,63.15mmol),于25℃搅拌5小时。TLC(PE/EA=5:1)显示原料已经反应完全。向反应液中加入水(100mL),用乙酸乙酯(100mL×3)萃取。有机相合并,用饱和食盐水洗后用5%LiCl水溶液洗。有机相用无水Na
2SO
4干燥,过滤,滤液旋干得到棕色油状化合物12B(5.75g,收率:57.82%,纯度:90.2%)。MS-ESI:m/z 285.2[M+H]
+。
步骤3将化合物12B(12.0g,42.2mmol)溶于甲醇(240mL)中,加入K
2CO
3(8.75g,63.3mmol),于20℃下搅拌3小时。LCMS显示原料已经转化完全。将反应液倒入DCM(240mL)中,加入0.5M HCl(100mL),分液,有机相用无水硫酸钠干燥。浓缩后得到类白色固体12C(10.0g,收率:97.7%)。MS-ESI:m/z 483.2[M+H]
+。
步骤4将化合物12C(9.00g,37.1mmol),化合物1C(13.9g,37.1mmol)和无水硫酸镁(13.4g,111mmol)加入到乙腈(270mL)中,0℃下滴加TfOH(16.7g,111mmol,9.84 mL),加完后逐渐升温至20℃,搅拌3小时。LCMS显示原料已经转化完全。反应液用饱和碳酸氢钠水溶液(60mL)淬灭,用乙酸乙酯(100mL×2)萃取,有机相用饱和食盐水(80mL)洗,无水硫酸钠干燥。浓缩后得到类白色固体12D(15.0g,收率:33.6%)。MS-ESI:m/z 1199.4[M+H]
+。
步骤5将化合物12D(290mg,粗品)加入到DMF(4mL)中,再加入DL-二硫苏糖醇(200mg,1.30mmol),氮气保护下室温反应16小时。LCMS显示反应完成。将反应液直接HPLC制备得到白色粉末状固体12(20mg,收率:13.8%)。MS-ESI:m/z 601.2[M+H]
+。
1H NMR(400MHz,DMSO)δ7.37(d,J=8.1Hz,2H),7.31(d,J=10.1Hz,1H),7.23(dd,J=8.1,3.3Hz,4H),7.14(d,J=8.0Hz,2H),6.16(dd,J=10.1,1.7Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=5.0Hz,1H),4.78(s,1H),4.49(d,J=19.4Hz,1H),4.29(s,1H),4.17(d,J=19.5Hz,1H),3.88(d,J=11.3Hz,2H),3.67(d,J=7.6Hz,2H),2.77(t,J=7.6Hz,1H),2.50-2.55(m,1H),2.45-2.25(m,1H),2.25-2.05(m,2H),1.80–1.53(m,5H),1.38(s,3H),1.14–0.94(m,2H),0.86(s,3H).
化合物13
步骤1将化合物12(7.00g,11.6mmol),化合物8A(4.29g,11.6mmol)加入到DMF(49.0mL)中,加入TfOH(3.50g,23.3mmol,2.06mL),于25℃下搅拌16小时。LCMS显示原料已经转化完全。反应液用饱和碳酸氢钠水溶液(20mL)淬灭,用乙酸乙酯(100mL×3)萃取三次,有机相用饱和食盐水(100mL)洗,无水硫酸钠干燥。浓缩得到黄色油体化合物13A(15.0g,粗品不计算收率)。MS-ESI:m/z 909.3[M+H]
+。
步骤2将化合物13A(15.0g,16.5mmol)加入到乙腈(105mL)中,加入二乙胺(6.03g,82.5mmol,8.50mL)并在25℃下搅拌16小时。LCMS显示原料已经转化完全。反应液用乙腈打浆(20.0mL),过滤,将得到的滤饼抽干,粗品通过反相制备(水:乙腈=25%-55%,20min),冻干后得到白色固体化合物13B(0.900g,收率:7.94%)。MS-ESI:m/z 687.3[M+H]
+。
步骤3将化合物13B(500mg,727μmol)和化合物8D(526mg,1.09mmol)加入到DMF(5mL)中,加入HATU(830mg,2.18mmol)和2,6-lutidine(56.0mg,1.46mmol,169μl),于20℃下搅拌3小时。LCMS显示原料已经转化完全。将反应液抽真空,得到550mg粗品。取250mg粗品通过反相制备,得到白色固体化合物13C(100mg,收率:26.2%)。MS-ESI:m/z 1151.4[M+H]
+。
步骤4将化合物13C(50.0mg,43.4μmol)加入到乙腈中(1mL)中,加入二乙胺(15.8mg,217μmol,22.3μL),于25℃下搅拌6小时。LCMS显示原料已经转化完全。将反应液旋干,用甲基叔丁基醚(3.00mL)打浆,得到黄色固体化合物13D(40.0mg,收率:99.1%)。MS-ESI:m/z 929.2[M+H]
+。
步骤5将EEDQ(31.9mg,129μmol),溴乙酸(11.3mg,81.8μmol)溶于DMF(0.8mL)中,室温搅拌1小时,加入化合物13D(40.0mg,43.0μmol)25℃搅拌2小时。LCMS显示原料已经转化完全。旋干后得到黄色固体化合物13E(粗品直接投下一步)。MS-ESI:m/z1049.2[M+H]
+。
步骤6将化合物13E(45.0mg,42.8μmol)溶于DCM(1.50mL)中,加入三氟乙酸(770mg,6.75mmol,500μL),于25℃下搅拌1小时。LCMS显示原料已经转化完全。旋干后,粗品通过反相制备纯化,得到黄色固体化合物13(3.06mg,收率:7.18%)。MS-ESI:m/z 993.2[M+H]
+。
1HNMR(400MHz,DMSO-d
6)δ7.83(br d,1H,J=7.6Hz),7.63(br d,1H,J=7.2Hz),7.4(m,2H),7.26(br d,2H,J=8.0Hz),7.16(br d,1H,J=7.6Hz),4.92(br s,1H),4.48(br s,1H),4.30(br s,2H),4.1-4.3(m,2H),4.02(br d,1H,J=13.6Hz),3.92(br d,2H,J=8.4Hz),3.81(br d,2H,J=5.2Hz),3.74(br s,3H),3.63(br s,2H),2.91(s,2H),2.75(br s,1H),2.3-2.4(m,2H),2.27(br s,2H),2.1-2.1(m,1H),2.02(br s,1H),1.92(br s,1H),1.77(br s,3H),1.3-1.5(m,8H),1.25(s,2H),1.18(br d,1H,J=7.2Hz),1.02(br s,1H),0.8-1.0(m,2H).
化合物14(参照化合物P1):
参考专利CN109476699A合成得到。
化合物15(参照化合物LP1):
参考专利CN111465399A合成得到。
化合物16(参照化合物LP2):
参考专利CN111417410A合成得到。
实施例2
在本申请中pH=5.5的20mM Histidine的缓冲水溶液是将20mM组氨酸水溶液用HOAc调pH至5.5得到。储备液1:10mM EDTA缓冲液,pH=4.7;储备液2:800mM Sodium citrate缓冲水溶液,pH=8.4;储备液3:500mM Urea水溶液;储备液4:10mM三(2-羧乙基)膦的水溶液。
本申请中ADC的蛋白纯度是通过SEC方法检测,参数如下表示。
本申请中ADC的DAR值可通过LC-MS方法检测的。实验操作如下:在 40.0μg ADC样品溶液中加入75.0μL 8.0mol/L盐酸胍(Gdn-HCl)、5.0μL 1.0mol/L Tris-HCl和 2.0μL 1 mol/L DTT。将该溶液用超纯水稀释至100.0μL,充分混合,在22℃下孵育30分钟。然后使用LC-MS分析药物/抗体比(DAR)。LC参数如下表示。
MS参数如下表示。
仪器 | Agilent Technologies 6224 TOF LC/MS |
电离模式 | Positive |
气体温度 | 350℃ |
气流 | 13L/min |
喷雾器压力 | 45psig |
毛细管电压 | 5000V |
破碎电压 | 250V |
锥孔电压 | 65V |
八极杆上射频电压的峰峰 | 750V |
采集模式 | MS(seg) |
质量范围 | 500-8000m/z |
采集速率 | 1spectra/s |
采集时间 | 1.4-7.0min |
本申请中ADC的DAR值也可通过HIC方法检测,参数如下表示。
鼠抗TNFαmIgG2a 8c11:轻链氨基酸序列如SEQ ID NO:31所示,且其重链氨基酸序列如SEQ ID NO:32所示,参考WO2015191783A2制备。
抗体Adalimumab(Humira):轻链氨基酸序列如SEQ ID NO:9所示,且其重链氨基酸序列如SEQ ID NO:10所示,参考US6090382A制备。
抗体Litifilimab(BIIB059):轻链氨基酸序列如SEQ ID NO:42所示,且其重链氨基酸序列如SEQ ID NO:37所示,参考CN105452295B制备。
抗体Iscalimab:轻链氨基酸序列如SEQ ID NO:19所示,且其重链氨基酸序列如SEQ ID NO:20所示,参考CN105949314B制备。
2.1偶联物1(8c11-conjugate1)
在37℃条件下,向抗鼠TNFαmIgG2a 8c11的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-1(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为6.5的0.05M的PBS缓冲水溶液,含0.001M的EDTA),得到式(Va)的示例性产物的PBS缓冲液(5.0mg/mL,1.1mL)。
将ADC的PBS缓冲液的pH值用1M的Tris缓冲液调节至pH=9,置于37℃下孵育24小时,用1mol/L的柠檬酸缓冲液调节pH至6.5,得到偶联物1(3.3mg/mL,5.5ml)。N
a-I可以经LC-MS检测。
2.2偶联物2(8c11-conjugate2)
在37℃条件下,向抗体8c11的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-12(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物2(5.0mg/mL,1.1mL)。
N
a-I可以经LC-MS检测。
2.3偶联物3(8c11-conjugate 3)
在37℃条件下,向抗体8c11的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-11(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物3(5.3mg/mL,1.5mL)。
N
a-I可以经LC-MS检测。
2.4偶联物4(8c11-conjugate 4)
在37℃条件下,向抗体8c11的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-60(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物4(4.7mg/mL,2.2mL)。
N
a-I可以经LC-MS检测。
2.5偶联物5(8c11-conjugate 5)
在37℃条件下,向抗体8c11的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-81(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物5(2.9mg/mL,4.3mL)。
N
a-I可以经LC-MS检测。
2.6偶联物6(8c11-conjugate 6)
在37℃条件下,向抗体8c11的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-91(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物6(3.6mg/mL,5.5mL)。
N
a-I可以经LC-MS检测。
2.7偶联物V-6
在37℃条件下,向抗体Adalimumab(Humira)的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-1(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为6.5的0.05M的PBS缓冲水溶液,含0.001M的EDTA),得到式(Va)的示例性产物的PBS缓冲液(2.8mg/mL,4.7mL)。
将ADC的PBS缓冲液的pH值用1M的Tris缓冲液调节至pH=9,置于37℃下孵育24小时,用1mol/L的柠檬酸缓冲液调节pH至6.5,得到偶联物V-6(3.3mg/mL,5.5ml)。N
a-I可以经LC-MS检测。
2.8偶联物V-13
在37℃条件下,向抗体Humira的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-12(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物V-13(3.5mg/mL,5.6mL)。
N
a-I可以经LC-MS检测。
2.9偶联物V-12
在37℃条件下,向抗体Humira的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-11(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物V-12(4.4mg/mL,4.3mL)。
N
a-I可以经LC-MS检测。
2.10偶联物V-49
在37℃条件下,向抗体Humira的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-60(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物V-53(2.7mg/mL,4.7mL)。
N
a-I可以经LC-MS检测。
2.11偶联物V-70(Humira-coujugate 5)
在37℃条件下,向抗体8c11的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液; 2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物IV-81(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物V-74(2.8mg/mL,5.1mL)。
N
a-I可以经LC-MS检测。
2.12偶联物9(8c11-conjugate 9)
在22℃条件下,向抗体8c11的NaOAc缓冲水溶液(pH=7.4的0.05M的NaOAc缓冲水溶液,含0.29mM EDTA和11.53mM Sodium citrate。10.6mL,3.4mg/mL,0.243μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.073mL,0.729μmol),化合物9(3.56mg,3.645μmol)的DMSO(0.36mL)溶液,置于水浴振荡器,于22℃振荡反应3小时,停止反应。
往反应液中加入1/3体积的100mM Histidine缓冲水溶液(pH=5.5),用Zeba脱盐离心柱(40K MWCO)脱盐纯化(洗脱相:pH为5.5的0.02M的组氨酸缓冲水溶液),得到偶联物9-1(36.94mg,4.22mg/mL,收率:102%)。N
a-I经RP检测,为3.69。
将偶联物9-1(36.94mg,4.22mg/mL)与1.55mL偶联物10(3.38mg/mL,5.24mg,RP-DAR 6.13)混合,得到偶联物9(39mg,4.22mg/mL)。N
a-I经RP检测,为4.05。
2.13偶联物10(8c11-conjugate 10)
在22℃条件下,向抗体8c11的NaOAc缓冲水溶液(pH=7.4的0.05M的NaOAc缓冲水溶液,含0.29mM EDTA和11.53mM Sodium citrate。13.2mL,3.4mg/mL,0.303μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.164mL,1.64μmol),化合物9(4.44mg,4.545μmol)的DMSO(0.44mL)溶液,置于水浴振荡器,于22℃振荡反应3小时,停止反应。
往反应液中加入1/3体积的100mM Histidine缓冲水溶液(pH=5.5),用Zeba脱盐离心柱(40K MWCO)脱盐纯化(洗脱相:pH为5.5的0.02M的组氨酸缓冲水溶液),得到偶联物10(39mg,3.38mg/mL,收率:87%)。
N
a-I经RP检测,为6.13。
2.14偶联物11(8c11-conjugate 11)
在22℃条件下,向抗体8c11的NaOAc缓冲水溶液(pH=5.5的0.05M的NaOAc缓冲水溶液,含0.29mM EDTA和11.53mM Sodium citrate。11.9mL,3.4mg/mL,0.273μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.123mL,1.23μmol),化合物11(3.72mg,4.10μmol)的DMSO(0.37mL)溶液,置于水浴振荡器,于22℃振荡反应3小时,停止反应。
往反应液中加入1/3体积的100mM Histidine缓冲水溶液(pH=5.5),用Zeba脱盐离心柱(40K MWCO)脱盐纯化(洗脱相:pH为5.5的0.02M的组氨酸缓冲水溶液),得到偶联物11(20mg,2.48mg/mL,收率:49%)。
N
a-I经RP方法检测,为4.58。
2.15偶联物12(8c11-conjugate 12)
在22℃条件下,向抗体8c11的NaOAc缓冲水溶液(pH=5.5的0.05M的NaOAc缓冲水溶液。3.8mL,11.3mg/mL,0.290μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.103mL,1.03μmol),置于水浴振荡器,于22℃振荡反应3小时,停止反应。加入储备液1和储备液2,使缓冲体系含0.29mM EDTA和11.53mM Sodium citrate。
将化合物10(4.73mg,5.22μmol)溶解于0.47mL DMSO中,加入到上述溶液中,置于水浴振荡器,于22℃振荡反应9小时,停止反应。往反应液中加入1/3体积的800mM Sodium citrate缓冲水溶液(pH=5.5),用Zeba脱盐离心柱(40K MWCO)脱盐纯化(洗脱相:pH为5.5的0.02M的组氨酸缓冲水溶液),得到偶联物12(35.39mg,2.17mg/mL,收率:82%)。
N
a-I经RP检测,为4.21。
2.16偶联物13(8c11-conjugate 13)
在22℃条件下,向抗体8c11的NaOAc缓冲水溶液(pH=5.5的0.05M的NaOAc缓冲水溶液,含0.29mM EDTA和11.53mM Sodium citrate。2.5mL,3.4mg/mL,0.057μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.026mL,0.26μmol),置于水浴振荡器,于22℃振荡反应3小时,停止反应。
将化合物13(1.02mg,1.026μmol)溶解于0.10mL DMSO中,加入到上述溶液中,置于水浴振荡器,于22℃振荡反应6小时,停止反应。将反应液用Zeba脱盐离心柱(40K MWCO)脱盐纯化(洗脱相:pH为5.5的0.02M的组氨酸缓冲水溶液),得到偶联物13(5.8mg,1.72mg/mL,收率:68%)。
N
a-I经LC-MS检测,为3.76。
2.17偶联物14(8c11-conjugate 14,参照ADC1)
在22℃条件下,向抗体8c11的NaOAc缓冲水溶液(pH=5.5的0.05M的NaOAc缓冲 水溶液,含0.51mM EDTA和20.35mM Sodium citrate。11.0mL,6.0mg/mL,0.446μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.174mL,1.74μmol),化合物16(6.40mg,6.69μmol)的DMSO(0.64mL)溶液,置于水浴振荡器,于22℃振荡反应4.5小时,停止反应。
往反应液中加入1/3体积的800mM Sodium citrate缓冲水溶液(pH=5.5)和10%体积的Sucrose水溶液(60%),用Zeba脱盐离心柱(40K MWCO)脱盐纯化(洗脱相:pH为6.0的0.05M的Sodium citrate缓冲水溶液,含6%Sucrose),得到偶联物14(54mg,3.18mg/mL,收率:82%)
N
a-I经RP检测,为4.69。
2.20偶联物17(Adalimumab-conjugate 17)
在22℃条件下,向抗体Adalimumab的PB缓冲水溶液(pH=6.97的0.04M的PB缓冲水溶液,含100mM NaCl。10.0mL,20mg/mL,1.351μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.338mL,3.378μmol),化合物9(18.49mg,18.91μmol)的DMA(1.85mL)溶液,置于水浴振荡器,于22℃振荡反应3小时,停止反应。
在22℃条件下,向抗体Adalimumab的PB缓冲水溶液(pH=6.97的0.04M的PB缓冲水溶液,含100mM NaCl。60.0mL,20mg/mL,8.108μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,2.189mL,21.892μmol),化合物9(111.00mg,113.51μmol)溶解于DMA(11.10mL)溶液,置于水浴振荡器,于22℃振荡反应5小时,停止反应。
合并反应液,用UFDF纯化(24DV,3CV缓冲液+2CV缓冲液(含5%DMA)+3CV缓冲液+2CV缓冲液(5%DMA)+3CV缓冲液+6CV缓冲液+5CV缓冲液,缓冲液为pH为5.5的0.02M的组氨酸缓冲水溶液),并用0.22μm膜过滤,得到偶联物17(1390mg,18.47mg/mL,收率:99%)。
N
a-I经LC-MS检测,为3.66。N
a-I经RP检测,为3.83。N
a-I经HIC检测,为3.77。
2.21偶联物18(Iscalimab-conjugate 18)
在22℃条件下,向抗体Iscalimab的NaOAc缓冲水溶液(pH=5.5的0.05M的NaOAc缓冲水溶液。7.5mL,4.0mg/mL,0.203μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.173mL,1.726μmol),化合物9(2.98mg,3.045μmol)溶解于DMSO(0.30mL)溶液,置于水浴振荡器,于22℃振荡反应4.5小时,停止反应。
将反应液用Zeba脱盐离心柱(40K MWCO)脱盐纯化(洗脱相:pH为5.5的0.02M的组氨酸缓冲水溶液),得到偶联物18(28mg,3.72mg/mL,收率:93%)。
N
a-I经LC-MS检测,为4.31。
2.22偶联物19(BIIB059-conjugate 19)
在37℃条件下,向抗体BIIB059的PBS缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5mL,9.96mg/mL,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/mL,并取出2.0mL溶液往下反应。
将化合物9(1.98mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0mL溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH=5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物19(2.42mg/mL,3.31mL)。收率:77%。
N
a-I经LC-MS检测,为4.75。
2.23偶联物20(BIIB059-conjugate 20)
在37℃条件下,向抗体BIIB059的PBS缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5mL,9.96mg/mL,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/mL,并取出2.0mL溶液往下反应。
将化合物16(1.93mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0mL溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH=5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物20(2.56mg/mL,3.52mL)。收率:83%。
N
a-I经LC-MS检测,为4.27。
2.24偶联物21(BIIB059-conjugate 21)
在37℃条件下,向抗体BIIB059的PBS缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5mL,9.96mg/mL,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/mL,并取出2.0mL溶液往下反应。
将化合物15(1.77mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0mL溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH=5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物21(2.49mg/mL,3.53mL)。收率:79%。
N
a-I经LC-MS检测,为4.30。
实施例3糖皮质激素受体报告基因GRE活性测定
3.1糖皮质激素受体报告基因GRE活性测定1
1.细胞培养
HEK293细胞在DMEM+10%FBS培养基中,在37摄氏度,5%二氧化碳浓度潮湿的二氧化碳培养箱中培养。
2.质粒转染和细胞种板
用胰酶消化HEK293细胞,把HEK293细胞重悬液用培养基调整到每毫升200,000个细胞(96孔板:100μL/孔)。
根据下面表格a和b配制转染试剂混合液,混匀并室温静置20分钟。
实验转染材料 | 体积(μL) |
pGL5质粒(100ng/uL) | 25 |
pBIND-GR(100ng/uL) | 25 |
Opti-MEM培养基 | 250.0 |
P3000 | 10.00 |
Opti-MEM培养基 | 250.0 |
Lipofectamine | 7.5 |
把准备好的转染混合液分别加入到10mL调整好细胞密度的重悬液中上下颠倒混匀,以100μL/孔的体积分别种入96孔板中。
96孔板置入37摄氏度,5%二氧化碳浓度潮湿培养箱中培养24小时。
3.药物处理
准备210μM Dexamethasone(地塞米松,上海上药信谊药厂有限公司)的DMSO溶液,3.3×连续稀释,得到10个浓度。将5μL上述Dexamethasone各浓度DMSO溶液分别加入45μL DMEM+10%FBS,混匀,得到10个浓度的Dexamethasone稀释液。
准备2.1μM的本申请化合物或参照例化合物溶液(使用培养基稀释),3.3×连续稀释,得到10个浓度的待测化合物稀释液。
每孔中(已有100μL细胞)加入5μL Dexamethasone稀释液或待测化合物稀释液。Min孔中加5μL10%DMSO培养基,Max孔中加入5μL 21μM Dexamethasone(溶于培养基,10%DMSO)。
将检测板放回培养箱中孵育24小时。
4.荧光素酶检测
使用Promega的Dual-Glo Luciferase Assay System试剂盒检测待侧板,使用Enspire分别读取Firefly luciferase荧光信号以及Renilla Luciferase荧光信号。
5.数据处理
最终测量值是Firefly luciferase荧光信号除以Renilla Luciferase荧光信号后得到的标准化数值“F/R”。
将数据复制粘贴到Excel中,通过方程得到激活率。
将数据导入MS Excel并使用XLFit excel add-in version 5.4.0.8进行曲线拟合,得到EC
50值
公式:Y=Bottom+(Top-Bottom)/(1+(EC50/X)^HillSlope
Y是激动率,X是化合物浓度。
表6显示,本申请化合物表现出更强的糖皮质激素受体激动活性。
表6糖皮质激素受体报告基因GRE活性测定1
化合物编号 | EC50(nM) |
Dexamethasone | 2.11 |
化合物14(参照化合物P1) | 0.19 |
化合物4 | 0.04 |
化合物4S | 1.42 |
3.2糖皮质激素受体报告基因GRE活性测定2
将实例HEK293GRE细胞以50,000个细胞/孔铺板在96孔组织培养物处理的白色板(Costar:3917)上的50μL测定培养基(RPMI、1%CSFBS、1%L-谷氨酰胺、1%丙酮酸钠和1%MEAA)中。将本申请化合物以1μM的起始浓度在100%DMSO中三倍稀释,连续稀释9次。将2μl连续稀释的化合物转移到二级稀释板(1∶125稀释度)中的248μl测定培养基中将小分子化合物在测定培养基中进一步稀释。然后将细胞用25μL最终起始浓度为266.7nM(1∶3)的1∶125稀释的GR激动剂化合物或单独的培养基处理并且在37°、5%CO2下孵育24小时。孵育24小时之后,将细胞用75μL的Dual-Glo荧光素酶测定系统(Promega-E2920)处理10分 钟,并且使用TopCount或MicroBeta2(珀金埃尔默公司(PerkinElmer))分析发光。
表7显示,本申请化合物表现出显著的糖皮质激素受体激动活性。
表7糖皮质激素受体报告基因GRE活性测定2
化合物编号 | EC50(nM) |
化合物14(参照化合物P1) | 0.43 |
化合物6 | 0.12 |
实例例4 GR荧光素酶报告基因洗脱实验
实验目的
评估本申请化合物与GR结合后持续激活的能力。
实验方法
1.细胞培养
HEK293细胞在DMEM+10%FBS培养基中,在37摄氏度,5%二氧化碳浓度潮湿的二氧化碳培养箱中培养。
2.质粒转染和细胞种板
1)用胰酶消化HEK293细胞,把HEK293细胞重悬液用培养基调整到每毫升200,000个细胞(96孔板:100μL/孔)。
2)根据下面表格配制转染试剂混合液,混匀并室温静置20分钟。
实验转染材料 | 体积(μL) |
pGL5质粒(100ng/uL) | 25 |
pBIND-GR(100ng/uL) | 25 |
Opti-MEM培养基 | 250.0 |
P3000 | 10.00 |
Opti-MEM培养基 | 250.0 |
Lipofectamine | 7.5 |
3)把准备好的转染混合液分别加入到10mL调整好细胞密度的重悬液中上下颠倒混匀,以100μL/孔的体积分别种入96孔板中。
4)96孔板置入37摄氏度,5%二氧化碳浓度潮湿培养箱中培养24小时。
3.药物处理
1)准备210μM Dexamethasone的DMSO溶液,3×连续稀释,得到10个浓度。将5μL上诉Dexamethasone各浓度DMSO溶液分别加入 45μL DMEM+10%FBS,混匀,得到10个浓度的Dexamethasone稀释液。
2)准备210倍终浓度的待测化合物DMSO溶液,3×连续稀释,得到10个浓度的待测化合物稀释液。将5μL上诉各浓度DMSO溶液分别加入 45μL DMEM+10%FBS,混匀,得到10个浓度的稀释液。
3)每孔中(已有100μL细胞)加入5μL Dexamethasone稀释液或待测化合物稀释液。Min孔中加5μL 10%DMSO培养基,Max孔中加入5μL 21μM Dexamethasone(溶于培养基,10%DMSO)。
4)将检测板放回培养箱中孵育一定时间(15分钟/30分钟/1小时/2小时/4小时)后,用移液器小心缓慢移除上清,加入100μL/孔培养基,然后再次小心缓慢移除上清,最后加入100μL/孔培养基,放入培养箱孵育24小时。
4.荧光素酶检测
使用Promega的Dual-Glo Luciferase Assay System试剂盒检测待侧板,使用Enspire分别读取Firefly luciferase荧光信号以及Renilla Luciferase荧光信号。
5.数据处理
1)最终测量值是Firefly luciferase荧光信号除以Renilla Luciferase荧光信号后得到的标准化数值“F/R”。
2)将数据复制粘贴到Excel中,通过方程得到激活率。
3)将数据导入MS Excel并使用XLFit excel add-in version 5.4.0.8进行曲线拟合,得到EC
50值
公式:Y=Bottom+(Top-Bottom)/(1+(EC50/X)^HillSlope
Y是激动率,X是化合物浓度。
实验结果
根据表8结果显示,本申请化合物与糖皮质激素受体结合更紧密,不易被洗脱,并对糖皮质激素受体有较长时间的持续激活能力。
表8 GR荧光素酶报告基因洗脱实验结果
实施例5 MR荧光素酶报告基因实验
1.细胞培养
HEK293细胞在DMEM+10%FBS培养基中,在37摄氏度,5%二氧化碳浓度潮湿的二氧化碳培养箱中培养。
2.质粒转染和细胞种板
1)用胰酶消化HEK293细胞,把HEK293细胞重悬液用培养基调整到每毫升200,000个细胞(96孔板:100μL/孔)。
2)根据下面表格配制转染试剂混合液,混匀并室温静置20分钟。
实验转染材料 | 体积(μL) |
pGL5质粒(100ng/uL) | 25 |
pBIND-MR(100ng/uL) | 25 |
Opti-MEM培养基 | 250.0 |
P3000 | 10.00 |
Opti-MEM培养基 | 250.0 |
Lipofectamine | 7.5 |
3)把准备好的转染混合液分别加入到10mL调整好细胞密度的重悬液中上下颠倒混匀,以100μL/孔的体积分别种入96孔板中。
4)96孔板置入37摄氏度,5%二氧化碳浓度潮湿培养箱中培养24小时。
3.药物处理
5)准备21μM Aldosterone的DMSO溶液,3.3×连续稀释,得到10个浓度。将5μL上诉Aldosterone各浓度DMSO溶液分别加入 45μL DMEM+10%FBS,混匀,得到10个浓度的Aldosterone稀释液。
6)准备210倍终浓度的待测化合物DMSO溶液,3.3×连续稀释,得到10个浓度的待测化合物稀释液。将5μL上诉各浓度DMSO溶液分别加入 45μL DMEM+10%FBS,混匀,得到10个浓度的稀释液。
7)每孔中(已有100μL细胞)加入5μL Aldosterone稀释液或待测化合物稀释液。Min孔中加5μL 10%DMSO培养基,Max孔中加入5μL 2.1μM Aldosterone(溶于培养基,10%DMSO)。
8)将检测板放回培养箱中孵育24小时。
4.荧光素酶检测
使用Promega的Dual-Glo Luciferase Assay System试剂盒检测待测板,使用Enspire分别读取Firefly luciferase荧光信号以及Renilla Luciferase荧光信号。
5.数据处理
4)最终测量值是Firefly luciferase荧光信号除以Renilla Luciferase荧光信号后得到的标准化数值“F/R”。
5)将数据复制粘贴到Excel中,通过方程得到激活率。
6)将数据导入MS Excel并使用XLFit excel add-in version 5.4.0.8进行曲线拟合,得到EC
50值
公式:Y=Bottom+(Top-Bottom)/(1+(EC50/X)^HillSlope
Y是激动率,X是化合物浓度。
表9 MR荧光素酶报告基因实验结果
Compound ID | MR EC50(nM) |
Dexamethasone(地塞米松) | >1000.00 |
化合物4 | >1000.00 |
化合物5 | >1000.00 |
化合物3 | >1000.00 |
根据表9结果,本发明化合物对盐皮质激素受体有较低的亲和力。
实施例6 ERα荧光素酶报告基因实验
1.细胞培养
HEK293细胞在DMEM+10%FBS培养基中,在37摄氏度,5%二氧化碳浓度潮湿的二氧化碳培养箱中培养。
2.质粒转染和细胞种板
1)用胰酶消化HEK293细胞,把HEK293细胞重悬液用培养基调整到每毫升200,000个细胞(96孔板:100μL/孔)。
2)根据下面表格配制转染试剂混合液,混匀并室温静置20分钟。
实验转染材料 | 体积(μL) |
pGL5质粒(100ng/uL) | 25 |
pBIND-ERα(100ng/uL) | 25 |
Opti-MEM培养基 | 250.0 |
P3000 | 10.00 |
Opti-MEM培养基 | 250.0 |
Lipofectamine | 7.5 |
3)把准备好的转染混合液分别加入到10mL调整好细胞密度的重悬液中上下颠倒混匀,以100μL/孔的体积分别种入96孔板中。
4)96孔板置入37摄氏度,5%二氧化碳浓度潮湿培养箱中培养24小时。
3.药物处理
5)准备21μM Estradiol的DMSO溶液,3×连续稀释,得到10个浓度。将5μL上诉Estradiol各浓度DMSO溶液分别加入 45μL DMEM+10%FBS,混匀,得到10个浓度的Estradiol稀释液。
6)准备210倍终浓度的待测化合物DMSO溶液,3×连续稀释,得到10个浓度的待测化合物稀释液。将5μL上诉各浓度DMSO溶液分别加入 45μL DMEM+10%FBS,混匀,得到10个浓度的稀释液。
7)每孔中(已有100μL细胞)加入5μL Estradiol稀释液或待测化合物稀释液。Min孔中加5μL 10%DMSO培养基,Max孔中加入5μL 2.1μM Estradiol(溶于培养基,10%DMSO)。
8)将检测板放回培养箱中孵育24小时。
4.荧光素酶检测
使用Promega的Dual-Glo Luciferase Assay System试剂盒检测待测板,使用Enspire分别读取Firefly luciferase荧光信号以及Renilla Luciferase荧光信号。
5.数据处理
9)最终测量值是Firefly luciferase荧光信号除以Renilla Luciferase荧光信号后得到的标准化数值“F/R”。
10)将数据复制粘贴到Excel中,通过方程得到激活率。
11)将数据导入MS Excel并使用XLFit excel add-in version 5.4.0.8进行曲线拟合,得到EC
50值
公式:Y=Bottom+(Top-Bottom)/(1+(EC50/X)^HillSlope
Y是激动率,X是化合物浓度。
表10 ERα荧光素酶报告基因实验结果
Compound ID | ERαEC50(nM) |
Dexamethasone | >1000.00 |
化合物4 | >1000.00 |
化合物5 | >1000.00 |
化合物3 | >1000.00 |
根据表10结果,本发明化合物对雌激素受体有较低的亲和力。
实施例7本发明化合物对R848诱导的人外周血单核细胞IFNα和TNFα抑制作用
试验目的
检测本申请化合物对外周血单核细胞产生的抑制作用。以不同浓度的配体药物偶联物体外处理外周血单核细胞,一定时间后对外周血单核细胞产生的IFNα和TNFα进行定量检测。评价本发明化合物的体外活性。
试验方法
复苏冻存的人PBMC细胞,用完全培养基重悬细胞后计数,并将细胞悬液用培养液调整到2.5×10^6细胞/毫升培养过夜。第二天离心收集细胞后,使用新鲜培养液重悬细胞。将受试化合物用细胞培养液稀释到4倍终浓度,将50μl化合物加入96孔细胞板中,在含有化合物的96孔板中每孔加入100μl稀释后的细胞(800,000细胞/孔)后加入50μl R848至终浓度5μM。将细胞板放入37℃,5%CO2培养24h。。收集上清,利用ELISA试剂盒检测上清液中TNF-α和IFN-α浓度水平。
TNF-α浓度检测,使用达科卫TNF-αELISA试剂盒(货号1117202)进行检测,每孔加 入100μl梯度稀释后的Cytokine standard至标准品孔,加入100μl 10倍稀释的上述上清液至样本孔,加入1×Dilutionbuffer R 100μl至空白对照孔。每孔加入Biotinylated antibody工作液50μl。混匀后盖上封板膜,室温孵育3小时。洗板3次:扣去孔内液体,每孔加入1×Washing buffer工作液300μl;停留1分钟后弃去孔内液体。重复3次。每孔加入Streptavidin-HRP工作液100μl。盖上封板膜,室温孵育20分钟。洗板3次,每孔加入TMB液体100μl,室温(18-25℃)避光孵育25分钟。迅速每孔加入100μl Stop solution终止反应。终止后10分钟内,用M2e仪器检测波长450nm读值。
IFN-α浓度检测,使用达科卫IFN-αELISA试剂盒(货号1110012)进行检测,每孔加入100μl梯度稀释后的Cytokine standard至标准品孔,加入100μl 2倍稀释的上述上清液至样本孔,加入1×Dilutionbuffer R 100μl至空白对照孔。每孔加入Biotinylated antibody工作液50μl。混匀后盖上封板膜,室温孵育3小时。洗板3次:扣去孔内液体,每孔加入1×Washing buffer工作液300μl;停留1分钟后弃去孔内液体。重复3次。每孔加入Streptavidin-HRP工作液100μl。盖上封板膜,室温孵育20分钟。洗板3次,每孔加入TMB液体100μl,室温(18-25℃)避光孵育25分钟。迅速每孔加入100μl Stop solution终止反应。终止后10分钟内,用M2e仪器检测波长450nm读值。
通过OD450值计算TNF-α和IFN-α的含量。结果见表11-1和表11-2。
表11-1化合物抑制R848刺激条件下PBMC分泌TNF-α(pg/ml)
TNF-α含量用平均值±标准差表示。
表11-2化合物抑制R848刺激条件下PBMC分泌IFN-α(pg/ml)
IFN-α含量用平均值±标准差表示。
结果显示,本申请的化合物可以影响外周血单核细胞产生TNF-α和IFN-α的能力。本申请的配体药物偶联物可以具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
实施例8本发明药物偶联物对R848诱导的人外周血单核细胞IFNα、TNFα、IL-6和IL-8的抑制作用
试验目的
检测本申请配体药物偶联物(ADC)对外周血单核细胞产生IFNα的抑制作用。以不同浓度的配体药物偶联物体外处理外周血单核细胞,一定时间后对外周血单核细胞产生的IFNα和TNFα进行定量检测。评价配体药物偶联物的体外活性。
试验方法
复苏冻存的人PBMC细胞,用完全培养基重悬细胞后计数,并将细胞悬液用培养液调整到2.5×10^6细胞/毫升培养过夜。第二天离心收集细胞后,使用新鲜培养液重悬细胞,取100μl稀释后的细胞(800,000细胞/孔)加入96孔板中。使用新鲜培养液稀释待测样品至3倍最终刺激浓度,将50μl稀释后的测试物加入96孔细胞板中,将细胞板放入37℃,5%CO2培养12小时后每孔加入50μl 20μM R848。将细胞板放入37℃,5%CO2继续培养20h。收集上清,利用试剂盒检测上清液中细胞因子浓度。
TNF-α浓度检测,使用达科卫TNF-αELISA试剂盒(货号1117202)进行检测,每孔加入100μl梯度稀释后的Cytokine standard至标准品孔,加入100μl 10倍稀释的上述上清液至样本孔,加入1×Dilutionbuffer R 100μl至空白对照孔。每孔加入Biotinylated antibody工作液50μl。混匀后盖上封板膜,室温孵育3小时。洗板3次:扣去孔内液体,每孔加入1×Washing buffer工作液300μl;停留1分钟后弃去孔内液体。重复3次。每孔加入Streptavidin-HRP工作液100μl。盖上封板膜,室温孵育20分钟。洗板3次,每孔加入TMB液体100μl,室温(18-25℃)避光孵育25分钟。迅速每孔加入100μl Stop solution终止反应。终止后10分钟内,用M2e仪器检测波长450nm读值。
IFN-α浓度检测,使用达科卫IFN-αELISA试剂盒(货号1110012)进行检测,每孔加入100μl梯度稀释后的Cytokine standard至标准品孔,加入100μl 2倍稀释的上述上清液至样本孔,加入1×Dilutionbuffer R 100μl至空白对照孔。每孔加入Biotinylated antibody工作液50μl。混匀后盖上封板膜,室温孵育3小时。洗板3次:扣去孔内液体,每孔加入1×Washing buffer工作液300μl;停留1分钟后弃去孔内液体。重复3次。每孔加入Streptavidin-HRP工作液100μl。盖上封板膜,室温孵育20分钟。洗板3次,每孔加入TMB液体100μl,室温(18-25℃)避光孵育25分钟。迅速每孔加入100μl Stop solution终止反应。终止后10分钟内,用M2e仪器检测波长450nm读值。
IL-6浓度检测,使用达科卫IL-6ELISA试剂盒(货号DKW12-1060-096)进行检测,每 孔加入100μl梯度稀释后的Cytokine standard至标准品孔,加入100μl 2倍稀释的上述上清液至样本孔,加入1×Dilutionbuffer R 100μl至空白对照孔。每孔加入Biotinylated antibody工作液50μl。混匀后盖上封板膜,室温孵育3小时。洗板3次:扣去孔内液体,每孔加入1×Washing buffer工作液300μl;停留1分钟后弃去孔内液体。重复3次。每孔加入Streptavidin-HRP工作液100μl。盖上封板膜,室温孵育20分钟。洗板3次,每孔加入TMB液体100μl,室温(18-25℃)避光孵育25分钟。迅速每孔加入100μl Stop solution终止反应。终止后10分钟内,用M2e仪器检测波长450nm读值。
IL-8浓度检测,使用达科卫IL-8ELISA试剂盒(货号1110802)进行检测,每孔加入100μl梯度稀释后的Cytokine standard至标准品孔,加入100μl 2倍稀释的上述上清液至样本孔,加入1×Dilutionbuffer R 100μl至空白对照孔。每孔加入Biotinylated antibody工作液50μl。混匀后盖上封板膜,室温孵育3小时。洗板3次:扣去孔内液体,每孔加入1×Washing buffer工作液300μl;停留1分钟后弃去孔内液体。重复3次。每孔加入Streptavidin-HRP工作液100μl。盖上封板膜,室温孵育20分钟。洗板3次,每孔加入TMB液体100μl,室温(18-25℃)避光孵育25分钟。迅速每孔加入100μl Stop solution终止反应。终止后10分钟内,用M2e仪器检测波长450nm读值。
通过OD450值计算TNF-α、IFN-α、IL-6和IL-8的含量,结果见图1a、1b、1c和1d。
根据图1a,抗体BIIB059、偶联物19、偶联物20、偶联物21的孵育浓度为300nm时,检测体系中IFN-α含量分别为1639.9pg/ml、113.2pg/ml、1422.5pg/ml、911.9pg/ml,偶联物19、偶联物20和偶联物21对IFNα的抑制作用优于抗体BIIB059,且偶联物19显著优于偶联物20和偶联物21。
根据图1b,浓抗体BIIB059、偶联物19、偶联物20、偶联物21的孵育浓度为300nm时,检测体系中TNF-α含量分别为7040.1pg/ml、761.8pg/ml、3280.0pg/ml、2644.1pg/ml,偶联物19、偶联物20和偶联物21对TNF-α的抑制作用优于抗体BIIB059,且偶联物19显著优于偶联物20和偶联物21。
根据图1c,抗体BIIB059、偶联物19、偶联物20、偶联物21的孵育浓度为300nm时,检测体系中IL-6含量分别为65932.1pg/ml、8861.7pg/ml、34744.1pg/ml、29867.1pg/ml,偶联物19、偶联物20和偶联物21对IL-6的抑制作用优于抗体BIIB059,且偶联物19显著优于偶联物20和偶联物21。
根据图1d,抗体BIIB059、偶联物19、偶联物20、偶联物21的孵育浓度为300nm时,检测体系中IL-8含量分别为86905.7pg/ml、26565.5pg/ml、56315.8pg/ml、43544.9pg/ml, 偶联物19、偶联物20和偶联物21对IL-8的抑制作用优于抗体BIIB059,且偶联物19显著优于偶联物20和偶联物21。
结果显示,本申请的配体药物偶联物可以影响外周血单核细胞产生IFNα,TNFα,IL-6,IL-8的能力。本申请的配体药物偶联物可以具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
实施例9异硫氰酸荧光素(FITC)诱导的迟发型IV型超敏反应小鼠模型中的生物活性测定
在急性接触性超敏反应模型中评估ADC,所述模型是通过应用敏化剂(异硫氰酸荧光素,FITC),使用迟发型超敏反应(delayed type hypersensitivity,DTH)响应(T细胞驱动)引发急性皮肤炎症。通过减少耳朵肿胀的能力来测量本申请配体药物偶联物(ADC)的药效。实验开始前选取规定数量周龄为7-9周的雌性Balb/c,根据小鼠体重进行随机分组,每组10只小鼠,保证不同组间平均体重值相近以减少组间差异。将小鼠分组当天定义为实验第0天。随机分组后,所有小鼠在5%异氟烷轻度麻醉状态下,剃掉小鼠腹部毛发,疾病诱导组中小鼠于腹部涂抹100微升浓度为2%的异硫氰酸荧光素(FITC)溶液进行第一次致敏,同时疾病对照组中小鼠于腹部涂抹100微升溶媒对照溶液(丙酮:DBP,体积比1:1)。待溶媒溶液和2%FITC溶液吸收且腹部皮肤干燥后,待小鼠苏醒后放置回笼盒中。在实验第1天,重复上述描述步骤进行第二次2%FITC致敏。
实验第5天,所有小鼠进行体重称量。根据实验设计,溶媒对照组或各治疗组中小鼠分别腹腔注射无菌PBS溶液或指定给药溶液。给药1小时后,所有小鼠在5%异氟烷轻度麻醉状态下使用Mitutoya Caliper测量左耳及右耳的厚度。耳朵厚度测量后,疾病诱导组中所有小鼠于右耳处涂抹10微升1%FTIC溶液,于左耳处涂抹10微升溶媒对照溶液(丙酮:DBP,体积比1:1)。
实验第6天,在1%FTIC激发24小时后,所有小鼠在5%异氟烷轻度麻醉状态下使用Mitutoya Caliper测量左耳及右耳的厚度,并根据如下公式计算小鼠耳朵厚度变化:(R-L)-(R0-L0),其中R0和L0分别为1%FITC激发前小鼠右耳及左耳厚度,R和L分别为1%FITC激发24小时后小鼠右耳及左耳厚度。结果见图2。
根据图2所示,偶联物9、抗体8c11和偶联物14(参照ADC1)的给药浓度为20mg/kg时,小鼠耳厚度平均增加分别为0.066mm、0.249mm和0.128mm。偶联物9对超敏反应的抑制作用显著优于抗体8c11和偶联物14。
结果显示,本申请配体药物偶联物(ADC)具有抑制超敏反应能力,本申请配体药物偶 联物(ADC)可以用于预防和/或治疗炎症的疾病和或症状。
实施例10 II型牛胶原混合佐剂诱导的DBA/1小鼠关节炎模型的生物活性测定
胶原诱导的关节炎(CIA)模型中评估本申请配体药物偶联物(ADC)的药效。
雄性DBA/1J小鼠获自杰克逊实验室(Jackson Labs)。小鼠在6至8周龄时使用。将所有动物在12小时的明/暗循环下,在恒定的温度和湿度下,自由饮食饮水。监测体重和状况,并且如果呈现出>20%的体重减轻,则对动物实施安乐死。
牛胶原(Chondrex,Inc.Cat:20021)溶解于0.1M乙酸中,2-8C冰箱过夜,胶原浓度为8mg/mL,向胶原溶液中加入等体积CFA(完全弗氏佐剂,Difco,Laurence,KS),用高速匀浆机乳化胶原制成乳剂。Day 0,将需要免疫动物用2%-5%异氟烷麻醉后,在距离身体2-3cm尾根部皮下单点注射 50μL胶原/CFA乳剂进行一次免疫免疫雄性DBA/J小鼠。三周后,即第21天(Day 21),于尾根部同法注射相同体积胶原乳剂进行二次免疫。二次免疫后,挑选120只四肢关节炎评分平均分约等于2分的动物,随机分组。分组后动物按照实验设计单次腹腔注射治疗测试试剂。对于Dexamethasone(上海上药信谊药厂有限公司)治疗组,分组后当天给药直至试验结束。自二次免疫后开始,每周两次观察每组动物四肢的关节炎发病情况,一直持续到试验结束。
根据病变的不同程度(红肿)按照0-4分的标准进行评分,每个肢体的最高评分为4分,每只动物四肢总和最高评分为16分。评分标准如下:0分,无红肿;1分,1~2个指间关节红肿;2分,3~4个指间关节红肿;3分,4个以上指间关节红肿;4分,脚趾或手指到踝关节或腕关节严重红肿。对于关节肿胀,一次免疫前,用螺旋测微器测量每只动物后足的足踝厚度。自二次免疫后,每周测量2次,并比较免疫前后足踝的厚度的变化。试验结束后,所有动物经2-5%异氟烷麻醉后,利用放血法进行安乐死处理。
评分AUC:关节炎评分的曲线下面积。
结果见图3a和3b。
结果显示,与空白试剂相比,本申请配体药物偶联物(ADC)具有降低小鼠后爪肿胀的能力,可以呈现出约28天的延长的作用持续时间,本申请配体药物偶联物(ADC)具有降低关节炎严重程度的能力和生物安全性(例如血液安全性)。
实施例11
11.1 GRE活性测定
人和小鼠跨膜TNF-αGRE报告细胞系的产生
为了产生亲本细胞系,在37℃,5%CO
2下,在24小时内,将K562细胞以每孔500,000个细胞接种到具有2mL的完全生长培养基(RPMI,10%FBS,1%L-谷氨酰胺,1%丙酮酸钠和1%MEMNEAA(非必需氨基酸溶液))的6孔培养皿((柯仕达)Costar:3516)上。第二天,将1.5μg的pGL4.36[Luc2P/MMTV/Hygro](Promega)和3uL的PLUS试剂(Invitrogen))稀释到244μL的Opti-MEM(Gibco:31985-070)中,并在室温下孵育15分钟。pGL4.36[luc2P/MMTV/Hygro]载体含有鼠乳腺肿瘤病毒长末端重复序列,其响应于若干种核受体(例如糖皮质激素受体和雄激素受体)的激活而驱动荧光素酶报告基因luc2P的转录。在孵育后,将稀释的DNA溶液与1∶1脂转染胺(Lipofectamine)LTX溶液(13.2μL+256.8μLOpti-MEM)进行预孵育,并在室温下孵育25分钟以形成DNA-脂转染胺LTX复合物。在孵育后,将500μL的DNA-脂转染胺复合物直接添加到含有细胞的孔中。将K562细胞在37℃,5%CO
2下转染24小时。在孵育后,将细胞用3mL的PBS洗涤,并用含有125μg/mL的潮霉素B的完全生长培养基选择两周。产生“K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]”细胞。
为了产生鼠跨膜TNF-αGRE报告细胞,在37℃,5%CO
2下,在24小时内,将亲本细胞K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]以每孔500,000个细胞接种到含有2mL的完全生长培养基(RPMI,10%FBS,1%L-谷氨酰胺,1%丙酮酸钠和1%MEMNEAA)的6孔培养皿上。第二天,将3μg的编码未标记的小鼠TNF的mFL_TNFαDNA和3μL的PLUS试剂(英杰公司:10964-021)稀释到244μL的Opti-MEM(Gibco:31985-070)中,并在室温下孵育15分钟。在孵育后,将稀释的DNA溶液用1∶1脂转染胺LTX溶液)(13.2μL+256.8μLOpti-MEM)预孵育,并在室温下孵育25分钟,以形成DNA-脂转染胺LTX复合物。在孵育后,将500μL的DNA-脂转染胺复合物直接添加到含有细胞的孔中。将亲本K562pGL4.36\[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]细胞在37℃,5%CO
2下转染24小时。在孵育后,将细胞用3mL的PBS洗涤,并用含有125μg/mL的潮霉素B(英杰公司:10687-010)和250μg/mLG418(Gibco:10131-027)的完全生长培养基选择两周。产生“K562小鼠FL-TNFαGRE(pGL4.36[luc2P/MMTV/Hygro])”细胞。
为了产生人跨膜TNF-αGRE报告细胞系,用质粒hTNFδ1-12C-MycpcDNA3.1(-)质粒构建体来转染亲本细胞K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]。所述质粒是pcDNA3.1(赛默飞世尔,目录号V79020),其编码tace抗性跨膜TNF。(参见PerezC等人,《细胞(Cell)》63(2):251-8(1990),其讨论了tace抗性跨膜TNF。)。产生“K562人TNFδ1-12GRE(pGL4.36[luc2P/MMTV/Hygro])”细胞。然后将这些细胞系用于在随后的实例中描述的 TNF-α报告测定中。
将K562亲本GRE细胞(“K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]”细胞),和GRE-小鼠TNF-α细胞(“K562小鼠FL-TNFαGRE(pGL4.36[luc2P/MMTV/Hygro])”细胞)或GRE-人TNF-α细胞(“K562人TNFδ1-12GRE(pGL4.36[luc2P/MMTV/Hygro])”细胞),以每孔50,000个细胞接种到96孔板上。将本申请配体药物偶联物(ADC)用培养基以3X系列稀释后加入上述96孔板中,在37℃,5%CO
2下孵育48小时。用荧光素酶测定系统处理后分析发光。使用四参数曲线拟合分析数据以产生EC
50值。将最大活化%归一化为100nM地塞米松。本申请配体药物偶联物(ADC)在小鼠跨膜TNFαGRE报告测定中测体外活性;和在本申请配体药物偶联物(ADC)在人跨膜TNFαGRE报告测定中测体外活性
结果显示,本申请配体药物偶联物(ADC)具有影响细胞GRE激活水平的能力,本申请配体药物偶联物(ADC)可以影响糖皮质激素介导的信号通路的激活水平。
11.2脂多糖(LPS)诱导细胞因子释放及下游信号检测
原代人外周血单核细胞(PBMC)在50mL PBS中洗涤,重悬于具有5%DMSO的FBS(胎牛血清)中,等分并冷冻保存在液氮中直到使用。将PBMC解冻,重悬于有2%FBS和1%青霉素链霉素的细胞培养基(如RPMI细胞培养基)中,并且接种96孔板中。然后将细胞在37℃和5%CO
2下用不同浓度ADC孵育4小时。用一定浓度脂多糖(Lipopolysaccharides,LPS)等刺激物处理一定时间。随后将板以1000rpm旋转5分钟,并且将100μL的上清液培养基直接转移到另一个96孔板中,并分析IL-6和IL-1β等细胞因子浓度及磷酸化STAT1水平。
结果显示,本申请配体药物偶联物(ADC)具有影响PBMC细胞释放细胞因子的能力,如IL-6和IL-1β等,以及磷酸化STAT1的能力。
实施例12
12.1 I型干扰素诱导的响应原件信号检测
向HEK293细胞构建转入pHTS-ISRE荧光素报告基因质粒,构建I型干扰素响应信号的报告系统。细胞培养于含有一定浓度FBS和Geneticin的DMEM培养基,向其中加入梯度稀释的配体药物偶联物和一定浓度浆细胞样树突细胞诱导产生的I型干扰素IFN或重组I型干扰素进行孵育。裂解细胞,确定荧光素强度,使用非线性回归将剂量响应数据拟合为S形曲线,计算IC
50值。
结果显示,本申请的配体药物偶联物可以影响I型干扰素诱导的响应原件信号。本申请的配体药物偶联物可以具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
12.2 CpG-A等诱导细胞因子释放及下游信号分子检测
原代人外周血单核细胞(PBMC)在50mL PBS中洗涤,重悬于具有5%DMSO的FBS(胎牛血清)中,等分并冷冻保存在液氮中直到使用。将PBMC解冻,重悬于有2%FBS和1%青霉素链霉素的细胞培养基(如RPMI细胞培养基)中,并且接种96孔板中。然后将细胞在37℃和5%CO
2下用不同浓度配体药物偶联物进行孵育。用一定浓度CpG-A或其他刺激物处理一定时间。随后将板以1000rpm旋转5分钟,并且将100μL的上清液培养基直接转移到另一个96孔板中,并分析IL-6和IL-1β等细胞因子水平。
向人外周血单核细胞中加入一定浓度的配体药物偶联物进行培养。随后向其中加入一定浓度浆细胞样树突细胞诱导产生的I型干扰素IFN或重组I型干扰素进行孵育。裂解细胞进行电泳和western blot检测,利用抗人STAT1pTY701抗体确定STAT1磷酸化水平。
结果显示,本申请配体药物偶联物(ADC)具有影响PBMC细胞释放细胞因子的能力,以及磷酸化STAT1的能力。
12.3浆细胞样树突细胞异种移植老鼠模型中的药效评估
试验目的
将本申请配体药物偶联物(ADC)作用于人浆细胞样树突细胞异种移植老鼠模型,利用免疫组化,基因转录分析等手段评估配体药物偶联物的体内药效。
试验方法
1、咪喹莫特诱导模型
用4至8周龄的重度免疫缺陷小鼠(CB17/Icr-Prkdcscid/IcrIcoCrl,Charles River),剃毛背部。将5%咪喹莫特乳膏涂抹于小鼠背部,12小时后进行第二次涂抹。随后小鼠腹腔注射一定浓度的本申请配体药物偶联物或对照配体药物偶联物。12小时后向小鼠尾静脉注射1~10x10
5人浆细胞样树突细胞。再经12小时培养后,对小鼠实行安乐死,收集背部皮肤样品,进行检测。
2.博来霉素诱导模型
用4至8周龄的重度免疫缺陷小鼠(CB17/Icr-Prkdcscid/IcrIcoCrl,Charles River),剃毛背部。将一定浓度的博来霉素皮下注射于小鼠背部单一位点,每两天一次持续注射三周。在第一次博来霉素注射的第0,7,14天向小鼠尾静脉注射1~10x10
5人浆细胞样树突细胞。第一次博来霉素注射前24小时向小鼠腹腔注射一定浓度的本申请配体药物偶联物或对照配体药物偶联物,每5天一次注射。
3、检测方法与指标
(1)试剂盒抽提小鼠皮肤细胞RNA并反转录为cDNA,利用Real-time PCR,以对照配体药物偶联物处理小鼠样品为对照,确定配体药物偶联物对I型IFN信号途径应答基因转录的影响。
(2)小鼠皮肤样品用福尔马林固定并包埋于石蜡中,对石蜡以5μM切片,进行苏木精-伊红染色。以Masson染色法鉴定皮肤样品的纤维化程度。以pSTAT1 Tyr701抗体进行免疫组化分析。
(3)小鼠皮肤样品经处理后进行FACS分析,根据细胞表面标记物确定其中浆细胞样树突细胞所占比例。
(4)小鼠皮肤样品经处理后利用胶原分析方法进行胶原含量测定。
结果显示,本申请的配体药物偶联物可以影响(1)I型IFN信号途径应答基因转录能力、(2)影响皮肤样品纤维化的程度、(3)影响浆细胞样树突细胞增殖能力和/或(4)影响皮肤样品胶原含量。本申请的配体药物偶联物在体内可以具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
实施例13
13.1 CD40L和LPS诱导的人外周血单核细胞来源树突状细胞的细胞因子释放实验
准备新鲜人外周血单个核细胞(PBMC)。用人单核细胞(CD14+)分离试剂盒分离人单核细胞。洗涤后将细胞重悬,并加入人IL-4(80ng/mL)和人GM-CSF(100ng/mL),置于培养箱培养5天。
收集细胞,洗涤后以105/孔加入到96孔平底板中,用0.1ng/mL LPS刺激细胞2小时,然后洗掉上清。加入一定浓度的阳性化合物,孵育2小时。加入1μg/mL MegaCD40L和0.2ng/mL LPS,37℃,5%CO2培养箱孵育20小时。离心收集细胞上清,利用试剂盒检测上清中TNFα和IL-6的水平。使用非线性回归将剂量响应数据拟合为S形曲线,计算IC50值。
结果显示,本申请的配体药物偶联物可以抑制人外周血单核细胞来源树突状细胞的细胞因子释放。本申请的配体药物偶联物具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
13.2 LPS诱导的急性炎症模型的药效评估
将8-10周龄的CD40人源化雌性小鼠进行随机分组,向小鼠腹腔注射一定浓度的本申请配体药物偶联物或对照配体药物偶联物。2-16h后,向小鼠腹腔注射一定浓度的LPS。6小时后,收集100μl血样,利用试剂盒进行TNFα,IL-6和IL-1β含量的测定。再经18h后,对小鼠实施安乐死,收集脾脏进行单细胞处理,利用抗体对细胞进行染色,确定被激活的树突 状细胞的比例。
结果显示,本申请的配体药物偶联物可以抑制LPS诱导的急性炎症小鼠模型中细胞因子的释放,降低脾脏中活化的树突状细胞比例。本申请的配体药物偶联物具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
实施例14单次给药ADC的药代动力学和毒性研究
试验目的
猴单次静脉滴注本申请配体药物偶联物(ADC)后,考察药物在猴体内的药动学性质,同时观察动物的毒性表现。
试验方法
药代动力学:猴单次静脉滴注不同剂量的本申请配体药物偶联物(ADC)后,连续多个时间点采集血液样品,通过特异性检测方法检测药物在血液中的浓度。
毒性研究:猴单次静脉滴注不同剂量的本申请配体药物偶联物(ADC)后,通过临床观察、体重和摄食量、血液学、血生化、尿液、大体解剖等多个方面考察动物的耐受性,以及药物相关的毒性表现。
结果显示:(1)猴单次静脉滴注本申请配体药物偶联物(ADC)后,游离药物浓度很低,总抗体和本申请配体药物偶联物(ADC)的药代动力学性质相似,表明本申请配体药物偶联物(ADC)在猴中缓慢释放,偶联方式稳定,可以支持临床拟定的给药频率;(2)猴单次静脉滴注本申请配体药物偶联物(ADC)后,动物耐受性良好,未表现出严重或不可耐受的药物相关毒性,表明本申请配体药物偶联物(ADC)的安全性可控,可支持其进一步的临床应用。
前述详细说明是以解释和举例的方式提供的,并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的,且保留在所附的权利要求和其等同方案的范围内。
Claims (73)
- 式I的化合物:或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R 1、R 2、R 3、R 4和R 5各自独立地为任意基团;B不存在或B为任意基团;W不存在或W为任意基团;A1为取代的苯环;CR 4R 5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O) 2-、-C(=O)-、-C=C-和-C≡C-,其中R 4和R 5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;X选自:-O-,-S-,-NR-;Y 1为任意基团,m为0至4中的任意整数;其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR 2、-OC(O)NHR、-OC(O)NR 2、-SR、-S(O)R、-S(O) 2R、-NHR、-N(R) 2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O) 2NHR、-S(O) 2N(R) 2、-NHS(O) 2NR 2、-NRS(O) 2NR 2、-NHS(O) 2R、-NRS(O) 2R、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基。
- 根据权利要求1所述的式I的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其选自:其中,R 1、R 2、R 3、R 4和R 5各自独立地为任意基团;B不存在或B为任意基团;W不存在或W为任意基团;A1为取代的苯环;CR 4R 5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O) 2-、-C(=O)-、-C=C-和-C≡C-,其中R 4和R 5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;X选自:-O-,-S-,-NR-;Y 1为任意基团,m为0或1;其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR 2、-OC(O)NHR、-OC(O)NR 2、-SR、-S(O)R、-S(O) 2R、-NHR、-N(R) 2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O) 2NHR、-S(O) 2N(R) 2、-NHS(O) 2NR 2、-NRS(O) 2NR 2、-NHS(O) 2R、-NRS(O) 2R、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基和卤素取代的C 1-C 6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基。
- 根据权利要求1-2中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中X为-O-、-S-或-NH-。
- 根据权利要求1-3中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述CR 4R 5单元各自独立地不被替代或被选自以下组替代:-O-、-S-和-C(=O)-。
- 根据权利要求1-4中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中R 4和R 5各自独立地选自以下组:氢、氕、氘、氚、卤素、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-NH 2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中,当R 4和R 5包含亚甲基单元时,所述R 4和R 5的所述亚甲基单元各自独立地不被替代、或所述R 4和R 5的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O) 2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基。
- 根据权利要求5所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 4和R 5各自独立地选自:H、F、Cl、-OH、-NH 2和C 1-C 6烷基,或所述R 4和R 5一起形成C 3-C 6环烷基或3-6元杂环基;所述n选自1、2或3。
- 根据权利要求1-7中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述Y 1不存在或选自:氕、氘、氚、卤素、-OR、-SR、-NHR、-N(R) 2、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基;其中各R独立选自氢、氕、氘、氚、羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基。
- 根据权利要求1-8中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述Y 1不存在或选自:羟基、巯基、氨基和任选取代的C 1-C 6烷基。
- 根据权利要求1-10中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 1,R 2各自独立的选自:H,F,Cl,Br和任选取代的C 1-C 6烷基。
- 根据权利要求1-11中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 1,R 2各自独立的选自:H,F,Cl,Br和任选取代的甲基。
- 根据权利要求1-12中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 3选自:氢、任选取代的-OH、任选取代的-SH和任选取代的C 1-C 6烷基。
- 根据权利要求1-13中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 3选自:任选取代的-CH 2Cl、任选取代的-CH 2SH、任选取代的-CH 2OH、任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的-OH、任选取代的-OCH 3、任选取代的-OCH 2F、任选取代的-OCH 2Cl、任选取代的-OCH 2CN、任选取代的-OCH 2CH 3、任选取代的巯基、任选取代的-SCH 2F、任选取代的-SCH 2Cl、任选取代的-SCH 2CF 3、和任选取代的-SCH 2CN。
- 根据权利要求1-15中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述B选自:任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR 2、-OC(O)NHR、-OC(O)NR 2、-SR、-S(O)R、-S(O) 2R、-NHR、-N(R) 2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O) 2NHR、-S(O) 2N(R) 2、-NHS(O) 2NR 2、-NRS(O) 2NR 2、-NHS(O) 2R、-NRS(O) 2R、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、卤素、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基和卤素取代的C 1-C 6烷氧基。
- 根据权利要求1-18中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述W不存在或W选自:-S(=O)-、-S(=O) 2-、-O-、-S-、-C(=O)-、任选取代的-CH 2NHC(=O)-、任选取代的-NHC(=O)CH 2-、任选取代的-C(=O)NH-、任选取代的-NH-、任选取代的-CH=CH-、-C≡C-、任选取代的C 1-C 6亚烷基、任选取代的-OCH 2-、任选取代的-CH 2O-、任选取代的-SCH 2-、任选取代的-CH 2S-、任选取代的-NHC(=O)-、任选取代的-C(=O)CH 2-、任选取代的-CH 2NH-、任选取代的-NHCH 2-、任选取代的 任选取代的 任选取代的 任选取代的 和任选取代的
- 根据权利要求1-22中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其选自其中,所述X选自-O-,-S-和-NH-;R 4和R 5各自独立地选自以下组:H、F、Cl、-OH、-NH 2和C 1-C 6烷基;所述n选自1、2或3;所述Y 1不存在或选自:羟基、巯基、氨基和C 1-C 6烷基;所述R 1和R 2各自独立地选自氢、氟、氯和甲基;
- 式IIa或IIb的化合物:或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R 1、R 2、R 3、R 4和R 5各自独立地为任意基团;B不存在或B为任意基团;W不存在或W为任意基团;A2为取代的苯环;CR 4R 5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O) 2-、-C(=O)-、-C=C-和-C≡C-,其中R 4和R 5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;X选自:-O-,-S-,-NR-;Y 1为任意基团,m为0至4中的任意整数;Y 2选自-O-,-S-和-NR-;其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR 2、-OC(O)NHR、-OC(O)NR 2、-SR、-S(O)R、-S(O) 2R、-NHR、-N(R) 2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O) 2NHR、-S(O) 2N(R) 2、-NHS(O) 2NR 2、-NRS(O) 2NR 2、-NHS(O) 2R、-NRS(O) 2R、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基;其中各R独立选自氢、氕、氘、氚、氧、卤素、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、 环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基;
- 根据权利要求26所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 4和R 5各自独立地选自以下组:氢、氕、氘、氚、卤素、任选取代的-C(=O)H、任选取代的-OH、任选取代的-SH、任选取代的-NH 2、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基和任选取代的杂芳基;其中,当R 4和R 5包含亚甲基单元时,所述R 4和R 5的所述亚甲基单元各自独立地不被替代、或所述R 4和R 5的所述亚甲基单元各自独立地被选自以下组替代:-S(=O)-、-S(=O) 2-、-O-、-S-、-C(=O)-、任选取代的-PH-、任选取代的-P(=O)H-、任选取代的-NH-、任选取代的亚烷基、任选取代的亚烯基、任选取代的亚炔基、任选取代的亚环烷基、任选取代的亚杂环烷基、任选取代的亚芳基和任选取代的亚杂芳基。
- 根据权利要求27所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 4和R 5各自独立地选自以下组:H、F、Cl、-OH、-NH 2和C 1-C 6烷基;所述n选自1、2或3。
- 根据权利要求26-28中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,所述Y 1不存在或选自:-OR、-SR、-N(R) 2和任选取代的C 1-C 6烷基;其中各R独立选自氢、氕、氘、氚、C 1-C 6烷基、C 1-C 6烷氧基。
- 根据权利要求29所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,所述Y 1不存在或选自:羟基、巯基、氨基和C 1-C 6烷基。
- 根据权利要求26-31中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 1,R 2各自独立的选自:H,F,Cl,Br和任选取代的C 1-C 6烷基。
- 根据权利要求26-33中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 1,R 2各自独立的选自:H,F,Cl,Br和任选取代的甲基。
- 根据权利要求58-71中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 3选自:氢、任选取代的-OH、任选取代的-SH、和任选取代的C 1-C 6烷基。
- 根据权利要求26-34中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述R 3选自:任选取代的-CH 2Cl、任选取代的-CH 2SH、任选取代的-CH 2OH、任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的-OH、任选取代的-OCH 3、任选取代的-OCH 2F、任选取代的-OCH 2Cl、任选取代的-OCH 2CN、任选取代的-OCH 2CH 3、任选取代的巯基、任选取代的-SCH 2F、任选取代的-SCH 2Cl、任选取代的-SCH 2CF 3、和任选取代的-SCH 2CN。
- 根据权利要求26-36中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述B选自:任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 任选取代的 其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR 2、-OC(O)NHR、-OC(O)NR 2、-SR、-S(O)R、-S(O) 2R、-NHR、-N(R) 2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O) 2NHR、-S(O) 2N(R) 2、-NHS(O) 2NR 2、-NRS(O) 2NR 2、-NHS(O) 2R、-NRS(O) 2R、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基,其中各R独立选自氢、氕、氘、氚、氧、卤素、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基。
- 根据权利要求26-39中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述W不存在或W选自:-S(=O)-、-S(=O) 2-、-O-、-S-、-C(=O)-、任选取代的-CH 2NHC(=O)-、任选取代的-NHC(=O)CH 2-、任选取代的-C(=O)NH-、任选取代的-NH-、任选取代的-CH=CH-、-C≡C-、任选取代的C 1-C 6亚烷基、任选取代的-OCH 2-、任选取代的-CH 2O-、任选取代的-SCH 2-、任选取代的-CH 2S-、任选取代的-NHC(=O)-、任选取代的-COCH 2-、任选取代的-CH 2NH-、任选取代的-NHCH 2-、任选取代的-CH(CH 3)-、任选取代的 任选取代的 任选取代的 任选取代的 和任选取代的
- 根据权利要求26-43中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其选自其中,所述X选自-O-,-S-和-NH-;R 4和R 5各自独立地选自以下组:H、F、Cl、-OH、-NH 2和C 1-C 6烷基;所述n选自1、2或3;所述Y 1不存在或选自:羟基、巯基、氨基和C 1-C 6烷基;所述R 1和R 2各自独立地选自氢、氟、氯和甲基;
- 根据权利要求26-45中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、 外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,所述的化合物还包括Linker片段,所述的式IIa或IIb的化合物能够通过Linker片段与配体偶联,所述Linker片段包括L 1片段、L 2片段和/或L 3片段,所述化合物具有以下结构:其中,Tr不存在或Tr为任意基团;L 3选自多肽片段;L 2不存在或选自连接片段;L 1选自偶联单元;R 1、R 2、R 3、R 4和R 5各自独立地为任意基团;B不存在或B为任意基团;W不存在或W为任意基团;CR 4R 5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O) 2-、-C(=O)-、-C=C-和-C≡C-,其中R 4和R 5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;X选自:-O-,-S-,-NR-;Y 1为任意基团,m为0至4中的任意整数;Y 2选自-O-,-S-和-NR-;其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR 2、-OC(O)NHR、-OC(O)NR 2、-SR、-S(O)R、-S(O) 2R、-NHR、-N(R) 2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O) 2NHR、-S(O) 2N(R) 2、-NHS(O) 2NR 2、-NRS(O) 2NR 2、-NHS(O) 2R、-NRS(O) 2R、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基;其中各R独立选自氢、氕、氘、氚、氧、卤素、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基。
- 根据权利要求47所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述L 3选自二肽、三肽和四肽;所述二肽选自:GA、GG、AG、EG、EA、GE、DG、DA、GD、VC、VA、AA和VK,所述三肽选自:EAG、EGG、GEG、GEA、DAG、DGG、GDG、GDA、GGA、GAG、GFG、AAG、AAA、VAG、VCG、VKG,所述四肽选自:GGFG、GGAG、GGGG、GEGG、GEAG、GDGG、GDAG、AAAG和EAGG。
- 根据权利要求48所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述L 3选自以下组:甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)、丙氨酸-丙氨酸-丙氨酸-甘氨酸(AAAG)、甘氨酸-甘氨酸-甘氨酸-甘氨酸(GGGG)、缬氨酸-丙氨酸-甘氨酸(VAG)、缬氨酸-瓜氨酸-甘氨酸(VCG)、丙氨酸-丙氨酸-甘氨酸(AAG)、丙氨酸-丙氨酸-丙氨酸(AAA)、缬氨酸-丙氨酸(VA)、缬氨酸-瓜氨酸(VC)、丙氨酸-丙氨酸(AA)、谷氨酸-丙氨酸-甘氨酸-甘氨酸(EAGG)、甘氨酸- 谷氨酸-丙氨酸-甘氨酸(GEAG)、甘氨酸-谷氨酸-甘氨酸-甘氨酸(GEGG)、谷氨酸-甘氨酸-甘氨酸(EGG)、谷氨酸-丙氨酸-甘氨酸(EAG)、缬氨酸-赖氨酸-甘氨酸(VKG)、甘氨酸-谷氨酸-甘氨酸(GEG)、谷氨酸-丙氨酸(EA)、谷氨酸-甘氨酸(EG)和甘氨酸-谷氨酸(GE)。
- 根据权利要求46-49中任一项所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述L 2不存在,或L 2包含或不包含PEG支链或PEG直链。
- 根据权利要求26-45所述的式IIa或IIb的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述的化合物还包括Linker片段,所述的式IIa或IIb的化合物能够通过Linker片段与配体偶联,所述化合物具有以下结构:其中,Tr不存在或Tr为任意基团;L 3选自多肽片段;L 2不存在或选自连接片段;L 1选自偶联单元;通式IVa-1和IVb-1中L 1为连接形式;R 1、R 2、R 3、R 4、R 5、B、W、CR 4R 5、n、X、Y 1和Y 2分别如权利要求26-45中任一项所述;
- 一种偶联物,包含权利要求1-57中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,所述偶联物包含配体-药物偶联物。
- 根据权利要求58所述的偶联物,其中所述配体包括抗体或其抗原结合片段。
- 根据权利要求59所述的偶联物,其中所述抗体选自:人抗体、人源化抗体、嵌合抗体、多特异性抗体、单克隆抗体和多克隆抗体;所述抗原结合片段选自:Fab、Fab’、F(ab’)2、Fv、scFv、双抗体、Fd、dAb、VHH、大抗体和互补决定区(CDR)片段。
- 根据权利要求58-60所述的偶联物,其中所述配体特异性结合选自下组的抗原:AXL,BAFFR,BCMA,BCR–列表组分(BCR–list components),BDCA2,BDCA4,BTLA,BTNL2BTNL3,BTNL8,BTNL9,C10orf54,CCR1,CCR3,CCR4,CCR5,CCR6,CCR7,CCR9,CCR10,CD11c,CD137,CD138,CD14,CD163,CD168,CD 177,CD19,CD20,CD209,CD209L,CD22,CD226,CD248,CD25,CD27,CD274,CD276,CD28,CD30,CD300A,CD33,CD37,CD38,CD4,分化抗原簇40(CD40),CD44,CD45,CD46,CD47,CD48,CD5,CD52,CD55,CD56,CD59,CD62E,CD68,CD69,CD70,CD74,CD79a,CD79b,CD8,CD80,CD86,CD90.2,CD96,CLEC12A,CLEC12B,CLEC7A,CLEC9A,CR1,CR3,CRTAM,CSF1R,CTLA4,CXCR1/2,CXCR4,CXCR5,DDR1,DDR2,DEC-205,DLL4,DR6,FAP,FCamR,FCMR,FcR’s,Fire,GITR,HHLA2,II型HLA(HLA class II),HVEM,ICOSLG,IFNAR,I型干扰素受体亚基(IFNAR1),IFNLR1,IL10R1,IL10R2,IL12R,IL13RA1,IL13RA2,IL15R,IL17RA,IL17RB,IL17RC,IL17RE,IL20R1,IL20R2,IL21R,IL22R1,IL22RA,IL23R,IL27R,IL29R,IL2Rg,IL31R,IL36R,IL3RA,IL4R,IL6R,IL5R,IL7R,IL9R,整合素(Integrins),LAG3,LIFR,MAG/Siglec-4(唾液酸结合性免疫球蛋白样凝集素-4),MMR,MSR1,NCR3LG1,NKG2D,NKp30,NKp46,OX40(CD134),PDCD1,PROKR1,PVR,PVRIG,PVRL2,PVRL3,RELT,SIGIRR,Siglec-1(唾液酸结合性免疫球蛋白样凝集素-1),Siglec-10,Siglec-5,Siglec-6,Siglec-7,Siglec-8,Siglec-9,SIRPA, SLAMF7,TACI,TCR–列表组分/assoc(TCR-listcomponents/assoc),PTCRA,TCRb,CD3z,CD3,TEK,TGFBR1,TGFBR2,TGFBR3,TIGIT,TLR2,TLR4,肿瘤坏死因子α(TNFα),TROY,TSLPR,TYRO,VLDLR,VSIG4,IL2R-y和VTCN1。
- 根据权利要求61所述的偶联物,其中所述配体选自:抗TNFα抗体或其抗原结合片段,抗CD40抗体或其抗原结合片段和抗IFNAR1抗体或其抗原结合片段。
- 根据权利要求58-62所述的偶联物,其中所述配体选自:阿达木单抗(Adalimumab)、Iscalimab(CFZ533)、Anifrolumab(MEDI-546)、英利昔单抗(Infliximab)、阿非莫单抗(Afelimomab)、戈利木单抗(golimumab)、BIIB059、8c11、其衍生物、其生物类似物。
- 根据权利要求58-63所述的偶联物,其中所述配体-药物偶联物具有以下结构:其中,Ab代表能够与靶标结合的配体,N a-I为1至10中的任意数字;Tr不存在或Tr为任意基团;L 3选自多肽片段;L 2不存在或选自连接片段;L 1选自偶联单元;R 1、R 2、R 3、R 4和R 5各自独立地为任意基团;B不存在或B为任意基团;W不存在或W为任意基团;CR 4R 5单元各自独立地不被替代或被选自以下组替代:-O-、-S-、-NR-、-S(O)-、-S(O) 2-、-C(=O)-、-C=C-和-C≡C-,其中R 4和R 5可一起形成任选取代的环烷基、任选取代的杂环基、任选取代的桥环基、任选取代的杂桥环基、任选取代的螺环基和任选取代的杂螺环基,n为1-20中的任意整数;X选自:-O-,-S-,-NR-;Y 1为任意基团,m为0至4中的任意整数;Y 2选自-O-,-S-和-NR-;其中取代基选自:氕、氘、氚、卤素、-CN、=O、=N-OH、=N-OR、=N-R、-OR、-C(O)R、-C(O)OR、-OC(O)R、-OC(O)OR、-C(O)NHR、-C(O)NR 2、-OC(O)NHR、-OC(O)NR 2、-SR、-S(O)R、-S(O) 2R、-NHR、-N(R) 2、-NHC(O)R、-NRC(O)R、-NHC(O)OR、-NRC(O)OR、-S(O) 2NHR、-S(O) 2N(R) 2、-NHS(O) 2NR 2、-NRS(O) 2NR 2、-NHS(O) 2R、-NRS(O) 2R、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基;其中各R独立选自氢、氕、氘、氚、氧、卤素、C 1-C 6烷基、C 1-C 6烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤素取代的C 1-C 6烷基、和卤素取代的C 1-C 6烷氧基。
- 根据权利要求58-65所述的偶联物,其中所述配体-药物偶联物具有以下结构:其中,Ab代表能够与靶标结合的配体,N a-I为1至10中的任意数字;所述X选自-O-,-S-和-NH-;R 4和R 5各自独立地选自以下组:H、F、Cl、-OH、-NH 2和C 1-C 6烷基;所述n选自1、2或3;所述Y 1不存在或选自:羟基、巯基、氨基和C 1-C 6烷基;所述R 1和R 2各自独立地选自氢、氟、氯和甲基;
- 一种药物组合物,其包含权利要求1-57中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐和/或权利要求58-68中任一项所述的偶联物,以及任选地药学上可接受的载体。
- 一种影响免疫系统功能的方法,包括向受试者施用权利要求1-57中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐、权利要求58-68中任一项所述的偶联物和/或权利要求69所述的药物组合物。
- 权利要求1-57中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐、权利要求58-68中任一项所述的偶联物和/或权利要求69所述的药物组合物在制备药物中的用途,所述药物用于预防和/或治疗疾病和/或症状,所述疾病和/或症状包含与糖皮质激素受体信号转导相关的疾病和/或症状。
- 根据权利要求72所述的用途,所述疾病和/或症状选自以下组:类风湿关节炎、系统性红 斑狼疮、硬皮病、干燥综合症、强直性脊柱炎、韦格纳肉芽肿病和系统性硬化、自身免疫性溶血性贫血、恶性贫血、特发性血小板减少性紫癜、特发性血小板减少症和血管炎、多发性硬化、重症肌无力和古兰巴雷综症、溃疡性结肠炎、克罗恩病、自身免疫性病和萎缩性胃炎、IgA肾病、原发性肾病综合征、自身免疫性肾小球肾炎、肺肾出血综合征和狼疮肾炎、I型糖尿病、Grave's病、桥本甲状腺炎、原发性肾上腺皮质萎缩和慢性甲状腺炎、银屑病、寻常型天孢疹、皮肤红斑狼疮、皮肌炎和风湿性多肌痛和哮喘。
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