WO2024114677A1 - Preparation, application and use of benzospiroindole compounds - Google Patents

Preparation, application and use of benzospiroindole compounds Download PDF

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Publication number
WO2024114677A1
WO2024114677A1 PCT/CN2023/134984 CN2023134984W WO2024114677A1 WO 2024114677 A1 WO2024114677 A1 WO 2024114677A1 CN 2023134984 W CN2023134984 W CN 2023134984W WO 2024114677 A1 WO2024114677 A1 WO 2024114677A1
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alkyl
cycloalkyl
compound
pharmaceutically acceptable
acceptable salt
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PCT/CN2023/134984
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French (fr)
Chinese (zh)
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周明伟
别平彦
彭建彪
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上海济煜医药科技有限公司
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Publication of WO2024114677A1 publication Critical patent/WO2024114677A1/en

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  • the present invention belongs to the field of pharmaceutical chemistry, and in particular, relates to the preparation, application and use of benzospiroindole compounds.
  • the complement system is a critical component of the innate immune system and includes a group of proteins that are usually present in an inactive state. These proteins are organized in three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Molecules, antibodies, or cellular components from microorganisms can activate these pathways, leading to the formation of protease complexes called C3-convertase and C5-convertase.
  • the classical pathway is a calcium/magnesium-dependent cascade that is usually activated by the formation of antigen-antibody complexes. It can also be activated by the binding of C-reactive protein complexed with ligands and by many pathogens (including Gram-positive bacteria) in an antibody-independent manner.
  • the alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain sensitive surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
  • the present invention provides a compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from C(R 5 ) 2 , O or N(R 5 );
  • R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-9 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl or C 3-9 cycloalkyl is optionally substituted with 1, 2 or 3 R;
  • R 2 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
  • L is selected from a single bond, O, S, NH, The NH Optionally substituted with 1, 2 or 3 R;
  • R3 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
  • R4 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
  • R 3 and R 4 are linked together to form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;
  • R5 is selected from H, F, Cl, CN, OH, C1-6 alkyl, C1-6 heteroalkyl and C3-9 cycloalkyl, wherein the C1-6 alkyl, C1-6 heteroalkyl or C3-9 cycloalkyl The group is optionally substituted with 1, 2 or 3 R;
  • R 6 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally substituted with 1, 2 or 3 R;
  • R is independently selected from OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;
  • the present invention also provides a compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, the structure of which is shown below:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
  • R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino and C 3-6 cycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino or C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 1 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
  • R2 is selected from H, OH, CN, F, Cl, Br, I, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 2 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
  • R3 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio and 3-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 3 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
  • R4 is selected from H, OH, CN, F, Cl, Br, I, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino and 3-6 membered heterocycloalkyl, wherein the C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 4 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , The CH 3 , Optionally substituted with 1, 2 or 3 R.
  • R 4 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
  • R3 and R4 are connected together to form a C3-6 cycloalkyl or a 3-6 membered heterocycloalkyl, which means that R3 and R4 are connected together, together with L and the carbon atoms on the ring connected to R4 , form a C3-6 cycloalkyl or a 3-6 membered heterocycloalkyl.
  • R3 and R4 are linked together to form Said Optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.
  • R3 and R4 are linked together to form Other variables are as defined herein.
  • R 5 is selected from H, F, Cl, CN, OH, CH 3 , Other variables are as defined herein.
  • the present invention also provides a compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, which is selected from:
  • the present invention also provides a pharmaceutical composition.
  • the pharmaceutical composition protects the aforementioned compound, its optical isomer or a pharmaceutically acceptable salt thereof.
  • the above-mentioned pharmaceutical composition further comprises a pharmaceutical excipient.
  • the present invention also provides the use of the above-mentioned compound, its optical isomer or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and/or preventing diseases related to complement factor B activity and expression.
  • the object of the present invention is to provide a compound as a complement factor B inhibitor or its stereoisomers, deuterated products, solvent compounds, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods, as well as their use in the preparation of drugs for treating diseases related to complement factor B activity and expression.
  • the compounds of the present invention can be used to treat and/or prevent diseases mediated by complement factor B (Factor B), involvement of the complement system, or some kidney diseases or disorders with significant unmet needs, including IgA nephropathy (IgAN), C3 glomerular disease (C3G), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN), paroxysmal nocturnal hemoglobinuria (PNH), etc., as well as other diseases related to the complement cascade, including age-related macular degeneration (AMD), geographic atrophy (GA), hemodialysis complications, neuromyelitis (NMO), liver diseases, inflammatory bowel disease, myasthenia gravis (MG) and other diseases.
  • IgA nephropathy IgAN
  • C3G C3 glomerular disease
  • aHUS atypical hemolytic uremic syndrome
  • MN membranous nephropathy
  • PNH paroxysmal nocturnal hemoglobinuria
  • the phrase "at least one" used when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements.
  • This definition also allows that there may be optionally elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic functional groups, and
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are prepared by reacting with a stoichiometric amount of an appropriate base or acid.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.
  • a hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent.
  • C1-6 alkylcarbonyl- refers to a C1-6 alkyl group that is attached to the rest of the molecule via a carbonyl group.
  • the "-" may be omitted.
  • the dashed line indicates the point of attachment of the group to the rest of the molecule.
  • the dashed line represents a single bond or its absence, which also means Represents a single bond or double bond
  • substituted or “substituted by" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • substituent which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • optionally substituted or “optionally substituted by" means that it may be substituted or not substituted. Unless otherwise specified, the type and number of substituents are the same as those that can be achieved chemically. The basis can be arbitrary.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may optionally be substituted with 1 or 2 or 3 R's, and each occurrence of R' has independent options.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituents When the listed substituents do not specify through which atom they are bonded to the substituted group, such substituents may be bonded through any atom thereof.
  • a pyridyl substituent may be bonded to the substituted group through any carbon atom on the pyridine ring.
  • linking group L is -CH 2 O-, in which case -CH 2 O- can connect phenyl and cyclopentyl in the same direction as the reading order from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • the number of atoms on the ring refers to the number of atoms that constitute the ring itself in a compound (such as a monocyclic compound, a paracyclic compound, a spirocyclic compound, a bridged ring compound, a cross-linked compound, a carbocyclic compound, a heterocyclic compound) in which atoms are bonded to form a ring.
  • the number of atoms on the ring is usually defined as the number of members of the ring. For example, a "3-6 membered ring” refers to a "ring” with 3-6 atoms arranged around it.
  • benzene is a 6-membered ring
  • naphthalene is a 10-membered ring
  • thiophene is a 5-membered ring.
  • alkyl refers to a saturated hydrocarbon group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which may represent a straight chain and/or branched chain alkyl group, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Unless otherwise specifically stated in the specification, an alkyl group may be optionally substituted.
  • C 1-6 alkyl is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or polyvalent (such as divalent ).
  • Examples of C 1-6 alkyl include, but are not limited to, CH 3 , wait.
  • C 1-4 alkyl is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or polyvalent (such as divalent ).
  • Examples of C 1-4 alkyl groups include, but are not limited to, CH 3 , wait.
  • alkenyl refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, which can represent a straight chain and/or branched alkenyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight chain alkenyl chain. It can be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkenyl group may be optionally substituted.
  • C 2-6 alkenyl is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group.
  • the C 2-6 alkenyl includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl, etc.; It may be monovalent, divalent or polyvalent.
  • C2-6 alkenyl examples include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentylene, hexadienyl, ethenylene, propenylene, sec-butenylene and the like.
  • C 2-3 alkenyl is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group.
  • the C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group can be monovalent, divalent or polyvalent. Examples of C 2-3 alkenyl groups include but are not limited to wait.
  • alkynyl refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond, which may represent a straight and/or branched alkynyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight alkynyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkynyl group may be optionally substituted.
  • C 2-6 alkynyl is used to represent a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent.
  • the C 2-6 alkynyl group includes C 2-3 , C 2-4 , C 2-5 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , C 5-6 , C 6 , C 5 , C 4 , C 3 and C 2 alkynyl groups. Examples of C 2-6 alkynyl groups include, but are not limited to wait.
  • C 2-3 alkynyl is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent.
  • the C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl groups include, but are not limited to wait.
  • oxo refers to an oxygen atom doubly bonded to a carbon atom or another element, including to the nitrogen of a pyridine ring to form a pyridine N-oxide.
  • oxo 5-6 membered heteroaryl includes but is not limited to
  • heteroalkyl by itself or in combination with another term means a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group, wherein the “alkyl” in the “alkyl radical” is defined as above in the present invention.
  • the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
  • the heteroalkyl group is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl group is C 1-3 heteroalkyl.
  • heteroalkyl groups include, but are not limited to , -OCH3 , -OCH2CH3 , -OCH2CH2CH3 , -OCH2 ( CH3 ) 2 , -CH2 - CH2 - O - CH3 , -NHCH3 , -N(CH3) 2 , -NHCH2CH3 , -N ( CH3 )( CH2CH3 ), -CH2 - CH2 - NH- CH3 , -CH2- CH2 - N( CH3 ) -CH3 , -SCH3 , -SCH2CH3 , -SCH2CH3 , -SCH2CH2CH3 , -SCH2 ( CH3 ) 2 , -CH2 -S- CH2 -CH3, -CH2 - CH2 , -S- CH2 -CH3, -CH2 - CH2 , -S
  • alkoxy refers to an alkyl group connected to the rest of the molecule via an oxygen atom, wherein “alkyl” in “alkyl group” is as defined above in the present invention. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms that are connected to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc.
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, etc.
  • C 1-3 alkoxy refers to an alkyl group containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkoxy groups, etc.
  • Examples of C 1-3 alkoxy groups include but are not limited to Not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethyleneoxy, propyleneoxy and the like.
  • amino may be a monovalent Two-price Or multiple price
  • alkylamino refers to an alkyl group attached to the rest of the molecule via an amino group as defined above, wherein “alkyl” in “alkyl group” is as defined above in the present invention. Unless otherwise specifically stated in the specification, the alkylamino group may be optionally substituted.
  • C 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group.
  • the C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2, C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino groups, etc.
  • C 1-6 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , and the like.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylamino groups, etc.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , etc.
  • alkylthio refers to an alkyl group connected to the rest of the molecule through a sulfur atom, wherein “alkyl” in “alkyl group” is as defined above in the present invention. Unless otherwise specifically stated in the specification, alkylthio may be optionally substituted.
  • C 1-6 alkylthio refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through a sulfur atom.
  • the C 1-6 alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylthio, etc.
  • Examples of C 1-6 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
  • C 1-3 alkylthio refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylthio groups, etc.
  • Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , etc.
  • cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic saturated hydrocarbon group consisting of carbon and hydrogen atoms, which may include a cyclocyclic, spirocyclic and/or bridged ring systems.
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc.
  • C 4-6 cycloalkyl means a cycloalkyl having 4-6 ring carbon atoms.
  • C 3-4 cycloalkyl means a cycloalkyl having 3-4 ring carbon atoms. Unless otherwise specifically stated in the specification, cycloalkyl may be optionally substituted.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • the heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl group, including the position at which the heterocycloalkyl group is attached to the rest of the molecule.
  • the heterocycloalkyl is a 3-20 membered heterocycloalkyl; in some embodiments, the heterocycloalkyl is a 3-10 membered heterocycloalkyl; in other embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. Unless otherwise specifically stated in the specification, the heterocycloalkyl may be optionally substituted.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from B, O, S and N or heteroatoms as described above, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl, including the position where the heterocycloalkyl can be connected to the rest of the molecule.
  • the 3-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc.
  • the term "3-9 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 9 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings.
  • heteroatoms may occupy the position at which the heterocyclyl is attached to the rest of the molecule.
  • the 3-9 membered heterocyclic group includes 3-8, 3-7, 3-6, 3-5, 3-4, 4-5, 4-6, 4-7, 4-8, 4-9, 5-6, 5-7, 5-8, 5-9, 6-7, 6-8, 6-9, 7-8, 3, 4, 5, 6, 7, 8 and 9 membered heterocyclic groups.
  • 3-9 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl,
  • 3-6 membered heterocyclyl by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings.
  • heteroatoms may occupy the connection position of the heterocyclyl with the rest of the molecule.
  • the 3-6 membered heterocyclyl includes 4-6, 5-6, 4, 5 and 6 membered heterocyclyls, etc.
  • 3-6 membered heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl,
  • the term "5-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings.
  • heteroatoms may occupy the position where the heterocyclyl is connected to the rest of the molecule.
  • the 5-6 membered heterocyclyl includes 5-membered and 6-membered heterocyclyls, etc.
  • 5-6 membered heterocyclyls include, but are not limited to, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazin
  • 5-9 membered heteroaromatic ring and “5-9 membered heteroaryl” are used interchangeably.
  • the term “5-9 membered heteroaryl” refers to a monocyclic group with a conjugated ⁇ electron system consisting of 5 to 9 ring atoms, wherein 1, 2, 3 or 4 ring atoms are independently selected from O, S and N heteroatoms, and the rest are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-9 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-9 membered heteroaryl includes 5-8, 5-7, 5-6, 6-9, 6-8, 6-7, 5 and 6 membered heteroaryl.
  • Examples of the 5-9 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” are used interchangeably.
  • the term “5-6 membered heteroaryl” refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and
  • a substituent connected to ring A when a substituent connected to ring A can be connected to ring A to form a ring, it means that the substituent can be connected to any position of ring A to form a new ring together with ring A, including a cyclic, spiro or bridged ring; wherein ring A can be selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc. as described above.
  • ring A can be selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc. as described above.
  • the R in connected to form a 6-membered ring examples of which include but are not limited to wait.
  • Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9 , C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 .
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.
  • substituted means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is replaced by a bond with a non-hydrogen atom, wherein the non-hydrogen atom includes, but is not limited to, halogen atoms (e.g., F, Cl, Br, I), oxygen atom-containing groups (e.g., hydroxyl, alkoxy, ester groups), sulfur atom-containing groups (e.g., thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, sulfoxide groups), nitrogen atom-containing groups (e.g., amine groups, amide groups,
  • halogen atoms e.g
  • substituted also means that one or more hydrogen atoms in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) are replaced by a higher order bond (e.g., double or triple bond) to a heteroatom, such as oxygen in carbonyl , carboxyl, and ester groups, and nitrogen in imine , oxime , hydrazone, and nitrile.
  • a higher order bond e.g., double or triple bond
  • Rg is the same as or different from Rh and is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl , aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl.
  • Substituted may also mean that one or more hydrogen atoms in any of the above groups are replaced by amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl.
  • each of the above substituents may also be optionally replaced by one or more of the above substituents.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction).
  • representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (
  • the compounds of formula (I) may contain one or more chiral centers and therefore may exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • stereoisomer refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, and the like.
  • enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.
  • diastereomer refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.
  • optically active compounds that is, they have the ability to rotate the plane of plane polarized light.
  • the prefixes D and L or R and S are used to represent the absolute configuration of the molecule about its chiral center.
  • the prefixes d and l or (+) and (-) are used to represent the sign of the compound rotating plane polarized light, where (-) or l represent that the compound is left-handed.
  • Compounds with the prefix of (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other.
  • stereoisomers can also be referred to as enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur in chemical reactions or methods without stereoselectivity or stereospecificity.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomers that do not have optical activity.
  • the racemic mixture can be used in its own form or resolved into individual isomers. Resolution can yield a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known and include physical methods, such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors.
  • the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, ⁇ -bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then freeing one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers that are substantially free of the other isomer, i.e., the desired stereoisomers having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight.
  • the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • the solvent used in the present invention is commercially available.
  • the compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration.
  • the chiral centers of some compounds disclosed in the present invention are marked with *R, *S, R*, or S*, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single configuration enantiomer monomer, or a single configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: other chiral center configurations have not been resolved).
  • FIG1 is a bar graph showing the results of a pharmacodynamic experiment of a compound according to an example of the present invention in LPS-induced AP-activated mice.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography-mass spectrometers.
  • HPLC determination was performed using a Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5 ⁇ m column).
  • the thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.
  • High performance liquid phase preparation used Waters 2767, Waters 2545, and Chuangxin Hengtong LC3000 preparative chromatographs.
  • the pressurized hydrogenation reaction used a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.
  • Microwave reactions were performed using a Biotage initiator+ microwave reactor.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 liter.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.
  • reaction temperature is room temperature, which ranges from 20°C to 30°C.
  • compound 1-6 (900 mg, 2.49 mmol) was dissolved in DMF (10 mL), and NaH (597.57 mg, 14.94 mmol, 60% purity) was slowly added at room temperature. After the mixture was stirred for 5 minutes, iodoethane (2.33 g, 14.94 mmol) was slowly added. The reaction solution was stirred at room temperature for 2 hours until the reaction was complete, and then an aqueous solution of ammonium chloride was added to quench the reaction. The product was extracted with ethyl acetate (10 mL ⁇ 2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product.
  • the racemic compound 1-11 (36 mg) was chirally separated and purified by SFC (SFC preparation method: instrument: MG II preparative SFC (SFC-13), column model: ChiralPak IC, 250 ⁇ 30 mm ID, 10 ⁇ m, mobile phase: A-CO 2 , B-ethanol (0.1% NH 3 ⁇ H 2 O), gradient: B 50%, flow rate: 80 mL/min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ⁇ 12 min) to obtain 14.7 mg of chiral compound 1 (the first peak) (analysis method: instrument: Waters UPC2analytical SFC (SFC-H), column model: ChiralPak IC, 100 ⁇ 4.6 mm ID, 3 ⁇ m, mobile phase: A-CO 2 , B-ethanol (0.05% DEA), gradient: B 50%, flow rate: 80 mL/min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ⁇ 12 min). 50%,
  • compound 1-6 (1g, 2.49mmol) was dissolved in DMF (11mL), and NaH (597.71mg, 14.94mmol, 60% purity) was slowly added, and then stirred at room temperature for five minutes, and then (iodomethyl) cyclopropane (0.96g, 4.98mmol) was added. After the reaction solution was heated to 60°C and stirred for 30 minutes, (iodomethyl) cyclopropane (0.96g, 4.98mmol) was added until compound 1-6 was completely reacted. The reaction solution was cooled to room temperature, and an aqueous solution of ammonium chloride was added to quench the reaction.
  • tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate 800 mg, 2.74 mmol was dissolved in DCM (8 mL), cooled to 0°C, and a dichloromethane solution (5 mL) of PPh 3 Br 2 (1.50 g, 3.57 mmol) was added. The reaction solution was stirred at 0°C for 1 hour, and then a dichloromethane solution (4 mL) of compound 2-2 (750 mg, 2.11 mmol) and DIEA (1.09 g, 8.44 mmol) was added.
  • the racemic compound 2-5 (530 mg) was chirally separated and purified by SFC (SFC preparation method: instrument: WATERS 150preparative SFC (SFC-26), column model: ChiralPak IC, 250 ⁇ 30 mm ID, 10 ⁇ m, mobile phase: A-CO 2 , B-ethanol (0.1% NH 3 ⁇ H 2 O), gradient: B 50%, flow rate: 130 mL/min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ⁇ 11 min) to obtain 238 mg of chiral compound 2 (analytical method: instrument: Waters UPC2analytical SFC (SFC-H), column model: ChiralPak IC, 100 ⁇ 4.6 mm ID, 3 ⁇ m, mobile phase: A-CO 2 , B-ethanol (0.05% DEA), gradient: B 50%). 50%, flow rate: 2.5 mL/min, back pressure: 100 bar, column temperature: 35°C, wavelength: 220 nm), the yield was 45%.
  • the compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (73.0 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and a dichloromethane solution (1 mL) of dibromotriphenylphosphine (137 mg, 0.32 mmol) was slowly added dropwise at 0°C. After the addition was completed, stirring was continued at 0°C for 1 hour, and then a dichloromethane solution (1 mL) of compound 1-3 (41 mg, 0.14 mmol) and diisopropylethylamine (52.4 mg, 0.40 mmol) was added.
  • compound 3-1 (32.0 mg, 0.055 mmol) was dissolved in a mixed solvent of methanol (0.5 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL), and sodium hydroxide (22.20 mg, 0.55 mmol) was added.
  • buffer the composition is: 50mM Tris-HCl, pH7.0, 50mM NaCl, 0.01% w/v Triton X-100.
  • the test compound is first diluted 3 times with DMSO, then 0.6uL is transferred to a 96-well plate with a pipette, 99.4 ⁇ L of buffer is added and pipetted to mix, and 2.5 ⁇ L of the diluted compound is transferred to a 384-well plate (ProxiPlate-384plus, PE).
  • 90nM His-FB protein (ab276729, Abcam) is prepared with buffer, and 2.5 ⁇ L is transferred to the 384-well plate containing the compound.
  • IC50 values of the test compounds for human complement Factor B protein binding test experiment are shown in Table 1, where A represents: IC50 value ⁇ 100nM; B represents: 100nM ⁇ IC50 value ⁇ 1000nM; C represents: IC50 value >1000nM.
  • the compounds of the present invention have significant binding activity to human complement Factor B protein.
  • C3 hydrolysis reaction The compound was first diluted three-fold with DMSO for a total of ten concentrations, then diluted 40-fold with reaction buffer, and 1 ⁇ L was transferred to a 384-well plate (ProxiPlate-384plus, PE). 2.5 nM CVF:Bb and 1 uM C3 (A401, Quidel) were prepared with reaction buffer. 2 ⁇ L CVF:Bb was transferred to the ProxiPlate 384 plate well containing the compound and incubated at 37°C for 30 minutes. 2 ⁇ L C3 was added to start the reaction and incubated at 37°C for 180 minutes. During the reaction, the 384-well plate was sealed.
  • 5uL 2x protease inhibitor cocktail (5892970001, Roche) was added to each well to stop the reaction. After mixing, 1.25 ⁇ L of the reaction solution was transferred to a 384-well black plate (OptiPlate-384F HB, PE), and 23.8 ⁇ L of coating buffer (containing 100mM sodium carbonate pH9.0: C3041, Sigma and 1M NaCl: A610476-0001, BBI Life Science), centrifuge at 1000rpm for 1 minute, and place at 4°C for overnight coating. The next day, discard the liquid in the 384-well plate coated the day before, pat dry on clean absorbent paper, and wash 3 times with PBST.
  • coating buffer containing 100mM sodium carbonate pH9.0: C3041, Sigma and 1M NaCl: A610476-0001, BBI Life Science
  • IC50 values of the test compounds for C3 enzymatic hydrolysis experiments are shown in Table 2, wherein A represents: IC50 value ⁇ 100nM; B represents: 100nM ⁇ IC50 value ⁇ 1000nM; C represents: IC50 value >1000nM, and LNP023 is the reference compound.
  • the compounds of the present invention have excellent in vitro activity and can significantly inhibit the hydrolytic activity of C3 enzyme.
  • the Zhangjiang Animal House of Charles River Pharmaceutical Technology (Shanghai) Co., Ltd. is located at the 4th floor of Building 2, No. 1077 Zhangheng Road, Pudong New District, Shanghai.
  • the breeding environment temperature 23 ⁇ 2°C, relative humidity 40-70%, lighting time 6AM/6PM switch lights; animals are fed with ordinary feed and sterilized drinking water freely. All animal experiments were approved by the Animal Ethics Committee of Charles River Pharmaceutical Technology (Shanghai) Co., Ltd.
  • test drug Add the compound to the solvent, stir ultrasonically until a uniform solution/suspension is obtained, and prepare the desired concentration.
  • LPS Salmonella enterica serovar Typhimurium lipopolysaccharide
  • each group of animals was first intraperitoneally injected with 0.1 mL PBS or LPS to establish the model, and then gavage with the solvent or the test compound.
  • mice in groups 1 to 5 were euthanized with CO2 or anesthetized with isoflurane and blood was collected from the heart.
  • EDTA-K2 was used as the anticoagulant.
  • the experimental data were expressed as mean ⁇ standard error (Means ⁇ SEM) and analyzed using Graphpad Prism 8.0 software and one-way analysis of variance. p ⁇ 0.05 was considered to be statistically significant.
  • the compound of the present invention has excellent in vivo activity in animals and has the effect of inhibiting bacterial lipopolysaccharide (LPS)-induced complement alternative pathway (AP) activation in C57 mice.
  • LPS lipopolysaccharide
  • AP complement alternative pathway

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Abstract

Disclosed in the present invention are preparation, application and the use of benzospiroindole compounds. Particularly, disclosed in the present invention are compounds shown as formula (I), optical isomers or pharmaceutically acceptable salts thereof, and the use of same for treating and/or preventing diseases related to activity and expression quantity of complement factor B.

Description

苯并螺环吲哚化合物的制备、应用及用途Preparation, application and use of benzospiroindole compounds
本发明主张如下优先权：The present invention claims the following priority:
申请号CN 202211516706.4，申请日2022年11月29日；Application number CN 202211516706.4, application date November 29, 2022;
申请号CN 202311563895.5，申请日2023年11月21日。Application number CN 202311563895.5, application date November 21, 2023.
技术领域Technical Field
本发明属于药物化学领域，具体地，本发明涉及苯并螺环吲哚化合物的制备、应用及用途。The present invention belongs to the field of pharmaceutical chemistry, and in particular, relates to the preparation, application and use of benzospiroindole compounds.
背景技术Background technique
补体系统是先天免疫系统的具有决定性的组成部分，包括一组通常以非活性状态存在的蛋白质。这些蛋白质以三个活化途径被组织：经典途径、凝集素途径和旁路途径。来自微生物的分子、抗体或细胞组份能活化这些途径，从而导致被称为C3-转变酶和C5-转变酶的蛋白酶复合物的形成。经典途径是钙/镁依赖性级联，其通常通过形成抗原-抗体复合物被活化。它还能被与配体复合的C-反应蛋白的结合和被许多病原体(包括革兰氏阳性细菌)以抗体-非依赖性方式被活化。旁路途径是镁依赖性级联，其通过C3在某些敏感表面(例如，酵母和细菌的细胞壁多糖，以及某些生物聚合物材料)上的沉积和活化而被活化。The complement system is a critical component of the innate immune system and includes a group of proteins that are usually present in an inactive state. These proteins are organized in three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Molecules, antibodies, or cellular components from microorganisms can activate these pathways, leading to the formation of protease complexes called C3-convertase and C5-convertase. The classical pathway is a calcium/magnesium-dependent cascade that is usually activated by the formation of antigen-antibody complexes. It can also be activated by the binding of C-reactive protein complexed with ligands and by many pathogens (including Gram-positive bacteria) in an antibody-independent manner. The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain sensitive surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
目前关于治疗与增加的补体活性相关的疾病或障碍的研究还较少，需要越来越多的相关研究。Currently, there is little research on the treatment of diseases or disorders associated with increased complement activity, and more and more related research is needed.
发明内容Summary of the invention
在本发明的一方面，本发明提供了式(I)所示化合物、其光学异构体或其药学上可接受的盐，
In one aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,
其中，in,
X选自C(R5)2、O或N(R5)；X is selected from C(R 5 ) 2 , O or N(R 5 );
R1选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C1-6杂烷基和C3-9环烷基，所述C1-6烷基、C1-6杂烷基或C3-9环烷基任选被1、2或3个R取代；R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-9 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl or C 3-9 cycloalkyl is optionally substituted with 1, 2 or 3 R;
R2选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C1-6杂烷基、C3-6环烷基和3-6元杂环烷基，所述C1-6烷基、C1-6杂烷基、C3-6环烷基或3-6元杂环烷基任选被1、2或3个R取代；R 2 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
L选自单键、O、S、NH、所述NH、 任选被1、2或3个R取代；L is selected from a single bond, O, S, NH, The NH Optionally substituted with 1, 2 or 3 R;
R3选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C3-6环烷基、C1-6杂烷基和3-6元杂环烷基，所述C1-6烷基、C3-6环烷基、C1-6杂烷基或3-6元杂环烷基任选被1、2或3个R取代； R3 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
R4选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C3-6环烷基、C1-6杂烷基和3-6元杂环烷基，所述C1-6烷基、C3-6环烷基、C1-6杂烷基或3-6元杂环烷基任选被1、2或3个R取代； R4 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
或者，R3和R4连接在一起，形成C3-6环烷基或3-6元杂环烷基，所述C3-6环烷基或3-6元杂环烷基任选被1、2或3个R取代；Alternatively, R 3 and R 4 are linked together to form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;
R5选自H、F、Cl、CN、OH、C1-6烷基、C1-6杂烷基和C3-9环烷基，所述C1-6烷基、C1-6杂烷基或C3-9环烷 基任选被1、2或3个R取代； R5 is selected from H, F, Cl, CN, OH, C1-6 alkyl, C1-6 heteroalkyl and C3-9 cycloalkyl, wherein the C1-6 alkyl, C1-6 heteroalkyl or C3-9 cycloalkyl The group is optionally substituted with 1, 2 or 3 R;
R6选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C2-6烯基和C2-6炔基，所述C1-6烷基、C2-6烯基或C2-6炔基任选被1、2或3个R取代；R 6 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally substituted with 1, 2 or 3 R;
R分别独立地选自OH、CN、F、Cl、Br、I、C1-6烷基、C1-6杂烷基、C3-6环烷基和3-6元杂环烷基；R is independently selected from OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;
所述C1-6杂烷基或3-6元杂环烷基包含1、2、3或4个独立选自-O-、-NH-、-N＝、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O)2-和N的杂原子或杂原子团。The C 1-6 heteroalkyl or 3-6 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.
本发明还提供了下式化合物、其光学异构体或其药学上可接受的盐，其结构如下所示，
The present invention also provides a compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, the structure of which is shown below:
其中，in,
L、R1、R2、R3、R4、R5和R6如上述所定义。L, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
在本发明的一些方案中，R1选自H、OH、CN、F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基和C3-6环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基或C3-6环烷基任选被1、2或3个R取代，其它变量如本发明所定义。In some embodiments of the present invention, R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino and C 3-6 cycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino or C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
在本发明的一些方案中，R1选自H、OH、CN、F、Cl、Br、I、CH3、 其它变量如本发明所定义。In some embodiments of the present invention, R 1 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
在本发明的一些方案中，R2选自H、OH、CN、F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C3-6环烷基和3-6元杂环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C3-6环烷基或3-6元杂环烷基任选被1、2或3个R取代，其它变量如本发明所定义。In some embodiments of the present invention, R2 is selected from H, OH, CN, F, Cl, Br, I, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
在本发明的一些方案中，R2选自H、OH、CN、F、Cl、Br、I、CH3、 其它变量如本发明所定义。In some embodiments of the present invention, R 2 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
在本发明的一些方案中，R3选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C3-6环烷基、C1-6烷氧基、C1-6烷硫基和3-6元杂环烷基，所述C1-6烷基、C3-6环烷基、C1-6烷氧基、C1-6烷硫基或3-6元杂环烷基任选被1、2或3个R取代，其它变量如本发明所定义。In some embodiments of the present invention, R3 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio and 3-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
在本发明的一些方案中，R3选自H、OH、CN、F、Cl、Br、I、CH3、 其它变量如本发明所定义。In some embodiments of the present invention, R 3 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
在本发明的一些方案中，结构单元选自H、OH、CN、F、Cl、Br、I、CH3、 其它变量如本发明所定义。In some embodiments of the present invention, the structural unit Selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
在本发明的一些方案中，R4选自H、OH、CN、F、Cl、Br、I、C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基和3-6元杂环烷基，所述C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基或3-6元杂环烷基任选被1、2或3个R取代，其它变量如本发明所定义。In some embodiments of the present invention, R4 is selected from H, OH, CN, F, Cl, Br, I, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino and 3-6 membered heterocycloalkyl, wherein the C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
在本发明的一些方案中，R4选自H、OH、CN、F、Cl、Br、I、CH3、 所述CH3、任选被1、2或3个R取代。In some embodiments of the present invention, R 4 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , The CH 3 , Optionally substituted with 1, 2 or 3 R.
在本发明的一些方案中，R4选自H、OH、CN、F、Cl、Br、I、CH3、 其它变量如本发明所定义。In some embodiments of the present invention, R 4 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , Other variables are as defined herein.
可以理解地，在本发明中，R3和R4连接在一起，形成C3-6环烷基或3-6元杂环烷基，指R3和R4连接在一起，与L以及和R4相连的环上的碳原子共同形成C3-6环烷基或3-6元杂环烷基。It can be understood that in the present invention, R3 and R4 are connected together to form a C3-6 cycloalkyl or a 3-6 membered heterocycloalkyl, which means that R3 and R4 are connected together, together with L and the carbon atoms on the ring connected to R4 , form a C3-6 cycloalkyl or a 3-6 membered heterocycloalkyl.
在本发明的一些方案中，R3和R4连接在一起，形成所述 任选被1、2或3个R取代，其它变量如本发明所定义。In some embodiments of the present invention, R3 and R4 are linked together to form Said Optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.
在本发明的一些方案中，R3和R4连接在一起，形成 其它变量如本发明所定义。In some embodiments of the present invention, R3 and R4 are linked together to form Other variables are as defined herein.
在本发明的一些方案中，R5选自H、F、Cl、CN、OH、CH3、其它变量如本发明所定义。In some embodiments of the present invention, R 5 is selected from H, F, Cl, CN, OH, CH 3 , Other variables are as defined herein.
本发明还提供了下式化合物、其光学异构体或其药学上可接受的盐或其同位素化合物，其选自：

The present invention also provides a compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, which is selected from:

在本发明的再一方面，本发明还提供了一种药物组合物。本发明的一些方案中，上述药物组合物保护前面所述的化合物、其光学异构体或其药学上可接受的盐。In yet another aspect of the present invention, the present invention also provides a pharmaceutical composition. In some embodiments of the present invention, the pharmaceutical composition protects the aforementioned compound, its optical isomer or a pharmaceutically acceptable salt thereof.
本发明的一些方案中，上述药物组合物进一步包含药用辅料。In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutical excipient.
在本发明的再一方面，本发明还提供了上述化合物、其光学异构体或其药学上可接受的盐或上述药物组合物在制备治疗和/或预防补体因子B活性和表达量相关疾病的药物中的应用。In another aspect of the present invention, the present invention also provides the use of the above-mentioned compound, its optical isomer or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and/or preventing diseases related to complement factor B activity and expression.
本发明的目的就是提供一种作为补体因子B抑制剂的化合物或者其立体异构体、氘代物、溶剂化合物、前药、代谢产物、药学上可以接受的盐或共晶，及其中间体和制备方法，以及在制备治疗补体因子B活性和表达量相关疾病的药物中的应用。The object of the present invention is to provide a compound as a complement factor B inhibitor or its stereoisomers, deuterated products, solvent compounds, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods, as well as their use in the preparation of drugs for treating diseases related to complement factor B activity and expression.
本发明的化合物可用于治疗和/或预防由补体因子B(Factor B)介导的疾病、补体系统受累、或存在显著未满足需求的一些肾脏疾病或障碍，包括IgA肾病(IgAN)、C3肾小球疾病(C3G)、非典型溶血性尿毒症综合征(aHUS)、膜性肾病(MN)、阵发性夜间血红蛋白尿(PNH)等以及与补体级联相关的其他疾病，包括年龄相关性黄斑变性(AMD)、地图状萎缩(GA)、血液透析并发症、神经脊髓炎(NMO)、肝脏性疾病、炎症性肠病、重症肌无力(MG)等疾病。The compounds of the present invention can be used to treat and/or prevent diseases mediated by complement factor B (Factor B), involvement of the complement system, or some kidney diseases or disorders with significant unmet needs, including IgA nephropathy (IgAN), C3 glomerular disease (C3G), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN), paroxysmal nocturnal hemoglobinuria (PNH), etc., as well as other diseases related to the complement cascade, including age-related macular degeneration (AMD), geographic atrophy (GA), hemodialysis complications, neuromyelitis (NMO), liver diseases, inflammatory bowel disease, myasthenia gravis (MG) and other diseases.
定义和说明 Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.
如本发明中，采用的短语“至少一个”在提及一个或多个要素的列表时应理解为意指至少一个选自所述要素列表中的任一个或多个要素的要素，但不必包括所述要素列表内具体列出的每一个要素中的至少一者，并且不排除所述要素列表中的要素的任何组合。这个定义还允许，可以任选地存在除短语“至少一个”指代的所述要素列表内具体确定的要素以外的要素，不论与那些具体确定的要素相关还是不相关。As in the present invention, the phrase "at least one" used when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that there may be optionally elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、三氟乙酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是:在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are prepared by reacting with a stoichiometric amount of an appropriate base or acid.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，可以选自等。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，C1-6烷基羰基-指通过羰基与分子的其余部分连接的C1-6烷基。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如，卤素取代基，“-”可以被省略。A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, C1-6 alkylcarbonyl- refers to a C1-6 alkyl group that is attached to the rest of the molecule via a carbonyl group. However, when the point of attachment of a substituent is obvious to one skilled in the art, for example, a halogen substituent, the "-" may be omitted.
当基团价键上带有虚线时，例如在中，该虚线表示该基团与分子其它部分的连接点。当单键上带有时，例如在中，该虚线代表单键或者不存在，也意味着代表了单键或者双键 When the group valence bond is marked with a dotted line When, for example, In the example, the dashed line indicates the point of attachment of the group to the rest of the molecule. When, for example, In the example, the dashed line represents a single bond or its absence, which also means Represents a single bond or double bond
术语“被取代的”或“被…取代”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。术语“任选被取代的”或“任选被…取代”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基 础上可以是任意的。The term "substituted" or "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted by..." means that it may be substituted or not substituted. Unless otherwise specified, the type and number of substituents are the same as those that can be achieved chemically. The basis can be arbitrary.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被1、2或3个R’所取代，则所述基团可以任选地1个或2个或3个R’所取代，并且每种情况下的R’都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1, 2, or 3 R's, the group may optionally be substituted with 1 or 2 or 3 R's, and each occurrence of R' has independent options. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如中L1代表单键时表示该结构实际上是 When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L 1 represents a single bond, it means that the structure is actually
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When the listed substituents do not specify through which atom they are bonded to the substituted group, such substituents may be bonded through any atom thereof. For example, a pyridyl substituent may be bonded to the substituted group through any carbon atom on the pyridine ring.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，中连接基团L为-CH2O-，此时-CH2O-既可以按与从左往右的读取顺序相同的方向连接苯基和环戊基构成也可以按照与从左往右的读取顺序相反的方向连接苯基和环戊基构成所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -CH 2 O-, in which case -CH 2 O- can connect phenyl and cyclopentyl in the same direction as the reading order from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
除非另有规定，环上原子的数目表示原子键合成环状而得到的化合物(如单环化合物、并环化合物、螺环化合物、桥环化合物、交联化合物、碳环化合物、杂环化合物)中构成该环自身的原子数。环上原子的数目通常被定义为环的元数，例如，“3-6元环”是指环绕排列3-6个原子的“环”。环被取代基所取代时，取代基所包含的原子不包括在成环原子内。在没有特别说明的情况下，苯为6元环，萘为10元环，噻吩为5元环。Unless otherwise specified, the number of atoms on the ring refers to the number of atoms that constitute the ring itself in a compound (such as a monocyclic compound, a paracyclic compound, a spirocyclic compound, a bridged ring compound, a cross-linked compound, a carbocyclic compound, a heterocyclic compound) in which atoms are bonded to form a ring. The number of atoms on the ring is usually defined as the number of members of the ring. For example, a "3-6 membered ring" refers to a "ring" with 3-6 atoms arranged around it. When a ring is substituted with a substituent, the atoms contained in the substituent are not included in the ring atoms. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.
除非另有规定，术语“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其组合的饱和烃基，其可以表示直链和/或支链烷基，其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。除非说明书中另有具体说明，否则烷基可任选被取代。Unless otherwise specified, the term "alkyl" refers to a saturated hydrocarbon group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which may represent a straight chain and/or branched chain alkyl group, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Unless otherwise specifically stated in the specification, an alkyl group may be optionally substituted.
除非另有规定，术语“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C6和C5烷基等；其可以是一价(如CH3)、二价(-CH2-)或者多价(如次)。C1-6烷基的实例包括但不限于CH3、 等。Unless otherwise specified, the term "C 1-6 alkyl" is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or polyvalent (such as divalent ). Examples of C 1-6 alkyl include, but are not limited to, CH 3 , wait.
除非另有规定，术语“C1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C1-4烷基包括C1-2、C1-3、C3-4和C2-3烷基等；其可以是一价(如CH3)、二价(-CH2-)或者多价(如次)。C1-4烷基的实例包括但不限于CH3、等。Unless otherwise specified, the term "C 1-4 alkyl" is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 alkyl group includes C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or polyvalent (such as divalent ). Examples of C 1-4 alkyl groups include, but are not limited to, CH 3 , wait.
除非另有规定，术语“烯基”是指包含具有至少一个不饱和部位，即碳-碳sp2双键的烃基，其可以表示直链和/或支链烯基，支链是指一个或多个烷基如甲基、乙基或丙基连接在直链烯基链上。其可以是一价、二价或者多价。除非说明书中另有具体说明，否则烯基可任选被取代。Unless otherwise specified, the term "alkenyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, which can represent a straight chain and/or branched alkenyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight chain alkenyl chain. It can be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkenyl group may be optionally substituted.
除非另有规定，“C2-6烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至6个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-6烯基包括C2-4、C2-3、C4、C3和C2烯基等； 其可以是一价、二价或者多价。C2-6烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基、己间二烯基、亚乙烯基、亚丙烯基、亚仲丁烯基等。Unless otherwise specified, "C 2-6 alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group. The C 2-6 alkenyl includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl, etc.; It may be monovalent, divalent or polyvalent. Examples of C2-6 alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentylene, hexadienyl, ethenylene, propenylene, sec-butenylene and the like.
除非另有规定，“C2-3烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至3个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-3烯基包括C3和C2烯基；所述C2-3烯基可以是一价、二价或者多价。C2-3烯基的实例包括但不限于等。Unless otherwise specified, "C 2-3 alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group. The C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group can be monovalent, divalent or polyvalent. Examples of C 2-3 alkenyl groups include but are not limited to wait.
除非另有规定，术语“炔基”是指包含具有至少一个不饱和部位，即碳-碳sp三键的烃基，其可以表示直链和/或支链炔基，支链是指一个或多个烷基如甲基、乙基或丙基连接在直链炔基链上。其可以是一价、二价或者多价。除非说明书中另有具体说明，否则炔基可任选被取代。Unless otherwise specified, the term "alkynyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond, which may represent a straight and/or branched alkynyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight alkynyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkynyl group may be optionally substituted.
除非另有规定，“C2-6炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至6个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。其可以是一价、二价或者多价。所述C2-6炔基包括C2- 3、C2-4、C2-5、C3-4、C3-5、C3-6、C4-5、C4-6、C5-6、C6、C5、C4、C3和C2炔基。C2-6炔基的实例包括但不限于等。Unless otherwise specified, "C 2-6 alkynyl" is used to represent a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-6 alkynyl group includes C 2-3 , C 2-4 , C 2-5 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , C 5-6 , C 6 , C 5 , C 4 , C 3 and C 2 alkynyl groups. Examples of C 2-6 alkynyl groups include, but are not limited to wait.
除非另有规定，“C2-3炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至3个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。其可以是一价、二价或者多价。所述C2-3炔基包括C3和C2炔基。C2-3炔基的实例包括但不限于等。Unless otherwise specified, "C 2-3 alkynyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl groups include, but are not limited to wait.
除非另有规定，术语“氧代”是指与碳原子或另一元素，包括与吡啶环的氮双键合以形成吡啶N-氧化物的氧原子。例如术语“氧代5-6元杂芳基”包括但不限于 Unless otherwise specified, the term "oxo" refers to an oxygen atom doubly bonded to a carbon atom or another element, including to the nitrogen of a pyridine ring to form a pyridine N-oxide. For example, the term "oxo 5-6 membered heteroaryl" includes but is not limited to
除非另有规定，术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物，其中“烷基原子团”中的“烷基”在本发明中的定义如上所述。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C1-6杂烷基；在另一些实施方案中，所述杂烷基为C1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置。杂烷基的实例包括但不限于-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2(CH3)2、-CH2-CH2-O-CH3、-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)(CH2CH3)、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2、-CH2-S-CH2-CH3、-CH2-CH2、-S(＝O)-CH3、-CH2-CH2-S(＝O)2-CH3等；其至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。除非说明书中另有具体说明，否则杂烷基可任选被取代。Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group, wherein the "alkyl" in the "alkyl radical" is defined as above in the present invention. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2 -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl group is C 1-3 heteroalkyl. The heteroatom or heteroatom group may be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples of heteroalkyl groups include, but are not limited to , -OCH3 , -OCH2CH3 , -OCH2CH2CH3 , -OCH2 ( CH3 ) 2 , -CH2 - CH2 - O - CH3 , -NHCH3 , -N(CH3) 2 , -NHCH2CH3 , -N ( CH3 )( CH2CH3 ), -CH2 - CH2 - NH- CH3 , -CH2- CH2 - N( CH3 ) -CH3 , -SCH3 , -SCH2CH3 , -SCH2CH2CH3 , -SCH2 ( CH3 ) 2 , -CH2 -S- CH2 -CH3, -CH2 - CH2 , -S(=O) -CH3 , -CH2 - CH2 -S(=O) 2 - CH3, and -SCH2 -CH2- CH3 . 3 , etc.; up to two heteroatoms thereof may be consecutive, for example -CH 2 -NH-OCH 3. Unless otherwise specifically stated in the specification, a heteroalkyl group may be optionally substituted.
除非另有规定，术语“烷氧基”表示通过一个氧原子连接到分子的其余部分的烷基基团，其中“烷基基团”中的“烷基”在本发明中的定义如上所述。除非说明书中另有具体说明，否则烷氧基可任选被取代。Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected to the rest of the molecule via an oxygen atom, wherein "alkyl" in "alkyl group" is as defined above in the present invention. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted.
除非另有规定，术语“C1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷氧基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4和C3烷氧基等。C1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基、亚甲氧基、亚乙氧基、亚丙氧基、亚丁氧基、亚戊氧基等。Unless otherwise specified, the term "C 1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms that are connected to the rest of the molecule through an oxygen atom. The C 1-6 alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, etc.
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-3、C1-2、C2-3、C1、C2和C3烷氧基等。C1-3烷氧基的实例包括但 不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、亚甲氧基、亚乙氧基、亚丙氧基等。Unless otherwise specified, the term "C 1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkoxy groups, etc. Examples of C 1-3 alkoxy groups include but are not limited to Not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethyleneoxy, propyleneoxy and the like.
除非另有规定，术语“氨基”可以是一价二价或者多价 Unless otherwise specified, the term "amino" may be a monovalent Two-price Or multiple price
除非另有规定，术语“烷氨基”表示通过如上定义所述的氨基连接到分子的其余部分的烷基基团，其中“烷基基团”中的“烷基”在本发明中的定义如上所述。除非说明书中另有具体说明，否则烷氨基可任选被取代。Unless otherwise specified, the term "alkylamino" refers to an alkyl group attached to the rest of the molecule via an amino group as defined above, wherein "alkyl" in "alkyl group" is as defined above in the present invention. Unless otherwise specifically stated in the specification, the alkylamino group may be optionally substituted.
除非另有规定，术语“C1-6烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷氨基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4、C3和C2烷氨基等。C1-6烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-N(CH2CH3)(CH2CH3)、-NHCH2CH2CH3、-NHCH2(CH3)2、-NHCH2CH2CH2CH3等。Unless otherwise specified, the term "C 1-6 alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group. The C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2, C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino groups, etc. Examples of C 1-6 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )(CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , and the like.
除非另有规定，术语“C1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氨基包括C1-3、C1-2、C2-3、C1、C2和C3烷氨基等。C1-3烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-NHCH2CH2CH3、-NHCH2(CH3)2等。Unless otherwise specified, the term "C 1-3 alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an amino group. The C 1-3 alkylamino group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylamino groups, etc. Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , etc.
除非另有规定，术语“烷硫基”表示通过一个硫原子连接到分子的其余部分的烷基基团，其中“烷基基团”中的“烷基”在本发明中的定义如上所述。除非说明书中另有具体说明，否则烷硫基可任选被取代。Unless otherwise specified, the term "alkylthio" refers to an alkyl group connected to the rest of the molecule through a sulfur atom, wherein "alkyl" in "alkyl group" is as defined above in the present invention. Unless otherwise specifically stated in the specification, alkylthio may be optionally substituted.
除非另有规定，术语“C1-6烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷硫基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4、C3和C2烷硫基等。C1-6烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2等等。Unless otherwise specified, the term "C 1-6 alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through a sulfur atom. The C 1-6 alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylthio, etc. Examples of C 1-6 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
除非另有规定，术语“C1-3烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷硫基包括C1-3、C1-2、C2-3、C1、C2和C3烷硫基等。C1-3烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2等。Unless otherwise specified, the term "C 1-3 alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom. The C 1-3 alkylthio group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylthio groups, etc. Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , etc.
除非另有规定，术语“环烷基”是指由碳和氢原子组成的稳定的非芳族单环或多环的饱和烃基，其可包括并环、螺环和/或桥环环系。单环环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。多环环烷基包括但不限于金刚烷基、降冰片基、十氢化萘基、7,7-二甲基-双环[2.2.1]庚基等。“C4-6环烷基”表示具有4-6个环碳原子的环烷基。类似地，“C3-4环烷基”表示具有3-4个环碳原子的环烷基。除非说明书中另有具体说明，否则环烷基可任选被取代。Unless otherwise specified, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic saturated hydrocarbon group consisting of carbon and hydrogen atoms, which may include a cyclocyclic, spirocyclic and/or bridged ring systems. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. "C 4-6 cycloalkyl" means a cycloalkyl having 4-6 ring carbon atoms. Similarly, "C 3-4 cycloalkyl" means a cycloalkyl having 3-4 ring carbon atoms. Unless otherwise specifically stated in the specification, cycloalkyl may be optionally substituted.
除非另有规定，“C3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C3-6环烷基包括C3-5、C4-5和C5-6环烷基等；其可以是一价、二价或者多价。C3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
除非另有规定，术语“杂环烷基”表示非芳族以单环、并环、螺环和/或桥环存在的饱和环状基团，其环原子至少一个为杂原子或杂原子团，其余为碳原子；在一些实施方案中，杂原子每次出现，独立地选自B、O、N和S，其中氮和硫原子任选地被氧化(即NO和S(O)p，p是1或2)，氮杂原子任选地被季铵化，在另一些实施方案中，杂原子团每次出现，独立地选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-和-S(＝O)N(H)-。杂原子或杂原子团可以位于杂环烷基的任何内部位置，包括该杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为3-20元杂环烷基；在一些实施方案中，所述杂环烷基为3-10元杂环烷基；在另一些实施方案中，所述杂环烷基为3-6元杂环烷基。除非说明书中另有具体说明，否则杂环烷基可任选被取代。Unless otherwise specified, the term "heterocycloalkyl" means a non-aromatic saturated cyclic group existing as a monocyclic, fused, spirocyclic and/or bridged ring, wherein at least one of the ring atoms is a heteroatom or heteroatom group, and the rest are carbon atoms; in some embodiments, each occurrence of the heteroatom is independently selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), and the nitrogen heteroatom is optionally quaternized; in other embodiments, each occurrence of the heteroatom group is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2 -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)-, and -S(=O)N(H)-. The heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl group, including the position at which the heterocycloalkyl group is attached to the rest of the molecule. In some embodiments, the heterocycloalkyl is a 3-20 membered heterocycloalkyl; in some embodiments, the heterocycloalkyl is a 3-10 membered heterocycloalkyl; in other embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. Unless otherwise specifically stated in the specification, the heterocycloalkyl may be optionally substituted.
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自B、O、S和N的杂原子或如上所述的杂原子团，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其 包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子或杂原子团可以位于杂环烷基的任何内部位置，包括可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from B, O, S and N or heteroatoms as described above, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). Including monocyclic and bicyclic systems, wherein bicyclic systems include spiro, fused and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", the heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl, including the position where the heterocycloalkyl can be connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc.
除非另有规定，术语“3-9元杂环基”本身或者与其他术语联合分别表示由3至9个环原子组成的饱和或部分不饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-9元杂环基”而言，杂原子可以占据杂环基与分子其余部分的连接位置。所述3-9元杂环基包括3-8元、3-7元、3-6元、3-5元、3-4元、4-5元、4-6元、4-7元、4-8元、4-9元、5-6元、5-7元、5-8元、5-9元、6-7元、6-8元、6-9元、7-8元、3元、4元、5元、6元、7元、8元和9元杂环基等。3-9元杂环基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、1,3-二氧戊烷、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。Unless otherwise specified, the term "3-9 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 9 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-9 membered heterocyclyl", heteroatoms may occupy the position at which the heterocyclyl is attached to the rest of the molecule. The 3-9 membered heterocyclic group includes 3-8, 3-7, 3-6, 3-5, 3-4, 4-5, 4-6, 4-7, 4-8, 4-9, 5-6, 5-7, 5-8, 5-9, 6-7, 6-8, 6-9, 7-8, 3, 4, 5, 6, 7, 8 and 9 membered heterocyclic groups. Examples of 3-9 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.
除非另有规定，术语“3-6元杂环基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和或部分不饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环基”而言，杂原子可以占据杂环基与分子其余部分的连接位置。所述3-6元杂环基包括4-6元、5-6元、4元、5元和6元杂环基等。3-6元杂环基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、1,3-二氧戊烷、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-6 membered heterocyclyl", heteroatoms may occupy the connection position of the heterocyclyl with the rest of the molecule. The 3-6 membered heterocyclyl includes 4-6, 5-6, 4, 5 and 6 membered heterocyclyls, etc. Examples of 3-6 membered heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.
除非另有规定，术语“5-6元杂环基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和或部分不饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-6元杂环基”而言，杂原子可以占据杂环基与分子其余部分的连接位置。所述5-6元杂环基包括5元和6元杂环基等。5-6元杂环基的实例包括但不限于1,3-二氧戊烷、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。Unless otherwise specified, the term "5-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "5-6 membered heterocyclyl", heteroatoms may occupy the position where the heterocyclyl is connected to the rest of the molecule. The 5-6 membered heterocyclyl includes 5-membered and 6-membered heterocyclyls, etc. Examples of 5-6 membered heterocyclyls include, but are not limited to, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.
除非另有规定，本发明术语“5-9元杂芳环”和“5-9元杂芳基”可以互换使用，术语“5-9元杂芳基”表示由5至9个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和 N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-9元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-9元杂芳基包括5-8元、5-7元、5-6元、6-9元、6-8元、6-7元、5元和6元杂芳基。所述5-9元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。Unless otherwise specified, the terms "5-9 membered heteroaromatic ring" and "5-9 membered heteroaryl" are used interchangeably. The term "5-9 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 9 ring atoms, wherein 1, 2, 3 or 4 ring atoms are independently selected from O, S and N heteroatoms, and the rest are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-9 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-9 membered heteroaryl includes 5-8, 5-7, 5-6, 6-9, 6-8, 6-7, 5 and 6 membered heteroaryl. Examples of the 5-9 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，当与环A相连的一个取代基可与环A连接而形成一个环时，指的是该取代基可与环A的任意位点连接，与环A一起形成一个新的环，包括并环、螺环或桥环；其中，环A可以选自如上所述的环烷基、杂环烷基、芳基、杂芳基等。例如，当中的R可与连接，形成一个6元环，其实施例包括但不限于等。Unless otherwise specified, when a substituent connected to ring A can be connected to ring A to form a ring, it means that the substituent can be connected to any position of ring A to form a new ring together with ring A, including a cyclic, spiro or bridged ring; wherein ring A can be selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc. as described above. For example, when The R in connected to form a 6-membered ring, examples of which include but are not limited to wait.
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1- 3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、5-10元环、6-7元环、6-8元环、6-9元环和6-10元环等。Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9 , C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 . 9-12 , etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.
本发明所使用的术语“取代的”表示任何上述基团(即烷基、烯基、炔基、杂烷基、烷氧基、烷氨基、烷硫基、环烷基、杂环烷基、环烯基、杂环烯基、芳基、杂芳基)中，至少一个氢原子被非氢原子的键取代，所述非氢原子包括但不限于卤素原子(如F、Cl、Br、I)、含氧原子的基团(如羟基、烷氧基、酯基)、含硫原子的基团(如硫醇基、硫代烷基、砜基、磺酰基、亚砜基)、含氮原子的基团(如胺基、酰胺、烷氨基、二烷基胺基、芳胺基、芳基-烷基-胺基、二芳胺基、N-氧化物基团、酰亚胺基、烯胺基)、含硅原子的基团(如三烷基硅基、双烷基芳基硅基、烷基双芳基硅基、三芳基硅基)以及各种其他基团 中的其他杂原子。The term "substituted" as used in the present invention means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is replaced by a bond with a non-hydrogen atom, wherein the non-hydrogen atom includes, but is not limited to, halogen atoms (e.g., F, Cl, Br, I), oxygen atom-containing groups (e.g., hydroxyl, alkoxy, ester groups), sulfur atom-containing groups (e.g., thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, sulfoxide groups), nitrogen atom-containing groups (e.g., amine groups, amide groups, alkylamino groups, dialkylamine groups, arylamine groups, aryl-alkyl-amine groups, diarylamine groups, N-oxide groups, imide groups, enamine groups), silicon atom-containing groups (e.g., trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups) and various other groups Other heteroatoms in
本发明所使用的术语“取代的”还表示任何上述基团(即烷基、烯基、炔基、杂烷基、烷氧基、烷氨基、烷硫基、环烷基、杂环烷基、环烯基、杂环烯基、芳基、杂芳基)中一个或多个氢原子被杂原子的高阶键(如双键或三键)取代，例如羰基、羧基和酯基中的氧，以及亚胺、肟、腙和腈中的氮。例如，“取代的”表示任何上述基团中的一个或多个氢原子被-NRgRh、-NRgC(＝O)Rh、-NRgC(＝O)NRgRh、-NRgC(＝O)ORh、-NRgSO2Rh、-OC(＝O)NRgRh、-ORg、-SRg、-SORg、SO2Rg、-OSO2Rg、-SO2ORg、＝NSO2Rg与-SO2NRgRh取代。“取代的”也可表示任何上述基团中的一个或多个氢原子被-C(＝O)Rg、-C(＝O)ORg、-C(＝O)NRgRh、-CH2SO2Rg、-CH2SO2NRgRh取代。所述Rg与Rh相同或不同，独立地选自氢、烷基、烯基、炔基、烷氧基、烷氨基、硫代烷基、芳基、芳烷基、环烷基、环烯基、环炔基、环烷基-烷基、卤代烷基、卤代烯基、卤代炔基、杂环基、N-杂环基、杂环烷基-烷基、杂芳基、N-杂芳基、杂芳基-烷基。“取代的”还可表示任何上述基团中的一个或多个氢原子被氨基、氰基、羟基、亚氨基、硝基、氧代、硫代、卤素、烷基、烯基、炔基、烷氧基、烷氨基、硫代烷基、芳基、芳烷基、环烷基、环烯基、环炔基、环烷基-烷基、卤代烷基、卤代烯基、卤代炔基、杂环基、N-杂环基、杂环烷基-烷基、杂芳基、N-杂芳基、杂芳基-烷基取代。另外，上述各取代基也可以任选地被一个或多个上述取代基取代。As used herein, the term "substituted" also means that one or more hydrogen atoms in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) are replaced by a higher order bond (e.g., double or triple bond) to a heteroatom, such as oxygen in carbonyl , carboxyl, and ester groups, and nitrogen in imine , oxime , hydrazone, and nitrile. For example, "substituted" means that one or more hydrogen atoms in any of the above groups are replaced by -NRgRh , -NRgC (=O) Rh , -NRgC ( =O) NRgRh , -NRgC(=O) ORh , -NRgSO2Rh , -OC( = O)NRgRh, -ORg , -SRg , -SORg , SO2Rg , -OSO2Rg , -SO2ORg , = NSO2Rg , and -SO2NRgRh . "Substituted" may also mean that one or more hydrogen atoms in any of the above groups are replaced by -C(=O) Rg , -C(=O ) ORg , -C (=O) NRgRh , -CH2SO2Rg , -CH2SO2NRgRh . Said Rg is the same as or different from Rh and is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl , aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. "Substituted" may also mean that one or more hydrogen atoms in any of the above groups are replaced by amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. In addition, each of the above substituents may also be optionally replaced by one or more of the above substituents.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
本领域技术人员应当理解的是，一些式(I)化合物可以包含一个或多个手性中心，因此存在两个或更多个立体异构体。因此，本发明的化合物可以以单个立体异构体(例如对映异构体、非对映异构体)及其任意比例的混合物例如外消旋物的形式存在，以及在适当的情况下，可以以其互变异构体和几何异构体的形式存在。It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and therefore may exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明要求保护的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
本文所用的术语“立体异构体”指具有相同化学构成、但在原子或基团的空间排列方面不同的化合物。立体异构体包括对映异构体、非对映异构体和构象异构体等。The term "stereoisomer" as used herein refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, and the like.
本文所用的术语“对映异构体”指化合物的彼此是不可重叠的镜像的两种立体异构体。As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.
本文所用的术语“非对映异构体”指具有两个或更多个手性中心并且其分子彼此不是镜像的立体异构体。非对映异构体具有不同的物理性质，例如熔点、沸点、光谱性质或生物活性。非对映异构体的混合物可以用高分辨率分析方法例如电泳和色谱例如HPLC分离。 The term "diastereomer" as used herein refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.
许多有机化合物以光学活性形式存在，即，它们具有旋转平面偏振光的平面的能力。在描述光学活性化合物时，前缀D和L或者R和S用于表示分子关于其手性中心的绝对构型。前缀d和l或者(+)和(-)用于表示化合物旋转平面偏振光的符号，其中(-)或l表示该化合物是左旋的。带有(+)或d的前缀的化合物是右旋的。对于给定的化学结构，除了它们彼此互为镜像之外，这些立体异构体是相同的。特定的立体异构体也可以称为对映异构体，这类异构体的混合物通常称为对映异构体混合物。对映异构体的50:50混合物被称为外消旋混合物或外消旋物，其可以出现在化学反应或方法中没有立体选择性或立体特异性的情况中。术语“外消旋混合物”和“外消旋物”指不具有光学活性的两种对映异构体的等摩尔混合物。Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to represent the sign of the compound rotating plane polarized light, where (-) or l represent that the compound is left-handed. Compounds with the prefix of (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be referred to as enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur in chemical reactions or methods without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that do not have optical activity.
外消旋混合物可以以其本身的形式使用或者拆分成单个异构体使用。通过拆分可以得到立体化学上的纯的化合物或者富集一种或多种异构体的混合物。分离异构体的方法是众所周知的，包括物理方法，例如使用手性吸附剂的色谱法。可以由手性前体制备得到手性形式的单个异构体。或者，可以通过与手性酸(例如10-樟脑磺酸、樟脑酸、α-溴樟脑酸、酒石酸、二乙酰基酒石酸、苹果酸、吡咯烷酮-5-羧酸等的单个对映异构体)形成非对映异构体盐而由混合物化学分离得到单个异构体，将所述的盐分级结晶，然后游离出拆分的碱中的一个或两个，任选地重复这一过程，从而得到一个或两个基本上不包含另一种异构体的异构体，即光学纯度以重量计为例如至少91％、92％、93％、94％、95％、96％、97％、98％、99％或99.5％的所需的立体异构体。或者，如本领域技术人员所熟知的，可以将外消旋物共价连接到手性化合物(辅助物)上，得到非对映异构体。The racemic mixture can be used in its own form or resolved into individual isomers. Resolution can yield a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known and include physical methods, such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then freeing one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers that are substantially free of the other isomer, i.e., the desired stereoisomers having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.
本发明所公开化合物可能有一个或多个手性中心，每个手性中心各自独立的具有R构型或者S构型。本发明所公开部分化合物手性中心标记为*R,*S,R*,或S*，表示该化合物该手性中心绝对构型未经鉴定，但是该化合物已经过手性拆分且该手性中心为单一构型的手性中心，该化合物为单一构型对映异构体单体，或单一构型的非对映异构体单体，或该手性中心构型单一的非对映异构体混合物(例如:其它手性中心构型未被拆分)。当本发明所公开化合物手性中心其绝对构型(R构型，或者S构型)未经鉴定时，该类化合物可根据其在相应色谱柱条件下(例如色谱柱型号，色谱柱填充物，色谱柱尺寸，流动相等)所对应保留时间(RT) 予以确认。The compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration. The chiral centers of some compounds disclosed in the present invention are marked with *R, *S, R*, or S*, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single configuration enantiomer monomer, or a single configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: other chiral center configurations have not been resolved). When the absolute configuration (R configuration or S configuration) of the chiral center of the compounds disclosed in the present invention has not been identified, such compounds can be identified according to their corresponding retention time (RT) under corresponding chromatographic column conditions (for example, chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc. ). Confirmed.
在下述实施例中更具体地解释本发明。然而，应当理解，这些实施例是为了举例说明本发明，而并不是以任何方式限制本发明的范围。下列实施例中如未注明具体条件的实验方法，通常按照这类反应的常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。除非另外说明，否则液体的比为体积比。The present invention is explained in more detail in the following examples. However, it should be understood that these examples are for illustrating the present invention and are not intended to limit the scope of the present invention in any way. The experimental methods in the following examples, if no specific conditions are specified, are usually based on the conventional conditions of this type of reaction, or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts. Unless otherwise stated, the ratio of liquid is volume ratio.
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1是根据本发明实施例的化合物在LPS诱导AP激活小鼠中的药效实验结果柱状图。FIG1 is a bar graph showing the results of a pharmacodynamic experiment of a compound according to an example of the present invention in LPS-induced AP-activated mice.
具体实施方式Detailed ways
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。The present application is described in detail below by way of examples, but it is not intended that there is any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.
本发明所使用的原料如无特殊说明，均来自市售。Unless otherwise specified, the raw materials used in the present invention are commercially available.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker ASCENDTM-400核磁仪，测定溶剂为氘基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR measurements were performed using a Bruker ASCEND TM -400 NMR spectrometer, with deuterated sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.
MS的测定用Agilent 6110，Agilent 1100，Agilent 6120，Agilent 6125B液相质谱联用仪。MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography-mass spectrometers.
HPLC的测定使用岛津HPLC-2010C高压液相色谱仪(XBRIDGE 2.1*50mm，3.5μm色谱柱)。HPLC determination was performed using a Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5μm column).
手性HPLC分析测定使用THARSFC X5。Chiral HPLC analysis was performed using THARSFC X5.
薄层层析硅胶板使用烟台青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.2mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。The thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.
柱层析一般使用青岛海洋硅胶200-300目硅胶为载体。Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.
高效液相制备使用Waters2767、Waters2545、和创新恒通LC3000制备型色谱仪。High performance liquid phase preparation used Waters 2767, Waters 2545, and Chuangxin Hengtong LC3000 preparative chromatographs.
手性制备柱层析使用Shimadzu LC20-AP、THARSFC PREP80。Chiral preparative column chromatography used Shimadzu LC20-AP and THARSFC PREP80.
加压氢化反应使用北京佳维科创科技GCD-500G型氢气发生器。The pressurized hydrogenation reaction used a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.
微波反应使用Biotage initiator+型微波反应器。Microwave reactions were performed using a Biotage initiator+ microwave reactor.
实验例中如无特殊说明，反应均在氩气氛或者氮气氛下进行。Unless otherwise specified in the experimental examples, the reactions were carried out under argon or nitrogen atmosphere.
氩气氛或者氮气氛指反应瓶连接一个约1升容积的氩气或者氮气气球。Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 liter.
氢气氛是指反应瓶连接一个约1升容积的氢气气球。Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.
实验例中如无特殊说明，反应温度均为室温，温度范围是20℃-30℃。Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, which ranges from 20°C to 30°C.
实施例1：化合物1的合成
Example 1: Synthesis of Compound 1
步骤1：化合物1-2的制备Step 1: Preparation of compound 1-2
将原料化合物1-1(5.00g,26.29mmol)，2-(2-甲基-1,3-二氧戊环-2-基)乙烷-1-胺(3.79g，28.92mmol)溶于甲苯(60.0mL)中，室温下加入分子筛(4.99g)。将反应体系在dean-stark分水器下140摄氏度搅拌回流5小时至反应完全，冷却至室温后加入二氯甲烷(50mL)并过滤，滤液真空浓缩至干燥，得到化合物1-2(7.97g)可直接用于下一步反应,所得粗品收率为100％。MS(ESI)m/z[M+H]+＝304.2。The raw material compound 1-1 (5.00 g, 26.29 mmol) and 2-(2-methyl-1,3-dioxolan-2-yl)ethane-1-amine (3.79 g, 28.92 mmol) were dissolved in toluene (60.0 mL), and molecular sieves (4.99 g) were added at room temperature. The reaction system was stirred and refluxed at 140 degrees Celsius under a dean-stark water separator for 5 hours until the reaction was complete. After cooling to room temperature, dichloromethane (50 mL) was added and filtered. The filtrate was vacuum concentrated to dryness to obtain compound 1-2 (7.97 g) which can be directly used in the next step reaction. The crude yield was 100%. MS (ESI) m/z [M+H] + = 304.2.
步骤2：化合物1-3的制备Step 2: Preparation of compound 1-3
氮气保护下，将对甲苯磺酸(9.04g,52.55mmol)溶于甲苯(40mL)中，加热至140摄氏度，反应体系在dean-stark分水器下搅拌加热回流1小时来除去体系中的水分，然后滴加化合物1-2(7.97g，26.27mmol)的甲苯溶液(30mL)，滴加完毕后，反应液在140摄氏度下继续搅拌反应30分钟至反应完全，冷却后，加饱和碳酸钠水溶液淬灭反应，加入乙酸乙酯(20mL×2)萃取，有机相经分液、无水硫酸钠干燥、真空浓缩后得到粗品。所得粗品用硅胶柱纯化(洗脱剂为：二氯甲烷：甲醇＝10：1)得到1-3(3.40g)，收率为42.6％。MS(ESI)m/z[M+H]+＝304.2。Under nitrogen protection, p-toluenesulfonic acid (9.04 g, 52.55 mmol) was dissolved in toluene (40 mL) and heated to 140 degrees Celsius. The reaction system was stirred and heated under reflux under a dean-stark water separator for 1 hour to remove the water in the system, and then a toluene solution (30 mL) of compound 1-2 (7.97 g, 26.27 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at 140 degrees Celsius for 30 minutes until the reaction was complete. After cooling, a saturated sodium carbonate aqueous solution was added to quench the reaction, and ethyl acetate (20 mL×2) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The obtained crude product was purified by silica gel column (eluent: dichloromethane: methanol = 10: 1) to obtain 1-3 (3.40 g), with a yield of 42.6%. MS (ESI) m/z [M+H] + = 304.2.
步骤3：化合物1-4的制备Step 3: Preparation of compound 1-4
将化合物1-3(600mg,1.98mmol)，溶于二氯甲烷(2mL)，室温下加入TFA(2mL)和TfOH(0.2mL)，室温下搅拌1小时至反应完全。反应液真空浓缩，所得油状物溶解于乙酸乙酯中，用饱和碳酸钠水溶液洗涤，有机相经分液、无水硫酸钠干燥、真空浓缩后得到化合物1-4粗品(500mg)，可直接用于下一步反应，粗品收率为97.5％。MS(ESI)m/z[M+H]+＝260.2。Compound 1-3 (600 mg, 1.98 mmol) was dissolved in dichloromethane (2 mL), TFA (2 mL) and TfOH (0.2 mL) were added at room temperature, and the mixture was stirred at room temperature for 1 hour until the reaction was complete. The reaction solution was concentrated in vacuo, and the obtained oil was dissolved in ethyl acetate and washed with saturated sodium carbonate aqueous solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude compound 1-4 (500 mg), which can be directly used in the next step reaction. The crude yield was 97.5%. MS (ESI) m/z [M+H] + = 260.2.
步骤4：化合物1-5的制备Step 4: Preparation of Compound 1-5
将化合物1-4(3.5g,13.50mmol)溶于Boc2O(5.83g,27.00mmol)和TEA(1.88g,18.58mmol,2.59mL)的混合液中，反应液升温至55℃搅拌反应1小时至原料反应完全，反应液冷却至室温后直接用硅胶柱(洗脱剂为：石油醚：乙酸乙酯＝4：1)分离纯化得到3.3g化合物1-5，收率为68％。Compound 1-4 (3.5 g, 13.50 mmol) was dissolved in a mixture of Boc 2 O (5.83 g, 27.00 mmol) and TEA (1.88 g, 18.58 mmol, 2.59 mL). The reaction solution was heated to 55°C and stirred for 1 hour until the reaction of the raw materials was complete. After the reaction solution was cooled to room temperature, it was directly separated and purified using a silica gel column (eluent: petroleum ether: ethyl acetate = 4:1) to obtain 3.3 g of compound 1-5 with a yield of 68%.
1HNMR(400MHz,Methanol-d4)δ7.85–7.72(m,2H),7.15(d,J＝8.0Hz,0H),4.25-4.12(m,1H),3.99-3.88(m,1H),3.80(s,3H),3.08–2.85(m,3H),2.75–2.59(m,1H),2.58–2.41(m,3H),2.04–1.89(m,1H),0.97(s,9H)；MS(ESI)m/z[M+H]+＝360.2。 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.85–7.72 (m, 2H), 7.15 (d, J=8.0 Hz, 0H), 4.25-4.12 (m, 1H), 3.99-3.88 (m, 1H), 3.80 (s, 3H), 3.08–2.85 (m, 3H), 2.75–2.59 (m, 1H), 2.58–2.41 (m, 3H), 2.04–1.89 (m, 1H), 0.97 (s, 9H); MS (ESI) m/z [M+H] + ＝360.2.
步骤5：化合物1-6的制备 Step 5: Preparation of Compound 1-6
将化合物1-5(370mg,1.03mmol)溶于EtOH(5mL)中，冷却至-10℃，分批缓慢加入NaBH4(38.95mg,1.03mmol)，然后将反应液升温至室温继续搅拌1小时至反应完全。反应液经真空浓缩后加入饱和食盐水淬灭反应，用乙酸乙酯(5mL×2)萃取产物，有机相经饱和氯化铵水溶液洗涤、分液、无水硫酸钠干燥后，真空下浓缩、干燥后得到化合物1-6(368.0mg)可直接用于下一步反应,收率为99％。Compound 1-5 (370 mg, 1.03 mmol) was dissolved in EtOH (5 mL), cooled to -10 °C, and NaBH 4 (38.95 mg, 1.03 mmol) was slowly added in batches, and then the reaction solution was warmed to room temperature and stirred for 1 hour until the reaction was complete. The reaction solution was concentrated in vacuo, and saturated brine was added to quench the reaction, and the product was extracted with ethyl acetate (5 mL × 2). The organic phase was washed with saturated ammonium chloride aqueous solution, separated, and dried over anhydrous sodium sulfate, concentrated in vacuo, and dried to obtain compound 1-6 (368.0 mg), which can be directly used in the next step reaction, with a yield of 99%.
1H NMR(400MHz,DMSO-d6)δ7.83-7.72(m,2H),7.157(d,J＝8.8Hz,1H),4.80(d,J＝3.2Hz,1H),4.05-3.93(m,1H),3.83(s,3H),3.70-3.62(m,1H),3.54-3.41(m,1H),2.98–2.83(m,2H),2.79–2.62(m,1H),2.37-2.18(m,2H),2.11-1.99(m,1H),1.82–1.69(m,2H),1.70-1.54(m,1H),0.95(s,9H)；MS(ESI)m/z[M+H]+＝362.2。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.83-7.72 (m, 2H), 7.157 (d, J=8.8 Hz, 1H), 4.80 (d, J=3.2 Hz, 1H), 4.05-3.93 (m, 1H), 3.83 (s, 3H), 3.70-3.62 (m, 1H), 3.54-3.41 (m, 1H), 2.98–2.83 (m, 2H), 2.79–2.62 (m, 1H), 2.37-2.18 (m, 2H), 2.11-1.99 (m, 1H), 1.82–1.69 (m, 2H), 1.70-1.54 (m, 1H), 0.95 (s, 9H); MS (ESI) m/z [M+H] + ＝362.2.
步骤6：化合物1-7的制备Step 6: Preparation of Compound 1-7
氮气保护下，将化合物1-6(900mg,2.49mmol)溶于DMF(10mL)，室温下缓慢加入NaH(597.57mg,14.94mmol,60％purity)，混合物搅拌反应5分钟后，缓慢加入碘乙烷(2.33g,14.94mmol)，反应液在室温下继续搅拌2小时至反应完全，然后加入氯化铵水溶液淬灭反应，用乙酸乙酯(10mL×2)提取产物，有机相经分液、无水硫酸钠干燥、真空浓缩得到粗品，所得粗品经硅胶柱(洗脱剂为：石油醚：乙酸乙酯＝5：1)分离纯化得到化合物1-7(640mg)，收率为66％。MS(ESI)m/z[M+H]+＝390.2。Under nitrogen protection, compound 1-6 (900 mg, 2.49 mmol) was dissolved in DMF (10 mL), and NaH (597.57 mg, 14.94 mmol, 60% purity) was slowly added at room temperature. After the mixture was stirred for 5 minutes, iodoethane (2.33 g, 14.94 mmol) was slowly added. The reaction solution was stirred at room temperature for 2 hours until the reaction was complete, and then an aqueous solution of ammonium chloride was added to quench the reaction. The product was extracted with ethyl acetate (10 mL × 2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was separated and purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5: 1) to obtain compound 1-7 (640 mg), with a yield of 66%. MS (ESI) m/z [M + H] + = 390.2.
步骤7：化合物1-8的制备Step 7: Preparation of Compound 1-8
室温下将化合物1-7(900mg，2.31mmol)溶于DCM(9mL)，加入2,6-lutidine(742.81mg,6.93mmol)和TMSOTf(769.48mg,3.47mmol)，然后将反应液在室温下继续搅拌1小时至反应完全，加入饱和碳酸钠水溶液淬灭反应，用DCM(5mL×2)萃取产物，有机相经分液、干燥、真空浓缩后得到666mg化合物1-8可直接用于下一步反应，收率100％。MS(ESI)m/z[M+H]+＝290.2。Compound 1-7 (900 mg, 2.31 mmol) was dissolved in DCM (9 mL) at room temperature, 2,6-lutidine (742.81 mg, 6.93 mmol) and TMSOTf (769.48 mg, 3.47 mmol) were added, and the reaction solution was stirred at room temperature for 1 hour until the reaction was complete, saturated sodium carbonate aqueous solution was added to quench the reaction, and the product was extracted with DCM (5 mL×2). The organic phase was separated, dried, and concentrated in vacuo to obtain 666 mg of compound 1-8, which can be directly used in the next step reaction, with a yield of 100%. MS (ESI) m/z [M+H] + = 290.2.
步骤8：化合物1-9的制备Step 8: Preparation of Compound 1-9
将4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(785.32mg,2.70mmol)溶于DCM(8mL)，0℃氮气保护下，加入PPh3Br2(1.48g,3.50mmol)的二氯甲烷溶液(5mL)，加完后反应液在0℃搅拌反应1小时，然后加入化合物1-8(600mg,2.07mmol)和DIEA(905.78mg,7.01mmol)的二氯甲烷溶液(4mL)，反应液在室温下继续搅拌2小时至反应完全。反应液加水淬灭反应，用二氯甲烷提取产物，有机相经分液、无水硫酸钠干燥、真空浓缩后得到粗品。粗品经硅胶柱(洗脱剂为：石油醚：乙酸乙酯＝5：1)纯化分离得到945mg化合物1-9，收率为81％。MS(ESI)m/z[M+H]+＝563.4。Dissolve tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (785.32 mg, 2.70 mmol) in DCM (8 mL), add PPh 3 Br 2 (1.48 g, 3.50 mmol) in dichloromethane (5 mL) at 0°C under nitrogen protection, stir the reaction solution at 0°C for 1 hour, then add compound 1-8 (600 mg, 2.07 mmol) and DIEA (905.78 mg, 7.01 mmol) in dichloromethane (4 mL), and continue stirring the reaction solution at room temperature for 2 hours until the reaction is complete. Add water to the reaction solution to quench the reaction, extract the product with dichloromethane, separate the organic phase, dry it with anhydrous sodium sulfate, and concentrate it in vacuo to obtain a crude product. The crude product is purified and separated by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 945 mg of compound 1-9, with a yield of 81%. MS (ESI) m/z [M+H] + = 563.4.
步骤9：化合物1-10的制备Step 9: Preparation of Compound 1-10
将化合物1-9(1.1g,1.95mmol)溶于MeOH(3mL)\THF(3mL)\水(3mL)的混合溶液中，搅拌下加入NaOH(781.89mg,19.55mmol)，然后反应液升温至60℃继续搅拌2小时至反应完全。冷却至室温后，反应液用柠檬酸水溶液调节至pH＝6.0，然后用乙酸乙酯(10mL×3)提取产物，有机相经分液、无水硫酸钠干燥、真空浓缩干燥后得到化合物1-10(873.6mg)，粗品收率为100％。MS(ESI)m/z[M+H)+＝449.2。Compound 1-9 (1.1 g, 1.95 mmol) was dissolved in a mixed solution of MeOH (3 mL)\THF (3 mL)\water (3 mL), and NaOH (781.89 mg, 19.55 mmol) was added under stirring, and then the reaction solution was heated to 60°C and stirred for 2 hours until the reaction was complete. After cooling to room temperature, the reaction solution was adjusted to pH = 6.0 with citric acid aqueous solution, and then the product was extracted with ethyl acetate (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, and vacuum concentrated to obtain compound 1-10 (873.6 mg), and the crude yield was 100%. MS (ESI) m/z [M + H) + = 449.2.
步骤10：化合物1-11的制备Step 10: Preparation of Compound 1-11
将化合物1-10(873.6mg)经HPLC制备分离纯化(分离条件：色谱柱：Agilent 10Prep-C18 21.2×250mm；柱温：25℃；流动相：水(0.1％FA)-乙腈；流动相乙腈比例15％-35％in 12min；流速30ml/min)得到480mg化合物1-11(为第2个峰)，收率为55％。MS(ESI)m/z[M+H)+＝449.2。Compound 1-10 (873.6 mg) was prepared, separated and purified by HPLC (separation conditions: chromatographic column: Agilent 10Prep-C18 21.2×250 mm; column temperature: 25° C.; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 15%-35% in 12 min; flow rate 30 ml/min) to obtain 480 mg of compound 1-11 (the second peak), with a yield of 55%. MS (ESI) m/z [M+H) + = 449.2.
步骤11：化合物1的制备Step 11: Preparation of Compound 1
消旋体化合物1-11(36mg)经SFC(SFC制备方法:仪器:MG II preparative SFC(SFC-13)，柱型号:ChiralPak IC,250×30mm I.D.,10μm，流动相:A-CO2、B-乙醇(0.1％NH3·H2O)，梯度:B 50％，流速:80mL/min，背压:100bar，柱温:38℃，波长:220nm，周期:～12min)手性分离纯化得到14.7mg手性化合物1(为第1个峰)(分析方法：仪器:Waters UPC2analytical SFC(SFC-H)，柱型号:ChiralPak IC,100×4.6mm I.D.,3μm，流动相:A-CO2、B-乙醇(0.05％DEA)，梯度:B 50％，流速:2.5mL/min，背压:100bar，柱温: 35℃，波长:220nm)，收率为41％。The racemic compound 1-11 (36 mg) was chirally separated and purified by SFC (SFC preparation method: instrument: MG II preparative SFC (SFC-13), column model: ChiralPak IC, 250×30 mm ID, 10 μm, mobile phase: A-CO 2 , B-ethanol (0.1% NH 3 ·H 2 O), gradient: B 50%, flow rate: 80 mL/min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ～12 min) to obtain 14.7 mg of chiral compound 1 (the first peak) (analysis method: instrument: Waters UPC2analytical SFC (SFC-H), column model: ChiralPak IC, 100×4.6 mm ID, 3 μm, mobile phase: A-CO 2 , B-ethanol (0.05% DEA), gradient: B 50%, flow rate: 80 mL/min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ～12 min). 50%, flow rate: 2.5mL/min, back pressure: 100bar, column temperature: 35°C, wavelength: 220nm), the yield was 41%.
1H NMR(400MHz,Methanol-d4)δ7.98(d,J＝8.0Hz,1H),7.88(s,1H),7.50(d,J＝7.6Hz,1H),7.19(s,1H),6.63(s,1H),6.15(s,1H),4.20-4.02(m,1H),3.96-3.86(m,1H),3.82–3.68(m,1H),3.57(s,3H),3.53-3.42(m,2H),3.33-3.26(m,1H),3.18–3.00(m,2H),3.01–2.89(m,1H),2.74-2.57(m,1H),2.39(s,3H),2.36-2.35(m,1H),2.25-2.14(m,2H),2.00-1.83(m,2H),1.19–1.13(m,3H)；MS(ESI)m/z[M+H]+＝449.2。 1 H NMR (400MHz, Methanol-d4) δ7.98 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 6.63(s,1H),6.15(s,1H),4.20-4.02(m,1H),3.96-3.86(m,1H),3.82–3.68(m,1H),3.57(s,3H),3. 53-3.42(m,2H),3.33-3.26(m,1H),3.18–3.00(m,2H),3.01–2.89(m,1H),2.74-2.57(m,1H),2.39(s,3H ), 2.36-2.35(m,1H), 2.25-2.14(m,2H), 2.00-1.83(m,2H), 1.19–1.13(m,3H); MS(ESI)m/z[M+H] + =449.2.
实施例2：化合物2的合成
Example 2: Synthesis of Compound 2
步骤1：化合物2-1的制备Step 1: Preparation of compound 2-1
氮气保护下，将化合物1-6(1g,2.49mmol)溶于DMF(11mL)，缓慢加入NaH(597.71mg,14.94mmol,60％purity)，然后室温搅拌反应五分钟，再加入(碘甲基)环丙烷(0.96g,4.98mmol)。反应液升温至60℃搅拌反应30分钟后，补加(碘甲基)环丙烷(0.96g,4.98mmol)直到化合物1-6反应完全。反应液冷却至室温，加入氯化铵水溶液淬灭反应，用乙酸乙酯(10mL×2)提取产物，有机相经分液、无水硫酸钠干燥、真空下浓缩得粗品。粗品经硅胶柱(洗脱剂为：石油醚：乙酸乙酯＝5：1)分离纯化得到853mg化合物2-1，收率为82％。MS(ESI)m/z[M+H]+＝416.2。Under nitrogen protection, compound 1-6 (1g, 2.49mmol) was dissolved in DMF (11mL), and NaH (597.71mg, 14.94mmol, 60% purity) was slowly added, and then stirred at room temperature for five minutes, and then (iodomethyl) cyclopropane (0.96g, 4.98mmol) was added. After the reaction solution was heated to 60°C and stirred for 30 minutes, (iodomethyl) cyclopropane (0.96g, 4.98mmol) was added until compound 1-6 was completely reacted. The reaction solution was cooled to room temperature, and an aqueous solution of ammonium chloride was added to quench the reaction. The product was extracted with ethyl acetate (10mL×2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. The crude product was separated and purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 853mg of compound 2-1, with a yield of 82%. MS (ESI) m/z [M+H] + = 416.2.
步骤2：化合物2-2的制备Step 2: Preparation of compound 2-2
将化合物2-1(1g,2.19mmol)溶于DCM(10mL)，室温下加入2,6-lutidine(705.59mg,6.58mmol)和TMSOTf(974.57mg,4.39mmol)，然后搅拌反应1小时至原料反应完全，加入碳酸钠水溶液淬灭反应，用DCM(5mL×2)提取产物，有机相经分液、无水硫酸钠干燥、真空下浓缩干燥得到690mg化合物2-2，收率为100％；MS(ESI)m/z[M+H]+＝316.2。Compound 2-1 (1 g, 2.19 mmol) was dissolved in DCM (10 mL), 2,6-lutidine (705.59 mg, 6.58 mmol) and TMSOTf (974.57 mg, 4.39 mmol) were added at room temperature, and then the reaction was stirred for 1 hour until the raw materials reacted completely, and an aqueous sodium carbonate solution was added to quench the reaction. The product was extracted with DCM (5 mL×2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated and dried under vacuum to obtain 690 mg of compound 2-2, with a yield of 100%; MS (ESI) m/z[M+H] + ＝316.2.
步骤3：化合物2-3的制备Step 3: Preparation of compound 2-3
氮气保护下，将4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(800mg,2.74mmol)溶于DCM(8mL)，冷却至0℃后加入PPh3Br2(1.50g,3.57mmol)的二氯甲烷溶液(5mL)，反应液在0℃下继续搅拌1小时，然后加入化合物2-2(750mg,2.11mmol)和DIEA(1.09g,8.44mmol)的二氯甲烷溶液(4mL)。反应液升温至室温后继续搅拌2小时直至反应完全，然后加水淬灭反应，用二氯甲烷提取产物，有机相经分液、无水硫酸钠干燥、真空下浓缩干燥得到粗品。粗品经硅胶柱(洗脱剂为：石油醚：乙酸乙酯＝5：1)分离纯化得到0.95g化合物2-3，收率为76.5％。MS(ESI)m/z[M+H]+＝589.4。Under nitrogen protection, tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (800 mg, 2.74 mmol) was dissolved in DCM (8 mL), cooled to 0°C, and a dichloromethane solution (5 mL) of PPh 3 Br 2 (1.50 g, 3.57 mmol) was added. The reaction solution was stirred at 0°C for 1 hour, and then a dichloromethane solution (4 mL) of compound 2-2 (750 mg, 2.11 mmol) and DIEA (1.09 g, 8.44 mmol) was added. The reaction solution was heated to room temperature and stirred for 2 hours until the reaction was complete, and then water was added to quench the reaction. The product was extracted with dichloromethane, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. The crude product was separated and purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 0.95 g of compound 2-3, with a yield of 76.5%. MS (ESI) m/z [M+H] + = 589.4.
步骤4：化合物2-4的制备Step 4: Preparation of compound 2-4
将化合物2-3(1.0g,1.70mmol)溶于MeOH(3mL)/THF(3mL)/水(3mL)的混合溶液中，加入NaOH(636mg,15.90mmol)，然后将反应液升温至60℃搅拌反应4小时，冷却后，将反应液用柠檬酸水溶液调节至pH＝6.0，用乙酸乙酯(10mL×3)提取产物，有机相经分液，无水硫酸钠干燥、真空下浓缩至干燥，得到807.5mg化合物2-4，收率为100％。MS(ESI)m/z[M+H]+＝475.2。 Compound 2-3 (1.0 g, 1.70 mmol) was dissolved in a mixed solution of MeOH (3 mL)/THF (3 mL)/water (3 mL), and NaOH (636 mg, 15.90 mmol) was added. The reaction solution was heated to 60°C and stirred for 4 hours. After cooling, the reaction solution was adjusted to pH = 6.0 with citric acid aqueous solution, and the product was extracted with ethyl acetate (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under vacuum to obtain 807.5 mg of compound 2-4, with a yield of 100%. MS (ESI) m/z [M + H] + = 475.2.
步骤5：化合物2-5的制备Step 5: Preparation of compound 2-5
将化合物2-4(807.5mg)经HPLC制备分离纯化(分离条件：色谱柱：Agilent 10Prep-C18 21.2×250mm；柱温：25℃；流动相：水(0.1％FA)-乙腈；流动相乙腈比例20％-40％in 12min；流速30ml/min)得到408mg化合物2-5(为P2峰)，收率为51％。Compound 2-4 (807.5 mg) was prepared, separated and purified by HPLC (separation conditions: chromatographic column: Agilent 10Prep-C18 21.2×250 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 20%-40% in 12 min; flow rate 30 ml/min) to obtain 408 mg of compound 2-5 (P2 peak) with a yield of 51%.
1H NMR(400MHz,Methanol-d4)δ8.10(d,J＝8.0Hz,1H),8.00(s,1H),7.61(d,J＝8.0Hz,1H),7.29(d,J＝3.2Hz,1H),6.74(s,1H),6.27(s,1H),4.23(d,J＝12.8Hz,1H),4.04(d,J＝12.0Hz,1H),3.85(s,1H),3.67(s,3H),3.48-3.42(m,2H),3.18–3.01(m,3H),2.49(s,3H),2.47–2.23(m,2H),2.12-1.99(m,3H),1.65-1.54(m,1H),1.16-1.05(m,1H),0.94-0.86(m,1H),0.56(d,J＝6.8Hz,2H),0.27(d,J＝4.4Hz,2H)；MS(ESI)m/z[M+H]+＝475.2。 1 H NMR (400 MHz, Methanol-d4) δ8.10 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 3.2 Hz,1H),6.74(s,1H),6.27(s,1H),4.23(d,J＝12.8Hz,1H),4.04(d,J＝12.0Hz,1H),3.85(s,1H), 3.67(s,3H), 3.48-3.42(m,2H),3.18–3.01(m,3H),2.49(s,3H),2.47–2.23(m,2H),2.12-1.99(m,3H),1.65-1.54(m,1H ), 1.16-1.05(m,1H), 0.94-0.86(m,1H), 0.56(d,J＝6.8Hz,2H), 0.27(d,J＝4.4Hz,2H); MS(ESI)m/ z[M+H] + =475.2.
步骤6：化合物2的制备Step 6: Preparation of Compound 2
消旋体化合物2-5(530mg)经SFC(SFC制备方法:仪器:WATERS 150preparative SFC(SFC-26),柱型号:ChiralPak IC,250×30mm I.D.,10μm,流动相:A-CO2、B-乙醇(0.1％NH3·H2O),梯度:B 50％,流速:130mL/min,背压:100bar,柱温:38℃,波长:220nm,周期:～11min)手性分离纯化得到238mg手性化合物2(分析方法：仪器:Waters UPC2analytical SFC(SFC-H)，柱型号:ChiralPak IC,100×4.6mm I.D.,3μm，流动相:A-CO2、B-乙醇(0.05％DEA)，梯度:B 50％，流速:2.5mL/min，背压:100bar，柱温:35℃，波长:220nm)，收率为45％。The racemic compound 2-5 (530 mg) was chirally separated and purified by SFC (SFC preparation method: instrument: WATERS 150preparative SFC (SFC-26), column model: ChiralPak IC, 250×30 mm ID, 10 μm, mobile phase: A-CO 2 , B-ethanol (0.1% NH 3 ·H 2 O), gradient: B 50%, flow rate: 130 mL/min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ～11 min) to obtain 238 mg of chiral compound 2 (analytical method: instrument: Waters UPC2analytical SFC (SFC-H), column model: ChiralPak IC, 100×4.6 mm ID, 3 μm, mobile phase: A-CO 2 , B-ethanol (0.05% DEA), gradient: B 50%). 50%, flow rate: 2.5 mL/min, back pressure: 100 bar, column temperature: 35°C, wavelength: 220 nm), the yield was 45%.
1H NMR(400MHz,Methanol-d4)δ8.10(d,J＝8.0Hz,1H),8.00(s,1H),7.61(d,J＝8.0Hz,1H),7.29(d,J＝3.2Hz,1H),6.74(s,1H),6.27(s,1H),4.23(d,J＝12.8Hz,1H),4.04(d,J＝12.0Hz,1H),3.85(s,1H),3.67(s,3H),3.48-3.42(m,2H),3.18–3.01(m,3H),2.49(s,3H),2.47–2.23(m,2H),2.12-1.99(m,3H),1.65-1.54(m,1H),1.16-1.05(m,1H),0.94-0.86(m,1H),0.56(d,J＝6.8Hz,2H),0.27(d,J＝4.4Hz,2H)；MS(ESI)m/z[M+H]+＝475.2。 1 H NMR (400 MHz, Methanol-d4) δ8.10 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 3.2 Hz,1H),6.74(s,1H),6.27(s,1H),4.23(d,J＝12.8Hz,1H),4.04(d,J＝12.0Hz,1H),3.85(s,1H), 3.67(s,3H), 3.48-3.42(m,2H),3.18–3.01(m,3H),2.49(s,3H),2.47–2.23(m,2H),2.12-1.99(m,3H),1.65-1.54(m,1H ), 1.16-1.05(m,1H), 0.94-0.86(m,1H), 0.56(d,J＝6.8Hz,2H), 0.27(d,J＝4.4Hz,2H); MS(ESI)m/ z[M+H] + =475.2.
实施例3：化合物3的合成
Example 3: Synthesis of Compound 3
步骤1：化合物3-1的制备Step 1: Preparation of compound 3-1
氮气保护下，将化合物4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(73.0mg,0.25mmol)溶于二氯甲烷(3mL)中，在0℃下缓慢滴加入二溴三苯基膦(137mg,0.32mmol)的二氯甲烷溶液(1mL)，加料完成后在0℃下继续搅拌1小时，然后加入化合物1-3(41mg,0.14mmol)和二异丙基乙胺(52.4mg,0.40mmol)的二氯甲烷溶液(1mL)，加入后反应液在室温下搅拌2小时至反应完全，加入水(2mL)淬灭反应，用二氯甲烷(10mL×2)萃取，有机相经分液、无水硫酸钠干燥、减压浓缩至干燥。剩余物经硅胶柱(石油醚:乙酸乙酯＝3:1)纯化得到化合物3-1(25mg)，产率为32.0％。MS(ESI)m/z[M+H]+＝577.2。Under nitrogen protection, the compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (73.0 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and a dichloromethane solution (1 mL) of dibromotriphenylphosphine (137 mg, 0.32 mmol) was slowly added dropwise at 0°C. After the addition was completed, stirring was continued at 0°C for 1 hour, and then a dichloromethane solution (1 mL) of compound 1-3 (41 mg, 0.14 mmol) and diisopropylethylamine (52.4 mg, 0.40 mmol) was added. After the addition, the reaction solution was stirred at room temperature for 2 hours until the reaction was complete, and water (2 mL) was added to quench the reaction, and extracted with dichloromethane (10 mL×2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain compound 3-1 (25 mg) with a yield of 32.0%. MS (ESI) m/z [M+H] + = 577.2.
步骤2：化合物3的制备Step 2: Preparation of compound 3
氮气保护下，将化合物3-1(32.0mg,0.055mmol)溶于甲醇(0.5mL)、四氢呋喃(0.5mL)、水(0.5mL)的混合溶剂中，再加入氢氧化钠(22.20mg,0.55mmol)，所得混合液升温至60℃搅拌1小时后冷却至室温，用饱和柠檬酸水溶液调节至pH＝4.0，用乙酸乙酯(2mL×3)萃取，有机相经分液、无水硫酸钠干燥、减压浓缩至干燥。剩余物经制备HPLC纯化(色谱柱：Welch xtimate C18 21.2mm*250mm 10um；柱温：25℃；流动相：水(0.1％碳酸氢铵)-乙腈；流动相乙腈比例25％-55％in 18min；流速30ml/min)得到化合物3(5.90mg)，产率为23％。MS(ESI)m/z[M+H]+＝463.2。Under nitrogen protection, compound 3-1 (32.0 mg, 0.055 mmol) was dissolved in a mixed solvent of methanol (0.5 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL), and sodium hydroxide (22.20 mg, 0.55 mmol) was added. The resulting mixture was heated to 60 ° C and stirred for 1 hour, then cooled to room temperature, adjusted to pH = 4.0 with saturated citric acid aqueous solution, extracted with ethyl acetate (2 mL × 3), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (chromatographic column: Welch xtimate C18 21.2mm*250mm 10um; column temperature: 25 ° C; mobile phase: water (0.1% ammonium bicarbonate)-acetonitrile; mobile phase acetonitrile ratio 25%-55% in 18min; flow rate 30ml/min) to obtain compound 3 (5.90 mg) with a yield of 23%. MS (ESI) m/z [M+H] + = 463.2.
1HNMR(400MHz,Methanol-d4)δ7.99(d,J＝8.0Hz,1H),7.89(s,1H),7.53(d,J＝8.1Hz,1H),7.19(d,J ＝3.2Hz,1H),6.63(s,1H),6.24–6.13(m,1H),4.11–3.90(m,4H),3.85(t,J＝6.3Hz,2H),3.57(s,3H),3.48(d,J＝16.0Hz,2H),3.16–3.02(m,2H),2.88(d,J＝10.2Hz,1H),2.71(d,J＝15.2Hz,2H),2.39(s,3H),2.01(dd,J＝14.3,3.0Hz,2H),1.88–1.75(m,1H)。 1 HNMR (400MHz, Methanol-d4) δ7.99 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.19 (d, J =3.2Hz,1H),6.63(s,1H),6.24–6.13(m,1H),4.11–3.90(m,4H),3.85(t,J＝6.3Hz,2H),3.57(s,3H),3.48(d,J＝16.0Hz,2H),3.16–3.02(m,2H),2.88(d,J＝10.2Hz,1H),2.71(d,J＝15.2Hz,2H),2.39(s,3H),2.01(dd,J＝14.3,3.0Hz,2H),1.88–1.75(m,1H).
实施例4：化合物4的合成
Example 4: Synthesis of Compound 4
步骤1：化合物4-2的制备Step 1: Preparation of compound 4-2
氮气保护下，将化合物4-1(102.58mg,0.5mmol)溶于二氯甲烷(20.20mL)中，再加入2-甲基-1,3-二氧戊环-2-乙胺(65.59mg,0.5mmol)、硫酸镁(250.00mg,2.08mmol)和对甲苯磺酸(4.31mg,0.025mmol)，所得反应液加热回流3小时至原料反应完全，冷却至室温，得到含化合物4-2的反应液直接用于下一步反应，粗品产率为100％。MS(ESI)m/z[M+H]+＝319.2。Under nitrogen protection, compound 4-1 (102.58 mg, 0.5 mmol) was dissolved in dichloromethane (20.20 mL), and 2-methyl-1,3-dioxolane-2-ethylamine (65.59 mg, 0.5 mmol), magnesium sulfate (250.00 mg, 2.08 mmol) and p-toluenesulfonic acid (4.31 mg, 0.025 mmol) were added. The resulting reaction solution was heated under reflux for 3 hours until the raw materials reacted completely, and then cooled to room temperature to obtain a reaction solution containing compound 4-2, which was directly used for the next step reaction. The crude yield was 100%. MS (ESI) m/z [M+H] + = 319.2.
步骤2：化合物4-3的制备Step 2: Preparation of compound 4-3
氮气保护下，上述所得化合物4-2(159.6mg，0.5mmol)的二氯甲烷(20.20mL)反应液中加入三氟化硼乙醚(221.88mg,0.75mmol,0.2mL,48％purity)溶液，所得混合液加热回流4小时至反应完全,冷却至室温，加入饱和NaHCO3水溶液(8mL)淬灭反应，反应液用乙酸乙酯(20mL×2)萃取，有机相经无水硫酸钠干燥、减压浓缩得化合物4-3(90mg)，产率为56.6％。MS(ESI)m/z[M+H]+＝319.2。Under nitrogen protection, a solution of boron trifluoride ether (221.88 mg, 0.75 mmol, 0.2 mL, 48% purity) was added to the reaction solution of compound 4-2 (159.6 mg, 0.5 mmol) in dichloromethane (20.20 mL), and the resulting mixture was heated under reflux for 4 hours until the reaction was complete, cooled to room temperature, and saturated NaHCO 3 aqueous solution (8 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (20 mL×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 4-3 (90 mg), with a yield of 56.6%. MS (ESI) m/z[M+H] + ＝319.2.
步骤3：化合物4-4的制备Step 3: Preparation of compound 4-4
氮气保护下，将化合物4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(73.0mg,0.25mmol)溶于二氯甲烷(10mL)，冷却至0℃，加入二溴三苯基膦(137.90mg,0.33mmol)，搅拌1.5小时后加入化合物4-3(80mg,0.25mmol)和二异丙基乙胺(97.44mg,0.75mmol)，在0℃下搅拌反应1小时后升温至室温下继续搅拌反应6小时至原料反应完全，加入水(2mL)淬灭反应，用二氯甲烷(10mL×2)萃取，有机相经分液、无水硫酸钠干燥、减压浓缩至干燥。剩余物经硅胶柱层析(石油醚：乙酸乙酯＝6：4)纯化得化合物4-4(130mg)，产率为87.4％。MS(ESI)m/z[M+H]+＝591.8。Under nitrogen protection, compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (73.0 mg, 0.25 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, dibromotriphenylphosphine (137.90 mg, 0.33 mmol) was added, stirred for 1.5 hours, compound 4-3 (80 mg, 0.25 mmol) and diisopropylethylamine (97.44 mg, 0.75 mmol) were added, stirred at 0°C for 1 hour, warmed to room temperature and continued to stir for 6 hours until the raw material reacted completely, water (2 mL) was added to quench the reaction, extracted with dichloromethane (10 mL×2), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:4) to obtain compound 4-4 (130 mg) with a yield of 87.4%. MS (ESI) m/z [M+H] + = 591.8.
步骤4：化合物4的制备Step 4: Preparation of compound 4
氮气保护下，将化合物4-4(110mg,0.18mmol)溶于水(1mL)/甲醇(1mL)/四氢呋喃(1mL)的混合溶剂中，加入氢氧化钠(111.54mg,2.79mmol)，所得反应液升温至60℃反应2小时至原料反应完全，用饱和柠檬酸水溶液调节至pH＝4.0，用乙酸乙酯(5mL×3)萃取，有机相经分液、无水硫酸钠干燥、减压浓缩至干燥。剩余物经制备HPLC纯化得化合物4(45mg)，产率为52％。MS(ESI)m/z[M+H]+＝478.2。Under nitrogen protection, compound 4-4 (110 mg, 0.18 mmol) was dissolved in a mixed solvent of water (1 mL)/methanol (1 mL)/tetrahydrofuran (1 mL), sodium hydroxide (111.54 mg, 2.79 mmol) was added, and the resulting reaction solution was heated to 60°C for 2 hours until the reaction of the raw materials was complete, and the pH was adjusted to 4.0 with saturated citric acid aqueous solution, extracted with ethyl acetate (5 mL×3), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to obtain compound 4 (45 mg) with a yield of 52%. MS (ESI) m/z[M+H] + ＝478.2.
1HNMR(400MHz,DMSO-d6)δ10.99–10.42(m,2H),7.84(d,J＝7.9Hz,1H),7.62(dd,J＝7.8,1.6Hz,1H),7.39(d,J＝1.5Hz,1H),7.22(t,J＝2.8Hz,1H),6.87(dd,J＝3.0,2.0Hz,1H),6.60(s,1H),3.90(d,J＝5.6Hz,1H),3.84–3.74(m,3H),3.62(s,3H),3.35(s,2H),2.86(t,J＝11.4Hz,1H),2.69–2.59(m,1H),2.40(s,3H),2.08(d,J＝13.4Hz,1H),1.74–1.61(m,2H),1.57(dt,J＝12.5,6.1Hz,1H)。 1 H NMR (400 MHz, DMSO-d6) δ 10.99–10.42 (m, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.39 (d, J＝1.5Hz,1H),7.22(t,J＝2.8Hz,1H),6.87(dd,J＝3.0,2.0Hz,1H),6.60(s,1H),3.90( d, J = 5.6 Hz, 1H), 3.84–3.74 (m, 3H), 3.62 (s, 3H), 3.35 (s, 2H), 2.86 (t, J = 11.4 Hz, 1H), 2.69–2.59 (m , 1H), 2.40(s, 3H), 2.08(d, J＝13.4Hz, 1H), 1.74–1.61(m, 2H), 1.57(dt, J＝12.5, 6.1Hz, 1H).
实施例5：化合物5的合成
Example 5: Synthesis of Compound 5
步骤1：化合物5-2的制备Step 1: Preparation of compound 5-2
氮气保护下，将化合物5-1(615.5mg,3mmol)溶于DMF(10mL)，0℃下加入钠氢(79.2mg,3.3mmol)，升温至室温反应30分钟后加入碘甲烷(510.98mg,3.60mmol)，所得反应液继续在室温下反应2小时至反应完全，加入水(5mL)淬灭，用乙酸乙酯(30mL×2)萃取，所得有机相经无水硫酸钠干燥、减压浓缩干燥，所得剩余物经硅胶柱层析(石油醚：乙酸乙酯＝1：1)得到化合物5-2(510mg)，产率为77.6％。MS(ESI)m/z[M+H]+＝220.0。Under nitrogen protection, compound 5-1 (615.5 mg, 3 mmol) was dissolved in DMF (10 mL), sodium hydrogen sulfide (79.2 mg, 3.3 mmol) was added at 0 ° C, the temperature was raised to room temperature and reacted for 30 minutes, and iodomethane (510.98 mg, 3.60 mmol) was added. The resulting reaction solution continued to react at room temperature for 2 hours until the reaction was complete, and water (5 mL) was added to quench, and extracted with ethyl acetate (30 mL × 2). The obtained organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound 5-2 (510 mg), with a yield of 77.6%. MS (ESI) m/z [M + H] + = 220.0.
1HNMR(400MHz,DMSO-d6)δ7.68(qd,J＝7.7,0.9Hz,2H),7.56(t,J＝0.9Hz,1H),3.91(s,3H),3.20(s,3H)。 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (qd, J = 7.7, 0.9 Hz, 2H), 7.56 (t, J = 0.9 Hz, 1H), 3.91 (s, 3H), 3.20 (s, 3H).
步骤2：化合物5-3的制备Step 2: Preparation of compound 5-3
氮气保护下，将化合物5-2((300mg,1.37mmol)溶于二氯甲烷(20mL)中，再加入2-甲基-1,3-二氧戊环-2-乙胺(179.53mg,1.37mmol)、硫酸镁(684.33mg,5.70mmol)和对甲苯磺酸(11.78mg,0.068mmol)，所得反应液加热回流3小时至原料反应完全，冷却至室温，得到含化合物5-3的反应液直接用于下一步反应，粗品产率为100％。MS(ESI)m/z[M+H]+＝333.0。Under nitrogen protection, compound 5-2 (300 mg, 1.37 mmol) was dissolved in dichloromethane (20 mL), and 2-methyl-1,3-dioxolane-2-ethylamine (179.53 mg, 1.37 mmol), magnesium sulfate (684.33 mg, 5.70 mmol) and p-toluenesulfonic acid (11.78 mg, 0.068 mmol) were added. The resulting reaction solution was heated under reflux for 3 hours until the raw materials reacted completely, and then cooled to room temperature to obtain a reaction solution containing compound 5-3, which was directly used for the next step reaction. The crude yield was 100%. MS (ESI) m/z [M+H] + = 333.0.
步骤2：化合物5-4的制备Step 2: Preparation of compound 5-4
氮气保护下，上述所得化合物5-3(454.8mg，1.37mmol)的二氯甲烷(20mL)反应液中加入三氟化硼乙醚(607.34mg,2.05mmol,0.54ml,48％purity)溶液，所得混合液加热回流6小时至反应完全,冷却至室温，加入饱和NaHCO3水溶液(8mL)淬灭反应，反应液用乙酸乙酯(20mL×2)萃取，有机相经无水硫酸钠干燥、减压浓缩得化合物5-4(300mg)，产率为66％。MS(ESI)m/z[M+H]+＝333.0。Under nitrogen protection, a solution of boron trifluoride ether (607.34 mg, 2.05 mmol, 0.54 ml, 48% purity) was added to the reaction solution of compound 5-3 (454.8 mg, 1.37 mmol) in dichloromethane (20 mL) obtained above, and the resulting mixture was heated under reflux for 6 hours until the reaction was complete, cooled to room temperature, and saturated NaHCO 3 aqueous solution (8 mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (20 mL×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 5-4 (300 mg), with a yield of 66%. MS (ESI) m/z[M+H] + ＝333.0.
步骤3：化合物5-5的制备Step 3: Preparation of compound 5-5
氮气保护下，将化合物4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(114mg,0.39mmol)溶于二氯甲烷(10mL)，冷却至0℃，加入二溴三苯基膦(214.7mg,0.51mmol)，搅拌1.5小时后加入化合物5-4(130.1mg,0.39mmol)和二异丙基乙胺(151.7mg,1.17mmol)，在0℃下搅拌反应1小时后升温至室温下继续搅拌反应6小时至原料反应完全，加入水(2mL)淬灭反应，用二氯甲烷(10mL×2)萃取，有机相经分液、无水硫酸钠干燥、减压浓缩至干燥。剩余物经硅胶柱层析(石油醚：乙酸乙酯＝7：3)纯化得化合物5-5(125mg)，产率为52.7％。MS(ESI)m/z[M+H]+＝606.0。Under nitrogen protection, compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (114 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, dibromotriphenylphosphine (214.7 mg, 0.51 mmol) was added, stirred for 1.5 hours, compound 5-4 (130.1 mg, 0.39 mmol) and diisopropylethylamine (151.7 mg, 1.17 mmol) were added, stirred at 0°C for 1 hour, warmed to room temperature and continued to stir for 6 hours until the raw material reacted completely, water (2 mL) was added to quench the reaction, extracted with dichloromethane (10 mL×2), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:3) to obtain compound 5-5 (125 mg) with a yield of 52.7%. MS (ESI) m/z [M+H] + = 606.0.
步骤4：化合物5的制备Step 4: Preparation of compound 5
氮气保护下，将化合物5-5(100mg,0.165mmol)溶于水(1.5mL)/甲醇(1.5mL)/四氢呋喃(1.5mL)的混合溶剂中，加入氢氧化钠(726.4mg,18.16mmol)，所得反应液升温至60℃反应3小时至原料反应完全，用饱和柠檬酸水溶液调节至pH＝4.0，用乙酸乙酯(5mL×3)萃取，有机相经分液、无水硫酸钠干燥、 减压浓缩至干燥。剩余物经制备HPLC纯化得化合物5(30mg)，产率为37％。MS(ESI)m/z[M+H]+＝492.2。Under nitrogen protection, compound 5-5 (100 mg, 0.165 mmol) was dissolved in a mixed solvent of water (1.5 mL)/methanol (1.5 mL)/tetrahydrofuran (1.5 mL), sodium hydroxide (726.4 mg, 18.16 mmol) was added, and the resulting reaction solution was heated to 60 ° C for 3 hours until the reaction of the raw materials was complete, and the pH was adjusted to 4.0 with saturated citric acid aqueous solution, and extracted with ethyl acetate (5 mL × 3), and the organic phase was separated, dried over anhydrous sodium sulfate, The residue was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 5 (30 mg) with a yield of 37%. MS (ESI) m/z [M+H] + = 492.2.
1HNMR(400MHz,DMSO-d6)δ10.77(s,1H),7.94(d,J＝7.9Hz,1H),7.75(dd,J＝7.8,1.5Hz,1H),7.52(d,J＝1.5Hz,1H),7.23(t,J＝2.8Hz,1H),6.84(dd,J＝3.0,2.0Hz,1H),6.60(s,1H),3.95–3.85(m,1H),3.85–3.73(m,3H),3.62(s,3H),3.24(s,4H),3.04(d,J＝11.8Hz,1H),2.87(t,J＝11.3Hz,1H),2.73–2.64(m,1H),2.40(s,3H),2.09(d,J＝13.5Hz,1H),1.78–1.52(m,3H)。 1 HNMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.75 (dd, J = 7.8, 1.5 Hz, 1H), 7.52 (d, J = 1.5Hz,1H),7.23(t,J＝2.8Hz,1H),6.84(dd,J＝3.0,2.0Hz,1H),6.60(s,1H),3.95 –3.85(m,1H),3.85–3.73(m,3H),3.62(s,3H),3.24(s,4H),3.04(d,J＝11.8Hz,1H),2.87(t,J＝11.3 Hz, 1H), 2.73–2.64 (m, 1H), 2.40 (s, 3H), 2.09 (d, J＝13.5 Hz, 1H), 1.78–1.52 (m, 3H).
生物学实施例Biological Examples
实验例1：人补体Factor B蛋白结合测试实验(TR-FRET法)Experimental Example 1: Human complement factor B protein binding test experiment (TR-FRET method)
配置缓冲液，成分为：50mM Tris-HCl，pH7.0，50mM NaCl，0.01％w/v Triton X-100。待测化合物首先用DMSO 3倍稀释，然后用移液器取出0.6uL转移至96孔板，加入99.4μL缓冲吹打混匀，转移2.5μL稀释后的化合物至384孔板(ProxiPlate-384plus，PE)。用缓冲液配置90nM的His-FB蛋白(ab276729，Abcam)，转移2.5μL至含有化合物的384孔板中。然后用缓冲液配置300nM带有Cy5荧光标记的探针，转移5μL至384孔板。最后加入5μL 15nM配置于缓冲液中的LANCE Eu-anti-6xHis antibody(AD0110，Perkin Elmer)，1000rpm离心30秒，避光室温孵育2小时。用Envision读取荧光值(Exc.Filter为UV2(TRF)320，Ems.Filter为APC665，2nd ems.filter为LANCE Laser attenuated Europium filter，50μs delay)，计算665nm/615nm比值。最后用GraphPad Prism 8软件分析数据，使用剂量-响应-抑制(四参数)等式通过GraphPadPrism软件计算IC50值。Prepare buffer, the composition is: 50mM Tris-HCl, pH7.0, 50mM NaCl, 0.01% w/v Triton X-100. The test compound is first diluted 3 times with DMSO, then 0.6uL is transferred to a 96-well plate with a pipette, 99.4μL of buffer is added and pipetted to mix, and 2.5μL of the diluted compound is transferred to a 384-well plate (ProxiPlate-384plus, PE). 90nM His-FB protein (ab276729, Abcam) is prepared with buffer, and 2.5μL is transferred to the 384-well plate containing the compound. Then 300nM probe with Cy5 fluorescent label is prepared with buffer, and 5μL is transferred to the 384-well plate. Finally, 5μL of 15nM LANCE Eu-anti-6xHis antibody (AD0110, Perkin Elmer) prepared in buffer is added, centrifuged at 1000rpm for 30 seconds, and incubated at room temperature for 2 hours in the dark. The fluorescence value was read with Envision (Exc.Filter was UV2 (TRF) 320, Ems.Filter was APC665, 2nd ems.filter was LANCE Laser attenuated Europium filter, 50 μs delay), and the 665nm/615nm ratio was calculated. Finally, the data were analyzed with GraphPad Prism 8 software, and the IC 50 value was calculated using the dose-response-inhibition (four-parameter) equation by GraphPad Prism software.
实验结果：Experimental results:
测试化合物对人补体Factor B蛋白结合测试实验(TR-FRET法)IC50值如表1所示，其中A代表：IC50值<100nM；B代表：100nM≤IC50值<1000nM；C代表：IC50值>1000nM。The IC50 values of the test compounds for human complement Factor B protein binding test experiment (TR-FRET method) are shown in Table 1, where A represents: IC50 value <100nM; B represents: 100nM≤IC50 value <1000nM; C represents: IC50 value >1000nM.
表1化合物对人补体Factor B蛋白结合测试实验的活性(TR-FRET法)
Table 1 Activity of compounds in human complement Factor B protein binding test (TR-FRET method)
结论：本发明化合物对人补体Factor B蛋白具有显著的结合活性。Conclusion: The compounds of the present invention have significant binding activity to human complement Factor B protein.
实验例2：C3蛋白水解实验Experimental Example 2: C3 protein hydrolysis experiment
1、准备CVF:Bb复合物：首先配置反应缓冲液(10mM MgCl2,0.05％w/v CHAPS,PBS pH 7.4),用反应缓冲液配置终浓度300nM FD(A409，Quidel),1μM FB(A408，Quidel),1μM CVF(A600，Quidel)的混合反应体系，37℃孵育3小时。将酶切产物分装成小份，储存在-80℃用于后续实验。1. Prepare CVF:Bb complex: First, prepare reaction buffer (10mM MgCl 2 , 0.05% w/v CHAPS, PBS pH 7.4), use reaction buffer to prepare a mixed reaction system with a final concentration of 300nM FD (A409, Quidel), 1μM FB (A408, Quidel), and 1μM CVF (A600, Quidel), and incubate at 37°C for 3 hours. Divide the enzyme digestion product into small portions and store at -80°C for subsequent experiments.
2、C3水解反应：化合物首先用DMSO三倍梯度稀释，共十个浓度，然后用反应缓冲液稀释40倍，转移1μL至384孔板(ProxiPlate-384plus，PE)中。用反应缓冲液配置2.5nM CVF:Bb和1uM C3(A401，Quidel)。转移2μL CVF:Bb至含有化合物的ProxiPlate 384板孔，37℃孵育30分钟。加入2μL C3起始反应，37℃孵育180分钟，反应过程中注意密封384孔板。每孔加入5uL 2x protease inhibitor cocktail(5892970001,Roche)停止反应，混匀后将1.25μL反应液转移至384孔黑板(OptiPlate-384F HB，PE)，加入23.8μL包被缓冲液(含有100mM sodium carbonate pH9.0：C3041,Sigma和1M NaCl：A610476-0001， BBI Life Science),1000rpm离心1分钟，放至4℃过夜包被。第二天弃去前一天包被好的384孔板中的液体，在干净的吸水纸上拍干，用PBST洗涤3遍。每孔加入25μL starting block T20(37539，Thermofisher)，室温孵育15分钟，弃去上清，用PBST洗涤3遍。每孔加入25μL 25ul Anti-C3a neo-epitope抗体(C7850-13G，US Biological，稀释倍数为100)，室温孵育1小时，弃去上清，用PBST洗涤3遍。加入25μL Quantablu fluorogenic peroxidase底物(15169，Thermofisher)，1000rpm离心30秒。室温孵育30分钟，用Envision(PE,Envision@2105)读取荧光值，激发波长为340nm，发射波长为460nm。最后用GraphPad Prism8软件分析数据，使用剂量-响应-抑制(四参数)等式通过GraphPadPrism软件计算IC50值。2. C3 hydrolysis reaction: The compound was first diluted three-fold with DMSO for a total of ten concentrations, then diluted 40-fold with reaction buffer, and 1 μL was transferred to a 384-well plate (ProxiPlate-384plus, PE). 2.5 nM CVF:Bb and 1 uM C3 (A401, Quidel) were prepared with reaction buffer. 2 μL CVF:Bb was transferred to the ProxiPlate 384 plate well containing the compound and incubated at 37°C for 30 minutes. 2 μL C3 was added to start the reaction and incubated at 37°C for 180 minutes. During the reaction, the 384-well plate was sealed. 5uL 2x protease inhibitor cocktail (5892970001, Roche) was added to each well to stop the reaction. After mixing, 1.25μL of the reaction solution was transferred to a 384-well black plate (OptiPlate-384F HB, PE), and 23.8μL of coating buffer (containing 100mM sodium carbonate pH9.0: C3041, Sigma and 1M NaCl: A610476-0001, BBI Life Science), centrifuge at 1000rpm for 1 minute, and place at 4℃ for overnight coating. The next day, discard the liquid in the 384-well plate coated the day before, pat dry on clean absorbent paper, and wash 3 times with PBST. Add 25μL starting block T20 (37539, Thermofisher) to each well, incubate at room temperature for 15 minutes, discard the supernatant, and wash 3 times with PBST. Add 25μL 25ul Anti-C3a neo-epitope antibody (C7850-13G, US Biological, dilution factor of 100) to each well, incubate at room temperature for 1 hour, discard the supernatant, and wash 3 times with PBST. Add 25μL Quantablu fluorogenic peroxidase substrate (15169, Thermofisher), centrifuge at 1000rpm for 30 seconds. Incubate at room temperature for 30 minutes, and read the fluorescence value with Envision (PE, Envision @ 2105), with an excitation wavelength of 340nm and an emission wavelength of 460nm. Finally, the data were analyzed using GraphPad Prism 8 software, and the IC 50 value was calculated using the dose-response-inhibition (four-parameter) equation using GraphPad Prism software.
实验结果：Experimental results:
测试化合物对C3酶水解实验IC50值如表2所示，其中A代表：IC50值<100nM；B代表：100nM≤IC50值<1000nM；C代表：IC50值>1000nM,LNP023为参照化合物。The IC50 values of the test compounds for C3 enzymatic hydrolysis experiments are shown in Table 2, wherein A represents: IC50 value <100nM; B represents: 100nM≤IC50 value <1000nM; C represents: IC50 value >1000nM, and LNP023 is the reference compound.
表2化合物对C3酶水解实验的活性
Table 2 Activity of compounds in C3 enzymatic hydrolysis assay
结论：本发明化合物具有优异的体外活性，能够显著抑制C3酶的水解活性。Conclusion: The compounds of the present invention have excellent in vitro activity and can significantly inhibit the hydrolytic activity of C3 enzyme.
实验例3：在LPS诱导AP激活小鼠中的药效Experimental Example 3: Drug efficacy in LPS-induced AP activation mice
1、实验目的1. Experimental purpose
通过血浆C3d/iC3b/C3c/activated C3检测，评估化合物抑制细菌脂多糖诱导C57小鼠补体旁路(AP)激活的作用。The inhibitory effects of compounds on bacterial lipopolysaccharide-induced complement alternative pathway (AP) activation in C57 mice were evaluated by plasma C3d/iC3b/C3c/activated C3 assay.
2、实验材料2. Experimental Materials
2.1实验动物2.1 Experimental animals
SPF级别雌性C57BL/6J小鼠，体重16-19g，7周龄，共44只；44 SPF female C57BL/6J mice, weighing 16-19 g, 7 weeks old;
来源：购买于北京维通利华实验动物技术有限公司；Source: Purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.;
动物生产许可证号：生产许可SCXK(沪)2017-0011或SCXK(京)2016-0006或SCXK(京)2016-0011或SCXK(浙)2019-0001Animal production license number: Production license SCXK (Shanghai) 2017-0011 or SCXK (Beijing) 2016-0006 or SCXK (Beijing) 2016-0011 or SCXK (Zhejiang) 2019-0001
查士利华医药技术(上海)有限公司张江动物房，地址：上海市浦东新区张衡路1077号2号楼4层。饲养环境：温度23±2℃，相对湿度40-70％，照明时间6AM/6PM开关灯；动物自由饲喂普通饲料和灭菌饮用水。所有动物实验都获得了查士利华医药技术(上海)有限公司动物伦理委员会的批准。The Zhangjiang Animal House of Charles River Pharmaceutical Technology (Shanghai) Co., Ltd. is located at the 4th floor of Building 2, No. 1077 Zhangheng Road, Pudong New District, Shanghai. The breeding environment: temperature 23±2℃, relative humidity 40-70%, lighting time 6AM/6PM switch lights; animals are fed with ordinary feed and sterilized drinking water freely. All animal experiments were approved by the Animal Ethics Committee of Charles River Pharmaceutical Technology (Shanghai) Co., Ltd.
2.2受试药与溶媒2.2 Test drug and solvent
(1)溶媒配方：0.5％MC+0.5％Tween 80；(1) Solvent formula: 0.5% MC + 0.5% Tween 80;
(2)受试药配制方法：将化合物加入溶媒中，超声搅拌至均一溶液/混悬液，配制成需要的浓度。(2) Preparation of test drug: Add the compound to the solvent, stir ultrasonically until a uniform solution/suspension is obtained, and prepare the desired concentration.
3、实验过程3. Experimental process
3.1动物适应3-7天后，依据体重，将动物按表3计划分组。 3.1 After 3-7 days of animal adaptation, the animals were grouped according to the plan in Table 3 based on their body weight.
表3实验分组
Table 3 Experimental groups
(溶媒：0.5％MC+0.5％Tween 80)(Solvent: 0.5% MC + 0.5% Tween 80)
3.2鼠沙门氏菌脂多糖(LPS)溶于无菌PBS，配置成200μg/mL溶液。3.2 Salmonella enterica serovar Typhimurium lipopolysaccharide (LPS) was dissolved in sterile PBS to prepare a 200 μg/mL solution.
3.3各组动物按表3计划，先腹腔注射0.1mL PBS或LPS造模，后灌胃溶剂或待测化合物。3.3 According to the plan in Table 3, each group of animals was first intraperitoneally injected with 0.1 mL PBS or LPS to establish the model, and then gavage with the solvent or the test compound.
3.4给药后1h，第1组至第5组动物，用CO2安乐死或将动物用异氟烷麻醉后心脏采血。抗凝剂用EDTA-K2。3.4 One hour after administration, animals in groups 1 to 5 were euthanized with CO2 or anesthetized with isoflurane and blood was collected from the heart. EDTA-K2 was used as the anticoagulant.
3.5血液置于湿冰中，4℃，4500g离心10分钟，收集血浆，分装为两管，10-50ul/管，保存于-80℃冰箱，用于测定C3d/iC3b/C3c/activated C3含量。3.5 Place the blood in wet ice and centrifuge at 4500g for 10 minutes at 4°C. Collect the plasma and divide it into two tubes, 10-50ul/tube, and store it in a -80°C refrigerator for the determination of C3d/iC3b/C3c/activated C3 content.
4、统计方法4. Statistical methods
实验数据以均数±标准误(Means±SEM)表示，采用Graphpad Prism 8.0软件，单因素方差分析，p<0.05将被认为有统计学显著性差异。The experimental data were expressed as mean ± standard error (Means ± SEM) and analyzed using Graphpad Prism 8.0 software and one-way analysis of variance. p < 0.05 was considered to be statistically significant.
5、实验结果5. Experimental results
实验结果如表4与图1所示。The experimental results are shown in Table 4 and Figure 1.
表4
Table 4
实验结论：本发明化合物具有优异的动物体内活性，具有抑制细菌脂多糖(LPS)诱导C57小鼠补体旁路(AP)激活的作用。Experimental conclusion: The compound of the present invention has excellent in vivo activity in animals and has the effect of inhibiting bacterial lipopolysaccharide (LPS)-induced complement alternative pathway (AP) activation in C57 mice.
以上对本发明的示例性实施方式进行了说明。应当理解，本申请的保护范围不限定于上述示例性的实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。 The exemplary embodiments of the present invention are described above. It should be understood that the protection scope of the present application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention should be included in the protection scope of the present application.

Claims (19)

  1. 式(I)所示化合物、其光学异构体或其药学上可接受的盐，
    The compound represented by formula (I), its optical isomer or its pharmaceutically acceptable salt,
    其中，in,
    X选自C(R5)2、O或N(R5)；X is selected from C(R 5 ) 2 , O or N(R 5 );
    R1选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C1-6杂烷基和C3-9环烷基，所述C1-6烷基、C1-6杂烷基或C3-9环烷基任选被1、2或3个R取代；R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-9 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl or C 3-9 cycloalkyl is optionally substituted with 1, 2 or 3 R;
    R2选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C1-6杂烷基、C3-6环烷基和3-6元杂环烷基，所述C1-6烷基、C1-6杂烷基、C3-6环烷基或3-6元杂环烷基任选被1、2或3个R取代；R 2 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
    L选自单键、O、S、NH、所述NH、 任选被1、2或3个R取代；L is selected from a single bond, O, S, NH, The NH Optionally substituted with 1, 2 or 3 R;
    R3选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C3-6环烷基、C1-6杂烷基和3-6元杂环烷基，所述C1-6烷基、C3-6环烷基、C1-6杂烷基或3-6元杂环烷基任选被1、2或3个R取代； R3 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
    R4选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C3-6环烷基、C1-6杂烷基和3-6元杂环烷基，所述C1-6烷基、C3-6环烷基、C1-6杂烷基或3-6元杂环烷基任选被1、2或3个R取代； R4 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
    或者，R3和R4连接在一起，形成C3-6环烷基或3-6元杂环烷基，所述C3-6环烷基或3-6元杂环烷基任选被1、2或3个R取代；Alternatively, R 3 and R 4 are linked together to form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;
    R5选自H、F、Cl、CN、OH、C1-6烷基、C1-6杂烷基和C3-9环烷基，所述C1-6烷基、C1-6杂烷基或C3-9环烷基任选被1、2或3个R取代；R 5 is selected from H, F, Cl, CN, OH, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-9 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl or C 3-9 cycloalkyl is optionally substituted with 1, 2 or 3 R;
    R6选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C2-6烯基和C2-6炔基，所述C1-6烷基、C2-6烯基或C2-6炔基任选被1、2或3个R取代；R 6 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally substituted with 1, 2 or 3 R;
    R分别独立地选自OH、CN、F、Cl、Br、I、C1-6烷基、C1-6杂烷基、C3-6环烷基和3-6元杂环烷基；R is independently selected from OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;
    所述C1-6杂烷基或3-6元杂环烷基包含1、2、3或4个独立选自-O-、-NH-、-N＝、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O)2-和N的杂原子或杂原子团。The C 1-6 heteroalkyl or 3-6 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.
  2. 根据权利要求1所述的化合物、其光学异构体或其药学上可接受的盐，其结构如下所示，
    The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, has the following structure:
    其中，in,
    L、R1、R2、R3、R4、R5和R6如权利要求1所定义。L, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 1 .
  3. 根据权利要求1或2所述化合物、其光学异构体或其药学上可接受的盐，其中，R1选自H、OH、CN、F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基和C3-6环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基或C3-6环烷基任选被1、2或3个R取代。The compound according to claim 1 or 2, its optical isomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino and C 3-6 cycloalkyl, and the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino or C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R.
  4. 根据权利要求3所述化合物、其光学异构体或其药学上可接受的盐，其中，R1选自H、OH、CN、F、Cl、Br、I、CH3、 The compound according to claim 3, its optical isomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, OH, CN, F, Cl, Br, I, CH 3 ,
  5. 根据权利要求1或2所述化合物、其光学异构体或其药学上可接受的盐，其中，R2选自H、OH、CN、F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C3-6环烷基和3-6元杂环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C3-6环烷基或3-6元杂环烷基任选被1、2或3个R取代。The compound according to claim 1 or 2, its optical isomer or pharmaceutically acceptable salt thereof, wherein R2 is selected from H, OH, CN, F, Cl, Br, I, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino , C3-6 cycloalkyl and 3-6 membered heterocycloalkyl, and the C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino , C3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R.
  6. 根据权利要求5所述化合物、其光学异构体或其药学上可接受的盐，其中，R2选自H、OH、CN、F、Cl、Br、I、CH3、 The compound according to claim 5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, OH, CN, F, Cl, Br, I, CH 3 ,
  7. 根据权利要求1或2所述化合物、其光学异构体或其药学上可接受的盐，其中，R3选自H、OH、CN、F、Cl、Br、I、C1-6烷基、C3-6环烷基、C1-6烷氧基、C1-6烷硫基和3-6元杂环烷基，所述C1-6烷基、C3-6环烷基、C1-6烷氧基、C1-6烷硫基或3-6元杂环烷基任选被1、2或3个R取代。The compound according to claim 1 or 2, its optical isomer or pharmaceutically acceptable salt thereof, wherein R3 is selected from H, OH, CN, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio and 3-6 membered heterocycloalkyl, and the C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R.
  8. 根据权利要求7所述化合物、其光学异构体或其药学上可接受的盐，其中，R3选自H、OH、CN、F、Cl、Br、I、CH3、 The compound according to claim 7, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, OH, CN, F, Cl, Br, I, CH 3 ,
  9. 根据权利要求8所述化合物、其光学异构体或其药学上可接受的盐，其中，结构单元选自H、OH、CN、F、Cl、Br、I、CH3、 The compound according to claim 8, its optical isomer or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from H, OH, CN, F, Cl, Br, I, CH 3 ,
  10. 根据权利要求1或2所述化合物、其光学异构体或其药学上可接受的盐，其中，R4选自H、OH、CN、F、Cl、Br、I、C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基和3-6元杂环烷基，所述C1-3烷基、C3-6环烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基或3-6元杂环烷基任选被1、2或3个R取代。The compound according to claim 1 or 2, its optical isomer or pharmaceutically acceptable salt thereof, wherein R4 is selected from H, OH, CN, F, Cl, Br, I, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 alkylthio , C1-3 alkylamino and 3-6 membered heterocycloalkyl, and the C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R.
  11. 根据权利要求10所述化合物、其光学异构体或其药学上可接受的盐，其中，R4选自H、OH、CN、F、Cl、Br、I、CH3、所述CH3、 任选被1、2或3个R取代。The compound according to claim 10, its optical isomer or pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, OH, CN, F, Cl, Br, I, CH 3 , The CH 3 , Optionally substituted with 1, 2 or 3 R.
  12. 根据权利要求11所述化合物、其光学异构体或其药学上可接受的盐，其中，R4选自H、OH、CN、F、Cl、Br、I、CH3、 The compound according to claim 11, its optical isomer or pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, OH, CN, F, Cl, Br, I, CH 3 ,
  13. 根据权利要求1或2所述化合物、其光学异构体或其药学上可接受的盐，其中，R3和R4连接在一起，形成所述任选被1、2或3个R取代。The compound according to claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are linked together to form Said Optionally substituted with 1, 2 or 3 R.
  14. 根据权利要求13所述化合物、其光学异构体或其药学上可接受的盐，其中，R3和R4连接在一起，形成 The compound according to claim 13, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are linked together to form
  15. 根据权利要求1或2所述化合物、其光学异构体或其药学上可接受的盐，其中，R5选自H、F、Cl、CN、OH、CH3、 The compound according to claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, F, Cl, CN, OH, CH 3 ,
  16. 下式化合物、其光学异构体或其药学上可接受的盐或其同位素化合物，其选自：

    The compound of the following formula, its optical isomer or its pharmaceutically acceptable salt or its isotope compound, which is selected from:

  17. 一种药物组合物，其中，包含权利要求1-16任一项所述的化合物、其光学异构体或其药学上可接受的盐。A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, its optical isomer or a pharmaceutically acceptable salt thereof.
  18. 权利要求1-16任一项所述的化合物、其光学异构体或其药学上可接受的盐或权利要求17所述的药物组合物在制备治疗和/或预防补体因子B活性和表达量相关疾病的药物中的应用。Use of the compound according to any one of claims 1 to 16, its optical isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a drug for treating and/or preventing diseases related to complement factor B activity and expression.
  19. 根据权利要求18所述的应用，其中，所述补体因子B活性和表达量相关疾病选自IgA肾病(IgAN)、C3肾小球疾病(C3G)、非典型溶血性尿毒症综合征(aHUS)、膜性肾病(MN)、阵发性夜间血红蛋白尿(PNH)、年龄相关性黄斑变性(AMD)、地图状萎缩(GA)、血液透析并发症、神经脊髓炎(NMO)、肝脏性疾病、炎症性肠病与重症肌无力(MG)中的一种或多种。 The use according to claim 18, wherein the disease related to complement factor B activity and expression is selected from one or more of IgA nephropathy (IgAN), C3 glomerular disease (C3G), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), geographic atrophy (GA), hemodialysis complications, neuromyelitis (NMO), liver diseases, inflammatory bowel disease and myasthenia gravis (MG).
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CN105579444A (en) * 2013-07-15 2016-05-11 诺华股份有限公司 Piperidinyl indole derivatives and their use as complement factor b inhibitors
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