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WO2024217462A1 - Sulfur pentafluoride substituted aromatic ring compound and use thereof - Google Patents

Sulfur pentafluoride substituted aromatic ring compound and use thereof Download PDF

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Publication number
WO2024217462A1
WO2024217462A1 PCT/CN2024/088358 CN2024088358W WO2024217462A1 WO 2024217462 A1 WO2024217462 A1 WO 2024217462A1 CN 2024088358 W CN2024088358 W CN 2024088358W WO 2024217462 A1 WO2024217462 A1 WO 2024217462A1
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compound
pharmaceutically acceptable
stereoisomer
acceptable salt
alkyl
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PCT/CN2024/088358
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French (fr)
Chinese (zh)
Inventor
钱文远
廖勇刚
奚正英
张路
肖瑶
刘超男
林军
江凯璇
王正
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2024217462A1 publication Critical patent/WO2024217462A1/en

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  • the present invention relates to a series of sulfur pentafluoride substituted aromatic ring compounds and their applications, and specifically to compounds represented by formula (II), their stereoisomers or pharmaceutically acceptable salts thereof.
  • NLRP3 inflammasome plays an important role in the occurrence and development of inflammatory diseases.
  • NLRP3 inflammasome is a macromolecular multiprotein complex with a molecular weight of about 700 kDa, which is composed of NLRP3, a member of the nucleotide-binding oligomerization domain-like receptor (NLRs) family, the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARC) and the effector protein Caspase-1. It can be detected in a variety of immune cells such as granulocytes, macrophages, dendritic cells, B cells and non-immune cells such as epithelial cells and keratinocytes.
  • NLRP3 Its core protein NLRP3 is composed of 11 leucine repeat sequences (LRR) at the C-terminus, the NACHT domain in the middle and the Pyrin domain (PYD) at the N-terminus. NLRP3 interacts with the adaptor protein ASC through its PYD domain, and then ASC recruits and activates pro-Caspase-1 through its CARC domain to form a protein complex, the NLRP3 inflammasome.
  • the NLRP3 inflammasome can be activated by a variety of pathogen-associated molecular patterns or damage-associated molecular patterns, and plays an extremely important role in the immune function of the innate immune system.
  • pro-inflammatory factor precursors such as pro-IL-1 and pro-IL-18 into mature IL-1 ⁇ and IL-18, activating and amplifying downstream inflammatory and injury responses, thereby causing serious or even fatal damage to the body.
  • NLRP3 inflammasomes are closely related to the occurrence and development of a variety of inflammatory diseases. For example, after urate crystals in the joints and surrounding areas of gout patients are phagocytosed by macrophages, they may activate NLRP3 inflammasomes by promoting potassium ion efflux and inducing mitochondria to produce a large amount of reactive oxygen species (ROS), thereby promoting the maturation and secretion of IL-1 ⁇ . After mature IL-1 ⁇ binds to the IL-1 receptor of target cells, it activates downstream signal transduction factors, generates a large amount of inflammatory mediators, and thus aggravates the inflammatory response. ⁇ -Amyloid protein can activate the NLRP3 inflammasome of microglia, leading to inflammatory responses in the brain, causing neuronal damage and death, and further causing the occurrence of neurodegenerative diseases such as Alzheimer's disease.
  • ROS reactive oxygen species
  • MCC950 a derivative of diarylsulfonylurea, can reduce the severity of experimental autoimmune encephalomyelitis (EAE) in mice by inhibiting the activity of NLRP3 inflammasome.
  • EAE experimental autoimmune encephalomyelitis
  • MCC950 can improve the disease scores of diseased mice and alleviate colon shortening and weight loss caused by colitis.
  • NLRP3 inhibitors have entered the clinical trial stage, such as Novartis' DFV-890, which is in Phase II clinical trials and is intended for inflammatory-related diseases; Roche has two NLRP3 inhibitors in Phase I clinical trials, of which Inzomelid is used to treat neurodegenerative diseases and Somalix is used for the body's other Inflammatory diseases in other parts of the body; in addition, ZYIL1 developed by Zyd ⁇ us Cadila is in Phase I clinical trials for a variety of inflammatory-related diseases.
  • NLRP3 inhibitors provide potential treatments for inflammatory diseases related to this pathway, which is of great significance and has broad prospects. At present, there is still a need to develop new NLRP3 inhibitors for the treatment of inflammatory diseases.
  • the present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • X is OH, NH 2 , NHCOCH 3 or CH 2 OH;
  • R 1 is H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl or C 3-6 cycloalkyl, wherein the C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl and C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3 Ra ;
  • R2 is H, F, Cl, Br, I, CN, C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 Rb ;
  • L is a single bond, -NH(CH 2 ) n - or -O-;
  • n 0, 1, 2 or 3;
  • R3 is C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 Rc ;
  • T is N or C
  • Ring B is a 5-7 membered cycloalkenyl, a 5-7 membered heterocycloalkenyl or a 5-6 membered heteroaryl;
  • Each Ra is independently H, F, Cl, Br, I, CN, OH or C1-3 alkoxy;
  • Each R b is independently H, F, Cl, Br, I, CN, OH or C 1-3 alkyl;
  • Each R c is independently H, F, Cl, Br, I , CN, OH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, and the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
  • Each R a1 is independently C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F;
  • hetero is selected from 1, 2 and 3 heteroatoms or heteroatom groups independently selected from O, NH, S or N;
  • the compound is not selected from the following molecules:
  • the present invention provides a compound represented by formula (P), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • R 1 is H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl or C 3-6 cycloalkyl, wherein the C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl and C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3 Ra ;
  • R2 is H, F, Cl, Br, I, CN, C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 Rb ;
  • T is N or C
  • Ring B is a 5-7 membered cycloalkenyl, a 5-7 membered heterocycloalkenyl or a 5-6 membered heteroaryl;
  • Each Ra is independently H, F, Cl, Br, I, CN, OH or C1-3 alkoxy;
  • Each R b is independently H, F, Cl, Br, I, CN, OH or C 1-3 alkyl;
  • Each R c is independently H, F, Cl, Br, I , CN, OH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, and the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
  • Each R a1 is independently C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F;
  • hetero is selected from 1, 2 and 3 heteroatoms or heteroatom groups which are independently O, NH, S or N.
  • R a1 is independently methyl or ethyl, and the methyl or ethyl is optionally substituted by 1, 2 or 3 F, and other variables are as defined in the present invention.
  • R a1 is independently methyl, difluoromethyl, trifluoromethyl or ethyl, and other variables are as defined in the present invention.
  • each R mentioned above is independently H, F, OH or -OCH 3 , and other variables are as defined in the present invention.
  • each Ra is independently H, F, Cl, Br, I, CN, OH, methoxy or ethoxy, and other variables are as defined in the present invention.
  • each Ra is independently H or F, and other variables are as defined in the present invention.
  • each R b is independently H, F or CH 3 , and other variables are as defined in the present invention.
  • each R c is independently H, F, OH, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, and the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are optionally independently substituted by 1, 2 or 3 R, and R and other variables are as defined in the present invention.
  • each R c is independently H, F, OH, -CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 or -N(CH 3 ) 2 , and other variables are as defined in the present invention.
  • R 1 is H, F, Cl, Br, I or CH 3 , and other variables are as defined in the present invention.
  • R 1 is H, and other variables are as defined in the present invention.
  • R 3 is C 1-3 alkyl, C 5-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 9-10 aryl or 9-10 membered heteroaryl, wherein the C 1-3 alkyl, C 5-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 9-10 aryl and 9-10 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
  • R 3 is CH 2 CH 3 , CH 2 CH 2 CH 3 , cyclohexanyl, tetrahydrofuranyl, piperidinyl, benzotetrahydrofuranyl, 1,3-dihydro-2H-benzimidazolyl or pyridotriazolyl, wherein the CH 2 CH 3 , CH 2 CH 2 CH 3 , cyclohexanyl, tetrahydrofuranyl, piperidinyl, benzotetrahydrofuranyl, 1,3-dihydro-2H-benzimidazolyl and pyridotriazolyl are each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
  • R 3 is CH 2 CH 3 , CH 2 CH 2 CH 3 , wherein, the CH 2 CH 3 , CH 2 CH 2 CH 3 , Optionally substituted with 1, 2 or 3 R c , R c and other variables are as defined herein.
  • the above L is NH or O, and other variables are as defined in the present invention.
  • the above-mentioned ring B is Other variables are as defined in the present invention.
  • the above-mentioned ring B is Other variables are as defined herein.
  • the above-mentioned ring A is Other variables are as defined herein.
  • the ring A is Other variables are as defined in the present invention.
  • the above compound has the structure shown in (II-1) or (II-2):
  • Ring B, X, L, T, R 1 , R 2 and R 3 are as defined in the present invention.
  • the above compound has the structure shown as follows (P-1), (P-2) or (P-3):
  • Ring B, T, R 1 , R 2 and R 3 are as defined in the present invention.
  • the above compound has the structure shown in (P-4) or (P-5):
  • Ring B, T, R 1 , R 2 and R c are as defined in the present invention.
  • the present invention also provides a compound of the following formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • the present invention also provides a compound of the following formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • the present invention also provides the use of the above compound, its stereoisomer or its pharmaceutically acceptable salt in the preparation of drugs for treating inflammatory disease-related diseases.
  • the compounds of the present invention exhibit good NLRP3 inhibitory activity and have great application prospects in the treatment of inflammation-related diseases; the compounds of the present invention have good drugability, high oral exposure in rodents and non-rodents, and no significant difference in oral absorption between species; the compounds of the present invention show a high degree of binding rate in the plasma of different species, good metabolic stability in CD-1 mice, SD rats, beagles, crab-eating monkeys and human hepatocytes, and good liver microsomal stability.
  • 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 humans 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 the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.
  • 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 reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • 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.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • 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.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes The groups connected in this way are just that when one chemical bond is connected, the H at the site will be reduced by one and become the corresponding monovalent piperidinyl.
  • C 1-3 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.
  • C 1-6 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl 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, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • 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 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2 , C 3 , C 4 , C 5 and C 6 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 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , etc.
  • C2-5 alkenyl is used to refer to a straight or branched hydrocarbon group consisting of 2 to 5 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 C2-5 alkenyl includes C2-3 , C2-4 , C5 , C4 , C3 and C2 alkenyl.
  • the C 2-5 alkenyl group may be monovalent, divalent or polyvalent. Examples of C 2-5 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like.
  • C 2-5 alkynyl is used to represent a straight or branched hydrocarbon group consisting of 2 to 5 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group.
  • the C 2-5 alkynyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It may be monovalent, divalent or polyvalent. Examples of C 2-5 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.
  • 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 and the like.
  • heteroalkyl by itself or in combination with another term refers to 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.
  • 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 is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3 heteroalkyl.
  • 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, but the terms "alkoxy,”"alkylamino,” and “alkylthio” (or thioalkoxy) are conventional expressions and refer to those alkyl groups attached to the remainder of the molecule through an oxygen, amino or sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example -
  • C 1-3 heteroalkyl by itself or in combination with another term refers to 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.
  • 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 is C 1-3 heteroalkyl.
  • heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy) are conventional expressions and refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom, amino group or sulfur atom, respectively.
  • the number of atoms in a ring is generally defined as the ring member number, for example, a “5-7 membered ring” refers to a “ring” having 5-7 atoms arranged around it.
  • C 3-8 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-8 cycloalkyl includes C 3-6 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • Examples of C 3-8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • 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.
  • C 3-7 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-7 cycloalkyl includes C 3-6 , C 4-6 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • Examples of C 3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C 5-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 5 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 5-6 cycloalkyl includes C5 and C6 cycloalkyl; it can be monovalent, divalent or polyvalent. Examples of C 5-6 cycloalkyl include, but are not limited to, cyclopentyl and cyclohexyl.
  • 5-7 membered cycloalkenyl means a cycloalkenyl group consisting of 5 to 7 ring atoms.
  • the ring includes a monocyclic ring, and also includes bicyclic ring systems such as spirocyclic rings, fused rings and bridged rings. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 5-7 membered ring includes a 5-6 membered ring, a 6-7 membered ring, a 5-membered ring, a 6-membered ring and a 7-membered ring.
  • "5-7 membered ring” includes, for example, phenyl, pyridyl and piperidyl.
  • the term "ring” also includes a ring system containing at least one ring, each of which independently meets the above definition.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated monocyclic radical 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 are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • heteroatoms may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule.
  • the 3-6 membered heterocycloalkyl includes 4-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc.
  • 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), and the like.
  • heterocycloalkyl means a heterocycloalkyl group consisting of 5 to 7 ring atoms.
  • the ring includes a monocyclic ring and also includes The term “heterocycloalkyl” includes piperidinyl, etc., but does not include phenyl.
  • the term “ring” also includes a ring system containing at least one ring, each of which independently meets the above definition.
  • 3-7 heterocycloalkyl means a heterocycloalkyl consisting of 3 to 7 ring atoms.
  • the ring includes a monocyclic ring, and also includes bicyclic ring systems such as spirocyclic rings, cyclic rings and bridged rings. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 3-7 membered ring includes 3-6, 3-5, 3-4, 4-7, 4-6, 4-5, 5-7, 4, 5, 6 and 7 members.
  • the term "5-7 membered heterocycloalkyl” includes piperidinyl, etc., but does not include phenyl.
  • ring also includes a ring system containing at least one ring, each of which "rings” independently meets the above definition.
  • 5-6 membered heterocycloalkyl by itself or in combination with other terms refers to a saturated 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).
  • the 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl.
  • 5-6 membered heterocycloalkyl groups include, but are not limited to, 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, hexahydro
  • the term "5-12 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 12 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 are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • 5-12 membered heterocycloalkyl includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, paracyclic and bridged rings, wherein at least one ring is aromatic, and the other rings can be any ring.
  • heteroatoms can occupy the position where the heterocycloalkyl connects to the rest of the molecule.
  • the 5-12 membered heterocycloalkyl includes 5-10 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heterocycloalkyl, etc.
  • Examples of 5-12 membered heterocycloalkyl groups include, but are not limited to, 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, hexa
  • 5-7 membered heterocycloalkenyl by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 7 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms 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).
  • 5-7 membered heterocycloalkenyl a heteroatom may occupy the position at which the heterocycloalkenyl is attached to the rest of the molecule.
  • the 5-7 membered heterocycloalkenyl includes 5-6 membered, 5 membered, 6 membered and 7 membered heterocycloalkenyl, etc. Examples of 5-7 membered heterocycloalkenyl include, but are not limited to
  • C 6-10 aromatic ring and “C 6-10 aryl” of the present invention can be used interchangeably.
  • the term “C 6-10 aromatic ring” or “C 6-10 aryl” means a cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated ⁇ electron system. It can be a monocyclic ring or a fused bicyclic ring system, wherein at least one ring is aromatic and the other rings can be any ring. It can be monovalent, divalent or polyvalent.
  • C 6-10 aryl includes C 6-9 , C 9 , C 10 and C 6 aryl. Examples of C 6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.),
  • C 9-10 aromatic ring and “C 9-10 aryl” in the present invention can be used interchangeably.
  • the term “C 9-10 aromatic ring” or “C 9-10 aryl” means a cyclic hydrocarbon group composed of 9 to 10 carbon atoms with a conjugated ⁇ electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, wherein at least one ring is aromatic, and the other rings can be any ring. It can be monovalent, divalent or polyvalent.
  • C 9-10 aryl includes C 9 and C 10 aryl. Examples of C 9-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.),
  • 5-10 membered heteroaromatic ring and “5-10 membered heteroaryl” of the present invention can be used interchangeably.
  • the term “5-10 membered heteroaryl” refers to a cyclic group consisting of 5 to 10 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. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein at least one ring is aromatic, and the other rings can be any rings.
  • 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 5-10 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom.
  • the 5-10 membered heteroaryl includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl, etc.
  • Examples of the 5-10 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), yl, 2-thiazolyl, 4-thiazolyl, 5-thi
  • the terms “5-6 membered heteroaromatic ring” and “5-6 membered heteroaryl” of the present invention can be used interchangeably, and the term “5-6 membered heteroaryl” means 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. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be 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 through 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
  • 9-10 membered heteroaromatic ring and “9-10 membered heteroaryl” of the present invention can be used interchangeably.
  • the term “9-10 membered heteroaryl” refers to a cyclic group consisting of 9 to 10 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. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein at least one ring is aromatic, and the other rings can be any rings.
  • 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 9-10 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom.
  • the 9-10 membered heteroaryl includes 9-membered and 10-membered heteroaryl.
  • Examples of the 9-10 membered heteroaryl include, but are not limited to, benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).
  • 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 on the ring is n to n+m
  • 3-12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, and 12-membered rings, and also include any range from n to n+m, for example, 3-12-membered rings include 3-6-membered rings, 3-9-membered rings, 5-6-membered rings, 5-7-membered rings, 6-7-membered rings, 6-8-membered rings, and 6-10-membered rings, etc.
  • 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 synthesis methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction (SXRC) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: Scan and collect relevant After obtaining the data, the direct method (Shelxs97) was further used to analyze the crystal structure to confirm the absolute configuration.
  • CO2 represents carbon dioxide
  • DCM dichloromethane
  • MeOH represents methanol
  • ATP represents adenosine triphosphate
  • LPS represents lipopolysaccharide
  • CBA represents cytokine microsphere assay technology
  • PMA represents crotonyl-12-tetradecanoate-13-acetate
  • NEAA represents non-essential amino acids
  • FBS represents fetal bovine serum
  • IL-1 ⁇ represents interleukin-1 ⁇
  • Human IL-1 ⁇ Flex Set represents human interleukin-1 ⁇ detection kit.
  • Figure 1 Bar graph of animal serum IL-1 ⁇ levels at 2 hours and 6 hours after administration of various test drugs at different dosages.
  • Step 1 Dissolve the compound intermediate 1-1 (317.8 mg, 1.4 mmol) and intermediate 1-2 (0.2 g, 1.4 mmol) in tert-amyl alcohol (5 mL) and water (1 mL), add potassium hydroxide (168.0 mg, 3.0 mmol), 5-(di-tert-butylphosphine)-1,3,5-triphenyl-1 hydrogen-[1,4]dipyrazole (141.2 mg, 278.6 ⁇ mol) and tris(dibenzylideneacetone)palladium (127.6 mg, 139.3 ⁇ mol). Stir at 90 ° C for 12 hours under nitrogen protection.
  • Step 2 Compound 1-2 (1.5 g, 5.02 mmol) was dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (1.39 g, 10.05 mmol) and iodomethane (1.07 g, 7.53 mmol) were added, and stirred at 60°C for 2 hours. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3). After the organic phase was dried and concentrated, the crude product was purified by column chromatography (petroleum ether) to obtain compound 1-3.
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ ppm 7.61-7.66 (m, 1H) 7.25-7.27 (m, 1H) 7.24 (s, 1H) 3.95 (s, 3H).
  • Step 3 Compound 1-3 (0.8 g, 2.6 mmol), bis-pinacol borate (800.0 mg, 3.2 mmol) and potassium acetate (502.0 mg, 5.1 mmol) were suspended in dioxane (6 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (200.0 mg, 273.3 ⁇ mol) was added. The mixture was stirred at 100 °C for 3 hours under nitrogen protection. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL*3).
  • Step 4 Compound 1-4 (270.0 mg, 749.7 ⁇ mol) and intermediate 1 (217.2 mg, 749.7 ⁇ mol) were dissolved in dioxane (10 mL) and water (2 mL), potassium carbonate (207.2 mg, 1.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (128.7 mg, 157.6 ⁇ mol) were added, and the reaction was stirred at 100 ° C for 4 hours under nitrogen protection. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL*3).
  • Step 1 Compound 1-4 (0.3 g, 833.0 ⁇ mol) and intermediate 2 (220.6 mg, 916.3 ⁇ mol) were dissolved in dioxane (10 mL) and water (2 mL), potassium carbonate (230.3 mg, 1.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (142.97 mg, 175.07 ⁇ mol) were added, and the reaction was stirred at 100 ° C for 0.5 hours under nitrogen protection. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL*3).
  • Step 2 Compound 2-1 (90.0 mg, 184.6 ⁇ mol) was dissolved in dichloromethane (1 mL), and boron tribromide (2.6 g, 10.4 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, it was quenched with water (5 mL) and methanol (5 mL), concentrated to dryness, and the crude product was separated by HPLC (chromatographic column: YMC Triart C18 150*25mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 12%-42%, 10 min) to obtain compound 2.
  • HPLC chromatographic column: YMC Triart C18 150*25mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 12%-42%, 10 min
  • Step 1 Cool a solution of compound 1-4 (15.4 g, 42.7 mmol) in dichloromethane (100 mL) to 0°C, slowly add boron tribromide (16.0 g, 64.0 mmol) dropwise, and stir at 0°C for 0.5 hours. After the reaction is complete, add a cooled saturated aqueous sodium carbonate solution (100 mL) at 0°C.
  • Step 2 Dissolve intermediate 4-3 (5.9 g, 21.20 mmol) in methanol (30 mL), add 10% dry palladium carbon ( ⁇ 1 g), react under hydrogen (15 Psi) atmosphere, stir at 25 ° C for 1 hour, filter after the reaction, and spin dry the filtrate to obtain intermediate 4.
  • Step 2 A mixture of compounds 3-2 and 4-2 (60 mg, 227.3 ⁇ mol) and intermediate 3 (64.3 mg, 227.3 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), potassium carbonate (173.5 mg, 1.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (91.8 mg, 125.5 ⁇ mol) were added, and the reaction was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3).
  • Step 2 Compound 5-2 (30.3 mg, 113.6 ⁇ mol) and intermediate 3 (30.0 mg, 113.6 ⁇ mol) were dissolved in dioxane (5 mL) and water (2 mL), potassium carbonate (47.1 mg, 340.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (25.0 mg, 34.1 ⁇ mol) were added, and the reaction was stirred at 90 ° C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3).
  • Step 2 Compound 6-2 (30.0 mg, 113.6 ⁇ mol) and intermediate 3 (26.1 mg, 113.6 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and potassium carbonate (47.1 mg, 340.9 ⁇ mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.4 mg, 56.8 ⁇ mol) were added. The reaction was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3).
  • Step 2 Compound 7-1 (94.8 mg, 303.1 ⁇ mol) and intermediate 3 (80.0 mg, 303.1 ⁇ mol) were dissolved in dioxane (8 mL) and water (3 mL), potassium carbonate (125.66 mg, 909.18 ⁇ mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (66.52 mg, 90.92 ⁇ mol) were added, and the reaction was stirred at 90 ° C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3).
  • Step 1 Compound 8-1 (1.2 g, 14.1 mmol) and tetrahydropyrrole (1.0 g, 14.1 mmol) were mixed, potassium carbonate (1.9 g, 14.1 mmol) was added at 0°C, reacted at 0°C for 1 hour, then heated to 25°C for 2 hours.
  • Dichloromethane (30 mL) and anhydrous sodium sulfate (10.0 g) were added to the reaction solution, filtered, and the filtrate was dried to obtain compound 8-2, which was used directly in the next step.
  • MS ESI calculated value C 13 H 19 ClN 4 O 2 [M+H] + 299, found value 299.
  • Step 2 Compound 9-1 (135.8 mg, 454.6 ⁇ mol) and intermediate 3 (120.0 mg, 454.6 ⁇ mol) were dissolved in dioxane (4 mL) and water (2 mL), potassium carbonate (188.5 mg, 1.4 ⁇ mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (74.3 mg, 90.9 ⁇ mol) were added, and the reaction was stirred at 90 ° C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3).
  • Step 2 Compound 10-2 (130.0 mg, 358.3 ⁇ mol) was dissolved in methanol (10 mL), and hydrochloric acid/ethyl acetate (20 mL, 4 M) was added, and the reaction was stirred at 25° C. for 2 hours. The reaction solution was concentrated to obtain compound 10-3, which was directly used in the next step. MS ESI calculated value C 10 H 13 ClF 2 N 4 [M+H] + 263, found value 263.
  • Step 3 Compound 10-3 (0.5 g, 2.3 mmol) and bromoethanol (94.2 mg, 753.8 ⁇ mol) were dissolved in acetonitrile (20 mL), and then sodium carbonate (217.8 mg, 2.0 mmol) was added, and the mixture was stirred at 60° C. for 4 hours. After the reaction was completed, the mixture was filtered and dried to obtain compound 10-4.
  • Step 2 Compound 11-1 (50.0 mg, 184.7 ⁇ mol) and compound 1-4 (66.5 mg, 184.7 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (67.6 mg, 92.3 ⁇ mol) and potassium carbonate (51.0 mg, 369.3 ⁇ mol) were added and stirred at 100 ° C for 0.5 hours under nitrogen protection.
  • Step 3 Compound 11-2 (70.0 mg, 149.4 ⁇ mol) was dissolved in dichloromethane (10 mL), and boron tribromide (1 M, 1.5 mL) was added at 0°C. The reaction was stirred at 0°C for 10 minutes. After the reaction was completed, the reaction was quenched with water (5 mL) and methanol (8 mL). After concentration, the crude product was separated by chromatographic column (Xtimate C18 150*40mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-33%, 10 min) to obtain the hydrochloride of compound 11.
  • Step 2 Compound 12-2 (30.0 mg, 124.1 ⁇ mol) and compound 1-4 (44.0 mg, 124.1 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18.1 mg, 24.8 ⁇ mol) and potassium carbonate (34.1 mg, 248.2 ⁇ mol) were added and stirred at 100 °C for 0.5 hours under nitrogen protection.
  • Step 3 Compound 12-3 (20.0 mg, 45.5 ⁇ mol) was dissolved in dichloromethane (10 mL), and boron tribromide (1 M, 455.1 ⁇ L) was added at 0°C and stirred at 0°C for 0.5 hours. After the reaction was completed, the mixture was quenched with water (5 mL) and methanol (8 mL). After concentration, the crude product was separated by chromatographic column (Phenomenex C18 150*40mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain compound 12.
  • Step 1 Compound 13-1 (0.2 g, 1.1 mmol) and intermediate 4 (152.7 mg, 1.1 mmol) were mixed and stirred at 130°C for 10 minutes. After the reaction was completed, the mixture was extracted with water (30 mL) and dichloromethane (50 mL*3), and the pH was adjusted to 7 with sodium hydroxide solution (1 M). The organic phase was dried over sodium sulfate, filtered and concentrated, and separated by a chromatographic column (Phenomenex C18 150*40mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 1%-30%, 10 min) to obtain compound 13-2. MS ESI calculated value C 14 H 21 ClN 4 O[M+H] + 297, found value 297.
  • Step 2 Compound 13-2 (33.7 mg, 113.6 ⁇ mol) and intermediate 3 (30.0 mg, 113.6 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (41.5 mg, 56.8 ⁇ mol) and potassium carbonate (34.4 mg, 227.3 ⁇ mol,) were added. The mixture was stirred at 100°C for 0.5 hours under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated.
  • the crude product was separated by a chromatographic column (Phenomenex C18 150*40mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain the hydrochloride of compound 13.
  • Step 2 Compound 14-2 (40.7 mg, 189.4 ⁇ mol) and intermediate 3 (50.0 mg, 189.4 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (69.3 mg, 94.7 ⁇ mol) and potassium carbonate (52.3 mg, 378.8 ⁇ mol) were added. The mixture was stirred at 100 °C for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3).
  • Step 1 Compound intermediate 2-1 (0.3 g, 1.84 mmol) and compound 15-1 (138.23 mg, 1.84 mmol) were mixed evenly and kept at 130°C for 10 minutes. After the reaction was completed, the mixture was extracted with water (30 mL) and dichloromethane (50 mL*3), and the pH was adjusted to 7 with sodium hydroxide solution (1 M, 2 mL). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by column chromatography (Phenomenex C18 150*40mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 1%-30%, 10min) to obtain compound 15-2. MS ESI calculated value C 8 H 12 ClN 3 O[M+H] + 202, found value 202.
  • Step 2 Compound 15-2 (38.2 mg, 189.4 ⁇ mol) and intermediate 3 (50.0 mg, 189.4 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (69.3 mg, 94.7 ⁇ mol) and potassium carbonate (52.4 mg, 378.8 ⁇ mol) were added. The mixture was stirred at 100 °C for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3).
  • Step 2 Compound 16-2 (1.0 g, 3.4 mmol) was dissolved in methanol (30 mL), 10% dry palladium carbon ( ⁇ 1.0 g) was added, and the mixture was stirred at 25°C for 1 hour under the protection of hydrogen (15 Psi). After the reaction was completed, the mixture was filtered and the filtrate was dried to obtain compound 16-3. MS ESI calculated value C 8 H 18 N 2 O [M+H] + 159, found value 159.
  • Step 4 Compound 16-4 (30.7 mg, 107.9 ⁇ mol) and intermediate 3 (28.4 mg, 107.9 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (39.4 mg, 53.9 ⁇ mol) and potassium carbonate (29.8 mg, 215.8 ⁇ mol) were added. The mixture was stirred at 100 °C for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3).
  • Step 1 Dissolve intermediate 1-2 (0.2 g, 1.4 mmol) and compound 17-1 (275.8 mg, 1.4 mmol) in tert-amyl alcohol (5 mL) and water (1 mL), then add potassium hydroxide (168.1 mg, 3.0 mmol) and 5-(di-tert-butylphosphino)-1,3,5-triphenyl-1 hydrogen-[1,4]dipyrazole (141.2 mg, 278.6 ⁇ mol), tris(dibenzylideneacetone)dipalladium (127.6 mg, 139.3 ⁇ mol), react at 90 ° C and stir for 1 hour.
  • Step 2 Compound 17-2 (19.7 mg, 75.7 ⁇ mol) and intermediate 3 (20.0 mg, 75.7 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.7 mg, 37.8 ⁇ mol) and potassium carbonate (20.9 mg, 151.5 ⁇ mol) were added. The reaction was stirred at 100° C. for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated.
  • Step 2 Compound 18-2 (34.3 mg, 151.5 ⁇ mol) and intermediate 3 (40.0 mg, 151.5 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (55.44 mg, 75.76 ⁇ mol) and potassium carbonate (41.8 mg, 303.0 ⁇ mol) were added. The reaction was stirred at 100 ° C for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3), and the organic phase was dried over sodium sulfate, filtered and concentrated.
  • Step 2 Compound 19-2 (1.0 g, 5.2 mmol) was dissolved in methanol (10 mL), hydrazine hydrate (1.0 g, 20.7 mmol) was added, the mixture was stirred at 100°C for 12 hours, and the mixture was filtered after completion of the reaction, the filter cake was collected, and compound 19-3 was obtained after drying.
  • Step 3 Compound 19-3 (0.2 g, 1.2 mmol) was mixed with phosphorus oxychloride (9.9 g, 64.5 mmol), and the mixture was stirred at 100°C for 12 hours. After the reaction was completed, the mixture was extracted with sodium bicarbonate aqueous solution (150 mL) and ethyl acetate (100 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated to obtain compound 19-4. MS ESI calculated value: C 6 H 4 C l2 N 4 [M+H] + 203, found value: 203.
  • Step 4 Compound 19-4 (70.0 mg, 344.7 ⁇ mol) and intermediate 2-2 (39.3 mg, 344.7 ⁇ mol) were mixed evenly, and the mixture was kept at 130°C for 10 minutes. After the reaction was completed, the mixture was extracted with water (30 mL) and dichloromethane (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by column chromatography (Phenomenex C18 150*40mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 1%-30%, 10 min) to obtain compound 19-5. MS ESI calculated value C 12 H 17 ClN 6 [M+H] + 281, found value 281.
  • Step 5 Compound 19-5 (18.1 mg, 64.4 ⁇ mol) and intermediate 3 (17.0 mg, 64.4 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (23.56 mg, 32.20 ⁇ mol) and potassium carbonate (17.8 mg, 128.8 ⁇ mol) were added. The reaction was stirred at 100 °C under nitrogen protection for 0.5 hours. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3).
  • Step 1 Compound 20-1 (0.5 g, 2.3 mmol) and bromoethanol (314.8 mg, 2.5 mmol) were dissolved in acetonitrile (10 mL), and then sodium carbonate (364.2 mg, 3.4 mmol) was added, and the mixture was stirred at 60°C for 4 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain compound 20-2.
  • Step 2 Compound 20-2 (0.6 g, 2.2 mmol) was dissolved in ethyl acetate (10 mL), and ethyl acetate hydrochloride (4 M, 0.6 mL) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction was completed, the mixture was filtered, and the filter cake was collected and dried to obtain the hydrochloride salt of compound 20-3. MS ESI calculated value C 5 H 11 FN 2 [M+H] + 119, found value 119.
  • Step 3 The hydrochloride of compound 20-3 (454.0 mg, 2.3 mmol) and potassium carbonate (410.9 mg, 2.9 mmol) were dissolved in tetrahydrofuran (12 mL) and water (10 mL), and benzyl chloroformate (409.7 mg, 2.4 mmol) was added dropwise at 0°C, and the reaction was stirred at 25°C for 1 hour. After the reaction was completed, the mixture was extracted with water (150 mL) and ethyl acetate (100 mL*3), and the organic phase was dried over sodium sulfate, filtered and concentrated to obtain compound 20-4. MS ESI calculated value C 13 H 17 FN 2 O 2 [M+H] + 253, found value 253.
  • Step 4 Compound 20-4 (0.6 g, 2.0 mmol) was dissolved in methanol (10 mL), 10% dry palladium on carbon (0.1 g) was added, and the mixture was stirred at 25°C for 1 hour under the protection of hydrogen (15 Psi). After the reaction was completed, the mixture was filtered and the filtrate was concentrated to dryness to obtain compound 20-3. MS ESI calculated value C 5 H 11 FN 2 [M+H] + 119, found value 119.
  • MS ESI calculated value C 12 H 18 ClFN 4 O [M + H] + 289, found value 289.
  • Step 5 Compound 20-5 (20.0 mg, 69.2 ⁇ mol) and intermediate 3 (18.2 mg, 69.2 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.3 mg, 34.6 ⁇ mol) and potassium carbonate (19.1 mg, 138.5 ⁇ mol), react at 100 ° C under nitrogen protection and stir for 0.5 hour, after the reaction is completed, extract with water (50 mL) and ethyl acetate (50 mL*3), the organic phase is dried over sodium sulfate, filtered and concentrated, and the crude product is subjected to column chromatography (chromatographic column: Xtimate C18 150*40mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 5%-45%, 10min) to obtain the hydrochlor
  • Step 1 Compound 21-1 (277.2 mg, 1.4 mmol) and intermediate 1-2 (0.2 g, 1.4 mmol) were dissolved in tert-amyl alcohol (5 mL) and water (1 mL), and then potassium hydroxide (168.1 mg, 3.0 mmol) and 5-(di-tert-butylphosphino)-1,3,5-triphenyl-1 hydrogen-[1,4]dipyrazole (141.2 mg, 278.6 ⁇ mol), tris(dibenzylideneacetone)dipalladium (127.5 mg, 139.3 ⁇ mol) were added, and the mixture was stirred at 90 ° C for 1 hour.
  • Step 2 Compound 21-2 (30.0 mg, 121.1 ⁇ mol) and intermediate 3 (33.6 mg, 127.1 ⁇ mol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.1 mg, 30.2 ⁇ mol) and potassium carbonate (33.4 mg, 242.2 ⁇ mol) were added. The reaction was stirred at 100 °C under nitrogen protection for 0.5 hour. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3).
  • Step 1 Compound 22-1 (77.7 mg, 674.8 ⁇ mol) and intermediate 2-1 (0.1 g, 613.4 ⁇ mol) were dissolved in tetrahydrofuran (2 mL), sodium hydrogen sulfide (60%, 98.1 mg, 2.4 mmol) was added at 0°C, and the reaction was stirred at 0°C for 1 hour. After the reaction was completed, the mixture was extracted with water (50 mL) and ethyl acetate (50 mL*3), and the organic phase was dried over sodium sulfate, filtered and concentrated to obtain compound 22-2.
  • Step 2 Dissolve compound 22-2 (32.7 mg, 124.1 ⁇ mol) and intermediate 3 (30.0 mg, 124.1 ⁇ mol) in dioxane (2 mL) and water (1 mL), add [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (22.7 mg, 31.0 ⁇ mol) and potassium carbonate (34.3 mg, 248.2 ⁇ mol) and stir at 100 °C under nitrogen protection for 0.5 hour. After the reaction is completed, filter and dry the filtrate.
  • the crude product is separated and purified by chromatographic column (Xtimate C18150*40mm*5 ⁇ m; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-45%, 10 min) to obtain the hydrochloride of compound 22.
  • MS ESI calculated value C 4 HN 2 Cl 2 Br[M+H] + /[M+H+2] + 227/229, found value 227/229.
  • Step 2 Compound 23-1 (9.0 g, 39.5 mmol), potassium vinyl trifluoroborate (6.3 g, 47.3 mmol), potassium carbonate (16.3 g, 118.4 mmol) was added to tetrahydrofuran (150 mL) and water (30 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.61 g, 1.97 mmol) was added under nitrogen protection, and the reaction was stirred at 80°C for 3 hours.
  • Step 3 Compound 23-2 (3.0 g, 17.1 mmol) and pyridine hydrofluoride (6.8 g, 68.5 mmol) were dissolved in dichloromethane (30 mL), dibromohydantoin (5.8 g, 20.5 mmol) was added at -20 degrees, and the reaction was stirred at 25°C for 12 hours. After the reaction was completed, the reaction was quenched with ice water (50 mL) and extracted with ethyl acetate (70 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated to obtain crude compound 23-3, which was directly used in the next step.
  • MS ESI calculated value C 6 H 4 N 2 Cl 2 FBr [M + H] + / [M + H + 2] + 273/275, found value 273/275.
  • Step 6 Compound 24-5 (39.6 mg, 158.2 ⁇ mol), intermediate 3 (41.7 mg, 158.2 ⁇ mol), and potassium carbonate (65.6 mg, 474.7 ⁇ mol) were dissolved in dioxane (3 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (11.5 mg, 15.8 ⁇ mol) was added under nitrogen protection. The reaction was stirred at 100 °C for 1 hour. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL*2).
  • This experiment uses human monocytic cell line THP1 to study the inhibitory activity (IC50) of NLRP3 inhibitors on cellular IL-1 ⁇ secretion.
  • PMA crotyl alcohol-12-tetradecanoate-13-acetate
  • LPS lipopolysaccharide
  • Toll-like receptor TLR4 an agonist of Toll-like receptor
  • Activated caspase-1 can enzymatically process pro-IL-1 ⁇ into mature IL-1 ⁇ that can be secreted.
  • NLRP3 inhibitors can effectively inhibit the maturation and activation of NLRP3 induced by ATP, as well as the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1 ⁇ .
  • test compound into the wells, and the screening concentrations are: 5 ⁇ M, 1 ⁇ M, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM. Incubate in a 37°C, 5% CO 2 incubator for 1 hour.
  • the compound of the present invention has good drugability and high oral availability.
  • the compound 2 intravenous injection group was at 0.0833, 0.5, 1, 2, 4, 8, 24 and 48 hours, and the gavage group was at 0.25, 1, 2, 4, 8, 24 and 48 hours.
  • the plasma and cerebrospinal fluid concentrations were determined by LC-MS/MS, using WinNonlin TM Version 6.3 pharmacokinetic software.
  • the relevant pharmacokinetic parameters were calculated using the non-compartmental linear logarithmic trapezoidal method. The test results are shown in Table 5 below.
  • the compounds of the present invention have good drugability and high bioavailability after oral administration to rats.
  • the systemic exposure of the hydrochloride salt of compound 11 increased in proportion to the dose after oral administration to rats.
  • Compound 2 had a higher exposure in the cerebrospinal fluid after oral administration to rats, and a higher brain-plasma free drug ratio (K p,uu, CSF), showing a higher ability to penetrate the blood-brain barrier.
  • the blood drug concentration was determined by LC-MS/MS, and the relevant pharmacokinetic parameters were calculated by the non-compartmental linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software. The test results are shown in Table 6 below.
  • the compound of the present invention has good drugability and high utilization after oral administration to dogs.
  • mice C57BL/6 mice were randomly divided into 6 groups, 5 mice in each group, and given vehicle (5% DMSO/10% solutol/85% water) or 1, 3, 10 mg/kg of compound 11 hydrochloride by gavage.
  • vehicle 5% DMSO/10% solutol/85% water
  • PBS PBS
  • Animal serum was collected at 2 hours and 6 hours for the detection of cytokine IL-1 ⁇ (BD, 560232) levels.
  • Table 7 The experimental grouping scheme is shown in Table 7 below:
  • test compound working solution 400 ⁇ M
  • warfarin working solution 400 ⁇ M
  • the final concentration of DMSO in organic phase is 0.5%; pipette 50 ⁇ L of test compound and warfarin plasma sample into the sample receiving plate (three parallels), immediately add the corresponding volume of blank plasma or PBS buffer, so that the final volume of each sample well is 100 ⁇ L, and the volume ratio of plasma: dialysis buffer is 1:1, then add 500 ⁇ L of stop solution to these samples, which will be used as T 0 samples for recovery and stability determination.
  • the test compound (10.0 mM) was graded diluted to prepare the working solution (100 ⁇ final concentration), and the working solution concentrations were 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150 and 0.00500 mM, respectively.
  • the working solution of each positive inhibitor of P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their specific substrate mixtures were prepared; human liver microsomes stored in a refrigerator below -60°C were thawed on ice, and after the human liver microsomes were completely dissolved, they were diluted with Potassium phosphate buffer (PB) to prepare a working solution of a certain concentration (0.253 mg/ml).
  • PB Potassium phosphate buffer
  • test compound control sample is 1:1 DMSO:MeOH, and the positive control samples are all 1:9 DMSO:MeOH; incubate in a 37°C water bath.
  • the generation rate of each probe substrate metabolite reflects the activity of each CYP isozyme.
  • the activity of each isozyme in the solvent control incubation system without the test sample or positive inhibitor was set to 100%.
  • the generation rate of the probe substrate metabolite when containing different concentrations of the test sample or positive inhibitor was compared with the generation rate of the metabolite of the solvent control sample and then multiplied by 100% as the residual activity percentage of each isozyme.
  • the three-parameter or four-parameter nonlinear regression analysis in the XL fit software was used to calculate the IC 50 values of the test sample and each positive inhibitor.
  • the IC 50 fitted by the XL fit software is greater than the highest administration concentration (50 ⁇ M) or the IC 50 cannot be fitted, the IC 50 value is marked as ">50 ⁇ M".
  • the experimental results are shown in Table 9.
  • the incubation conditions were 37°C, saturated humidity, and 5% CO 2 .
  • the final concentration of the test sample was 1 ⁇ M
  • the final concentration of the control sample was 3 ⁇ M
  • the final concentration of the hepatocytes was 0.5 ⁇ 10 6 cells/mL
  • the final concentration of the total organic solvent was 0.96%
  • the final concentration of DMSO was 0.1%.
  • the incubation plate was removed, and 25 ⁇ L of the mixture of the compound and the control compound and cells was taken out and added to the sample plate containing 125 ⁇ L of the stop solution (acetonitrile methanol solution containing 200 ng/mL tolbutamide (v:v, 5:95)).
  • the compounds of the present invention have good metabolic stability in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and human hepatocytes.
  • T60 incubation plate and NCF60 incubation plate Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate. Add 445 ⁇ L of microsomal working solution (liver microsomal protein concentration is 0.56 mg/mL) to the T60 incubation plate and NCF60 incubation plate, respectively, and then place the above incubation plates in a 37°C water bath for preincubation for about 10 minutes. After the preincubation, add 5 ⁇ L of the test sample or control compound working solution to the T60 incubation plate and the NCF60 incubation plate, respectively, and mix well.
  • microsomal working solution liver microsomal protein concentration is 0.56 mg/mL
  • the final reaction concentration of the compound, testosterone, diclofenac and propafenone is 1 ⁇ M
  • the concentration of liver microsomes is 0.5 mg/mL
  • the final concentrations of DMSO and acetonitrile in the reaction system are 0.01% (v/v) and 0.99% (v/v), respectively.
  • the compound of the present invention has good liver microsome stability.

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Abstract

Disclosed in the present invention are a series of sulfur pentafluoride substituted aromatic ring compounds and the use thereof. Specifically disclosed is a compound as represented by formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Description

五氟化硫取代的芳环化合物及其应用Sulfur pentafluoride substituted aromatic ring compounds and their applications
本发明主张如下优先权申请The present invention claims the priority application
申请号：CN2023104176651，申请日：2023年04月18日。Application number: CN2023104176651, application date: April 18, 2023.
技术领域Technical Field
本发明涉及了一系列五氟化硫取代的芳环化合物及其应用。具体涉及了式(Ⅱ)所示化合物、其立体异构体或其药学上可接受的盐。The present invention relates to a series of sulfur pentafluoride substituted aromatic ring compounds and their applications, and specifically to compounds represented by formula (II), their stereoisomers or pharmaceutically acceptable salts thereof.
背景技术Background Art
炎症小体(inflammasome)在炎症相关疾病的发生发展中发挥重要作用，NLRP3炎症小体是由核苷酸结合寡聚化结构域样受体(nucleotide-binding oligomerization domain-like receptors,NLRs)家族成员NLRP3、接头蛋白ASC(apoptosis-associated speck-like protein containing a CARC)和效应蛋白Caspase-1组成的一种分子量约为700kDa的大分子多蛋白复合体。在多种免疫细胞如粒细胞、巨噬细胞、树突状细胞、B细胞和非免疫细胞如上皮细胞和角细胞等都能够被检测到，其核心蛋白NLRP3由C-末端的11个亮氨酸重复序列(LRR)，中间的NACHT结构域以及N-末端的Pyrin结构域(PYD)组成。NLRP3通过PYD结构域与接头蛋白ASC相互作用，然后ASC通过其CARC结构域募集并激活pro-Caspase-1，形成蛋白复合物，即NLRP3炎症小体。NLRP3炎症小体能被多种病原相关的分子模式或损伤相关的分子模式活化，对固有免疫系统免疫功能的发挥具有极其重要的作用。但如果其被过度激活则可通过活化Caspase-1进而持续地将pro-IL-1和pro-IL-18等促炎症因子前体剪切为成熟的IL-1β和IL-18，激活并放大下游的炎症和损伤反应，从而对机体造成严重甚至致命的伤害。Inflammasome plays an important role in the occurrence and development of inflammatory diseases. NLRP3 inflammasome is a macromolecular multiprotein complex with a molecular weight of about 700 kDa, which is composed of NLRP3, a member of the nucleotide-binding oligomerization domain-like receptor (NLRs) family, the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARC) and the effector protein Caspase-1. It can be detected in a variety of immune cells such as granulocytes, macrophages, dendritic cells, B cells and non-immune cells such as epithelial cells and keratinocytes. Its core protein NLRP3 is composed of 11 leucine repeat sequences (LRR) at the C-terminus, the NACHT domain in the middle and the Pyrin domain (PYD) at the N-terminus. NLRP3 interacts with the adaptor protein ASC through its PYD domain, and then ASC recruits and activates pro-Caspase-1 through its CARC domain to form a protein complex, the NLRP3 inflammasome. The NLRP3 inflammasome can be activated by a variety of pathogen-associated molecular patterns or damage-associated molecular patterns, and plays an extremely important role in the immune function of the innate immune system. However, if it is overactivated, it can activate Caspase-1 and then continuously cleave pro-inflammatory factor precursors such as pro-IL-1 and pro-IL-18 into mature IL-1β and IL-18, activating and amplifying downstream inflammatory and injury responses, thereby causing serious or even fatal damage to the body.
越来越多的研究证实NLRP3炎症小体与多种炎症性疾病的发生发展密切相关。如痛风病人关节及周围的尿酸盐晶体被巨噬细胞吞噬后可能通过促进钾离子外流和诱导线粒体产生大量活性氧ROS，使NLRP3炎症小体活化，促使IL-1β成熟和分泌。成熟的IL-1β与靶细胞的IL-1受体结合后激活下游信号转导因子，生成大量炎症介质从而加重炎症反应。β-淀粉样蛋白可通过激活小胶质细胞的NLRP3炎症小体，导致脑内炎症反应，引起神经元的损伤和死亡，进而引起阿尔兹海默病等神经退行性疾病的发生。More and more studies have confirmed that NLRP3 inflammasomes are closely related to the occurrence and development of a variety of inflammatory diseases. For example, after urate crystals in the joints and surrounding areas of gout patients are phagocytosed by macrophages, they may activate NLRP3 inflammasomes by promoting potassium ion efflux and inducing mitochondria to produce a large amount of reactive oxygen species (ROS), thereby promoting the maturation and secretion of IL-1β. After mature IL-1β binds to the IL-1 receptor of target cells, it activates downstream signal transduction factors, generates a large amount of inflammatory mediators, and thus aggravates the inflammatory response. β-Amyloid protein can activate the NLRP3 inflammasome of microglia, leading to inflammatory responses in the brain, causing neuronal damage and death, and further causing the occurrence of neurodegenerative diseases such as Alzheimer's disease.
目前有多种NLRP3抑制剂在WO2016131098、WO2019025467、WO2019121691和WO2018015445等专利申请中被报道。二芳基磺酰脲的衍生物MCC950通过抑制NLRP3炎症小体活性，可以减轻小鼠脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)的严重程度。临床前研究发现，在Winnie小鼠自发性结肠炎模型中，MCC950能够改善发病小鼠的疾病评分，缓解结肠炎导致的结肠缩短和体重降低。已经有几款NLRP3抑制剂进入临床试验阶段，如诺华公司的DFV-890处于临床II期拟用于炎症相关疾病；罗氏有两个NLRP3抑制剂处于临床I期，其中Inzomelid用于治疗神经退行性疾病，Somalix用于身体其 他部位的炎症性疾病；此外Zydμus Cadila开发的ZYIL1用于多种炎症相关疾病已处于临床I期。
Currently, a variety of NLRP3 inhibitors have been reported in patent applications such as WO2016131098, WO2019025467, WO2019121691 and WO2018015445. MCC950, a derivative of diarylsulfonylurea, can reduce the severity of experimental autoimmune encephalomyelitis (EAE) in mice by inhibiting the activity of NLRP3 inflammasome. Preclinical studies have found that in the Winnie mouse spontaneous colitis model, MCC950 can improve the disease scores of diseased mice and alleviate colon shortening and weight loss caused by colitis. Several NLRP3 inhibitors have entered the clinical trial stage, such as Novartis' DFV-890, which is in Phase II clinical trials and is intended for inflammatory-related diseases; Roche has two NLRP3 inhibitors in Phase I clinical trials, of which Inzomelid is used to treat neurodegenerative diseases and Somalix is used for the body's other Inflammatory diseases in other parts of the body; in addition, ZYIL1 developed by Zydμus Cadila is in Phase I clinical trials for a variety of inflammatory-related diseases.
NLRP3抑制剂用于该通路相关的炎症性疾病提供潜在的治疗手段，有着重要意义和广阔的前景。目前，仍然存在开发新的NLRP3抑制剂用于治疗炎症性疾病的需求。NLRP3 inhibitors provide potential treatments for inflammatory diseases related to this pathway, which is of great significance and has broad prospects. At present, there is still a need to develop new NLRP3 inhibitors for the treatment of inflammatory diseases.
发明内容Summary of the invention
本发明提供了式(Ⅱ)所示化合物、其立体异构体或其药学上可接受的盐，
The present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
其中，in,
X为OH、NH2、NHCOCH3或CH2OH；X is OH, NH 2 , NHCOCH 3 or CH 2 OH;
R1为H、F、Cl、Br、I、C1-3烷基、C1-3杂烷基、C2-5烯基或C3-6环烷基，其中，所述C1-3烷基、C1-3杂烷基、C2-5烯基和C3-6环烷基各自独立地任选地被1、2或3个Ra取代；R 1 is H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl or C 3-6 cycloalkyl, wherein the C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl and C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3 Ra ;
R2为H、F、Cl、Br、I、CN、C1-3烷基、C2-5烯基、C2-5炔基、C1-3烷氧基、C3-6环烷基或3-6元杂环烷基，其中，所述C1-3烷基、C2-5烯基、C2-5炔基、C1-3烷氧基、C3-6环烷基和3-6元杂环烷基各自独立地任选地被1、2或3个Rb取代； R2 is H, F, Cl, Br, I, CN, C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 Rb ;
L为单键、-NH(CH2)n-或-O-；L is a single bond, -NH(CH 2 ) n - or -O-;
n为0、1、2或3；n is 0, 1, 2 or 3;
R3为C1-6烷基、C3-8环烷基、5-12元杂环烷基、C6-10芳基或5-10元杂芳基，其中，所述C1-6烷基、C3-8环烷基、5-12元杂环烷基、C6-10芳基和5-10元杂芳基各自独立地任选地被1、2或3个Rc取代； R3 is C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 Rc ;
环A为 Ring A is
为单价或双键； is a single bond or a double bond;
T为N或C；T is N or C;
环B为5-7元环烯基、5-7杂环烯基或5-6元杂芳基； Ring B is a 5-7 membered cycloalkenyl, a 5-7 membered heterocycloalkenyl or a 5-6 membered heteroaryl;
各Ra分别独立地为H、F、Cl、Br、I、CN、OH或C1-3烷氧基；Each Ra is independently H, F, Cl, Br, I, CN, OH or C1-3 alkoxy;
各Rb分别独立地为H、F、Cl、Br、I、CN、OH或C1-3烷基；Each R b is independently H, F, Cl, Br, I, CN, OH or C 1-3 alkyl;
各Rc分别独立地为H、F、Cl、Br、I、CN、OH、C1-6烷基、C1-6烷氧基或C1-6烷氨基，所述C1-6烷基、C1- 6烷氧基和C1-6烷氨基各自独立地任选地被1、2或3个R取代；Each R c is independently H, F, Cl, Br, I , CN, OH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, and the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
各R分别独立地为F、Cl、Br、I、OH、SRa1、-C(＝O)ORa1、-C(＝O)NH2、-S(＝O)Ra1、-S(＝O)2Ra1或C1-3烷氧基；Each R is independently F, Cl, Br, I, OH, SR a1 , -C(=O)OR a1 , -C(=O)NH 2 , -S(=O)R a1 , -S(=O) 2 R a1 or C 1-3 alkoxy;
各Ra1分别独立地为C1-3烷基，所述C1-3烷基任选被1、2或3个F取代；Each R a1 is independently C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F;
所述C1-3杂烷基、3-6元杂环烷基、5-7元杂环烯基、5-12元杂环烷基、5-6元杂芳基和5-10元杂芳基中“杂”选自1、2和3个独立为O、NH、S或N的杂原子或杂原子团；In the C 1-3 heteroalkyl, 3-6 membered heterocycloalkyl, 5-7 membered heterocycloalkenyl, 5-12 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-10 membered heteroaryl, "hetero" is selected from 1, 2 and 3 heteroatoms or heteroatom groups independently selected from O, NH, S or N;
条件是所述化合物不选自如下分子： Provided that the compound is not selected from the following molecules:
本发明提供了式(P)所示化合物、其立体异构体或其药学上可接受的盐，
The present invention provides a compound represented by formula (P), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
其中，in,
R1为H、F、Cl、Br、I、C1-3烷基、C1-3杂烷基、C2-5烯基或C3-6环烷基，其中，所述C1-3烷基、C1-3杂烷基、C2-5烯基和C3-6环烷基各自独立地任选地被1、2或3个Ra取代；R 1 is H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl or C 3-6 cycloalkyl, wherein the C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl and C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3 Ra ;
R2为H、F、Cl、Br、I、CN、C1-3烷基、C2-5烯基、C2-5炔基、C1-3烷氧基、C3-6环烷基或3-6元杂环烷基，其中，所述C1-3烷基、C2-5烯基、C2-5炔基、C1-3烷氧基、C3-6环烷基和3-6元杂环烷基各自独立地任选地被1、2或3个Rb取代； R2 is H, F, Cl, Br, I, CN, C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 Rb ;
环A为 Ring A is
为单价或双键； is a single bond or a double bond;
T为N或C；T is N or C;
环B为5-7元环烯基、5-7杂环烯基或5-6元杂芳基；Ring B is a 5-7 membered cycloalkenyl, a 5-7 membered heterocycloalkenyl or a 5-6 membered heteroaryl;
各Ra分别独立地为H、F、Cl、Br、I、CN、OH或C1-3烷氧基；Each Ra is independently H, F, Cl, Br, I, CN, OH or C1-3 alkoxy;
各Rb分别独立地为H、F、Cl、Br、I、CN、OH或C1-3烷基；Each R b is independently H, F, Cl, Br, I, CN, OH or C 1-3 alkyl;
各Rc分别独立地为H、F、Cl、Br、I、CN、OH、C1-6烷基、C1-6烷氧基或C1-6烷氨基，所述C1-6烷基、C1- 6烷氧基和C1-6烷氨基各自独立地任选地被1、2或3个R取代；Each R c is independently H, F, Cl, Br, I , CN, OH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, and the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
各R分别独立地为F、Cl、Br、I、OH、SRa1、-C(＝O)ORa1、-C(＝O)NH2、-S(＝O)Ra1、-S(＝O)2Ra1或C1-3烷氧基；Each R is independently F, Cl, Br, I, OH, SR a1 , -C(=O)OR a1 , -C(=O)NH 2 , -S(=O)R a1 , -S(=O) 2 R a1 or C 1-3 alkoxy;
各Ra1分别独立地为C1-3烷基，所述C1-3烷基任选被1、2或3个F取代；Each R a1 is independently C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F;
所述C1-3杂烷基、3-6元杂环烷基、5-7元杂环烯基和5-6元杂芳基中“杂”选自1、2和3个独立为O、NH、S或N的杂原子或杂原子团。In the C 1-3 heteroalkyl, 3-6 membered heterocycloalkyl, 5-7 membered heterocycloalkenyl and 5-6 membered heteroaryl, the “hetero” is selected from 1, 2 and 3 heteroatoms or heteroatom groups which are independently O, NH, S or N.
本发明的一些方案中，上述Ra1分别独立地为甲基或乙基，所述甲基或乙基任选被1、2或3个F取代，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned R a1 is independently methyl or ethyl, and the methyl or ethyl is optionally substituted by 1, 2 or 3 F, and other variables are as defined in the present invention.
本发明的一些方案中，上述Ra1分别独立地为甲基、二氟甲基、三氟甲基或乙基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned R a1 is independently methyl, difluoromethyl, trifluoromethyl or ethyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述各R分别独立地为H、F、OH或-OCH3，其他变量如本发明所定义。In some embodiments of the present invention, each R mentioned above is independently H, F, OH or -OCH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述各Ra分别独立地为H、F、Cl、Br、I、CN、OH、甲氧基或乙氧基，其他变量如本发明所定义。In some embodiments of the present invention, each Ra is independently H, F, Cl, Br, I, CN, OH, methoxy or ethoxy, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Ra分别独立地为H或F，其他变量如本发明所定义。In some embodiments of the present invention, each Ra is independently H or F, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Rb分别独立地为H、F或CH3，其他变量如本发明所定义。In some embodiments of the present invention, each R b is independently H, F or CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述各Rc分别独立地为H、F、OH、C1-3烷基、C1-3烷氧基或C1-3烷氨基，所述C1-3烷基、C1-3烷氧基和C1-3烷氨基任选独立地被1、2或3个R取代，R及其他变量如本发明所定义。In some embodiments of the present invention, each R c is independently H, F, OH, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, and the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are optionally independently substituted by 1, 2 or 3 R, and R and other variables are as defined in the present invention.
本发明的一些方案中，各Rc分别独立地为H、F、OH、-CH3、-CH2CH2OH、-CH2CH2OCH3或-N(CH3)2，其他变量如本发明所定义。In some embodiments of the present invention, each R c is independently H, F, OH, -CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 or -N(CH 3 ) 2 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R1为H、F、Cl、Br、I、CH3、CH2CH3、CH(CH3)2、-C(＝O)O-、-C(＝O)-、-S(＝O)、-S(＝O)2-、-C(＝O)N(H)-、-N(H)-、乙烯基、丙烯基、烯丙基、环丙基、环戊基或环己基，所述CH3、CH2CH3、CH(CH3)2、-C(＝O)O-、-C(＝O)-、-S(＝O)、-S(＝O)2-、-C(＝O)N(H)-、-N(H)-、乙烯基、丙烯基、烯丙基、环丙基、环戊基或环己基各自独立地任选地被1、2或3个Ra取代，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned R 1 is H, F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(＝O)O-, -C(＝O)-, -S(＝O), -S(＝O) 2 -, -C(＝O)N(H)-, -N(H)-, vinyl, propenyl, allyl, cyclopropyl, cyclopentyl or cyclohexyl, and the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(＝O)O-, -C(＝O)-, -S(＝O), -S(＝O) 2 -, -C(＝O)N(H)-, -N(H)-, vinyl, propenyl, allyl, cyclopropyl, cyclopentyl or cyclohexyl are each independently optionally substituted by 1, 2 or 3 Ra , and other variables are as defined in the present invention.
本发明的一些方案中，上述R1为H、F、Cl、Br、I或CH3，其他变量如本发明所定义。In some embodiments of the present invention, the above R 1 is H, F, Cl, Br, I or CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R1为H，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 1 is H, and other variables are as defined in the present invention.
本发明的一些方案中，R2为H、F、Cl、CN、CH3、-CH＝CH2、-CH2CH＝CH2、-CH2CH2CH＝CH2、-CH2CH2CH2CH＝CH2、-OCH3、乙炔基、环丙基或氧杂环丁烷基，其中，所述CH3、-CH＝CH2、-CH2CH＝CH2、-CH2CH2CH＝CH2、-CH2CH2CH2CH＝CH2、-OCH3、环丙基和氧杂环丁烷基任选地被1、2或3个Rb取代，Rb及其他变量如本发明所定义。In some embodiments of the present invention, R 2 is H, F, Cl, CN, CH 3 , -CH＝CH 2 , -CH 2 CH＝CH 2 , -CH 2 CH 2 CH＝CH 2 , -CH 2 CH 2 CH 2 CH＝CH 2 , -OCH 3 , ethynyl, cyclopropyl or oxetanyl, wherein the CH 3 , -CH＝CH 2 , -CH 2 CH＝CH 2 , -CH 2 CH 2 CH＝CH 2 , -CH 2 CH 2 CH 2 CH ＝CH 2 , -OCH 3 , cyclopropyl and oxetanyl are optionally substituted with 1, 2 or 3 R b , and R b and other variables are as defined herein.
本发明的一些方案中，上述R2为H、CN、CH3、-CH＝CH2、-CH2CH＝CH2、-CH2CH2CH＝CH2、-CH2CH2CH2CH＝CH2、-OCH3、其中，所述CH3、-CH＝CH2、-CH2CH＝CH2、-CH2CH2CH＝CH2、-CH2CH2CH2CH＝CH2、-OCH3、各自独立地任选地被1、2或3个Rb取代，Rb及其他变量如本发明所定义。In some embodiments of the present invention, R 2 is H, CN, CH 3 , -CH＝CH 2 , -CH 2 CH＝CH 2 , -CH 2 CH 2 CH＝CH 2 , -CH 2 CH 2 CH 2 ＝CH 2 , -OCH 3 , Wherein, the CH 3 , -CH=CH 2 , -CH 2 CH=CH 2 , -CH 2 CH 2 CH=CH 2 , -CH 2 CH 2 CH 2 CH=CH 2 , -OCH 3 , Each is independently optionally substituted with 1, 2 or 3 R b , R b and the other variables are as defined herein.
本发明的一些方案中，上述R2为H、CH3、-CH＝CH2、-CH2CH＝CH2、-CH2CH2CH＝CH2、-CH2CH2CH2CH＝CH2、-OCH3、其中，所述CH3、-CH＝CH2、-CH2CH＝CH2、-CH2CH2CH＝CH2、-CH2CH2CH2CH＝CH2、-OCH3、各自独立地任选地被1、2或3个Rb取代，Rb及其他变量如本发明所定义。In some embodiments of the present invention, R 2 is H, CH 3 , -CH＝CH 2 , -CH 2 CH＝CH 2 , -CH 2 CH 2 CH＝CH 2 , -CH 2 CH 2 CH 2 ＝CH 2 , -OCH 3 , Wherein, the CH 3 , -CH=CH 2 , -CH 2 CH=CH 2 , -CH 2 CH 2 CH=CH 2 , -CH 2 CH 2 CH 2 CH=CH 2 , -OCH 3 , Each is independently optionally substituted with 1, 2 or 3 R b , R b and the other variables are as defined herein.
本发明的一些方案中，上述R2为H、CN、CH3、-CH＝CH2、-CF＝CH2、-CH2CH＝CH2、-OCH3、 其他变量如本发明所定义。In some embodiments of the present invention, the above R 2 is H, CN, CH 3 , -CH=CH 2 , -CF=CH 2 , -CH 2 CH=CH 2 , -OCH 3 , Other variables are as defined in the present invention.
本发明的一些方案中，上述R2为H、CH3、-CH＝CH2、-CF＝CH2、-CH2CH＝CH2、-OCH3、 其他变量如本发明所定义。In some embodiments of the present invention, the above R 2 is H, CH 3 , -CH=CH 2 , -CF=CH 2 , -CH 2 CH=CH 2 , -OCH 3 , Other variables are as defined in the present invention.
本发明的一些方案中，上述R3为C1-3烷基、C5-6环烷基、5-6元杂环烷基、C9-10芳基或9-10元杂芳基，其中，所述C1-3烷基、C5-6环烷基、5-6元杂环烷基、C9-10芳基和9-10元杂芳基各自独立地任选地被1、2或3个Rc取代，Rc及其他变量如本发明所定义。In some embodiments of the present invention, the above R 3 is C 1-3 alkyl, C 5-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 9-10 aryl or 9-10 membered heteroaryl, wherein the C 1-3 alkyl, C 5-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 9-10 aryl and 9-10 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
本发明的一些方案中，上述R3为CH2CH3、CH2CH2CH3、环己烷基、四氢呋喃基、哌啶基、苯并四氢呋喃基、1,3-二氢-2H-苯并咪唑酮基或吡啶并三氮唑基，其中，所述CH2CH3、CH2CH2CH3、环己烷基、四氢呋喃基、哌啶基、苯并四氢呋喃基、1,3-二氢-2H-苯并咪唑酮基和吡啶并三氮唑基各自独立地任选地被1、2或3个Rc取代，Rc及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 3 is CH 2 CH 3 , CH 2 CH 2 CH 3 , cyclohexanyl, tetrahydrofuranyl, piperidinyl, benzotetrahydrofuranyl, 1,3-dihydro-2H-benzimidazolyl or pyridotriazolyl, wherein the CH 2 CH 3 , CH 2 CH 2 CH 3 , cyclohexanyl, tetrahydrofuranyl, piperidinyl, benzotetrahydrofuranyl, 1,3-dihydro-2H-benzimidazolyl and pyridotriazolyl are each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
本发明的一些方案中，上述R3为 其他变量如本发明所定义。In some embodiments of the present invention, the above R 3 is Other variables are as defined in the present invention.
本发明的一些方案中，上述R3为 其他变量如本发明所定义。In some embodiments of the present invention, the above R 3 is Other variables are as defined in the present invention.
本发明的一些方案中，上述R3为CH2CH3、CH2CH2CH3、 其中，所述CH2CH3、CH2CH2CH3、 任选地被1、2或3个Rc取代，Rc及其他变量如本发明所定义。In some embodiments of the present invention, the above R 3 is CH 2 CH 3 , CH 2 CH 2 CH 3 , Wherein, the CH 2 CH 3 , CH 2 CH 2 CH 3 , Optionally substituted with 1, 2 or 3 R c , R c and other variables are as defined herein.
本发明的一些方案中，上述L为NH或O，其他变量如本发明所定义。In some embodiments of the present invention, the above L is NH or O, and other variables are as defined in the present invention.
本发明的一些方案中，上述环B为 其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring B is Other variables are as defined in the present invention.
本发明的一些方案中，上述环B为 其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring B is Other variables are as defined herein.
本发明的一些方案中，上述环A为 其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring A is Other variables are as defined herein.
本发明的一些方案中，上述环A为 其他变量如本发明所定义。In some embodiments of the present invention, the ring A is Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元为 其他变量如本发明所定义。In some embodiments of the present invention, the above structural unit for Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元为 其他变量如本发明所定义。In some embodiments of the present invention, the above structural unit for Other variables are as defined in the present invention.
本发明的一些方案中，上述化合物具有如下(II-1)或(II-2)所示结构：
In some embodiments of the present invention, the above compound has the structure shown in (II-1) or (II-2):
其中，为单价或双键；环B、X、L、T、R1、R2和R3如本发明所定义。in, is a monovalent or double bond; Ring B, X, L, T, R 1 , R 2 and R 3 are as defined in the present invention.
本发明的一些方案中，上述化合物具有如下(P-1)、(P-2)或(P-3)所示结构：
In some embodiments of the present invention, the above compound has the structure shown as follows (P-1), (P-2) or (P-3):
其中，为单价或双键；环B、T、R1、R2和R3如本发明所定义。in, is a monovalent or double bond; Ring B, T, R 1 , R 2 and R 3 are as defined in the present invention.
本发明的一些方案中，上述化合物具有如下(P-4)或(P-5)所示结构：
In some embodiments of the present invention, the above compound has the structure shown in (P-4) or (P-5):
其中，为单价或双键；环B、T、R1、R2和Rc如本发明所定义。in, is a monovalent or double bond; Ring B, T, R 1 , R 2 and R c are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。Some other solutions of the present invention are obtained by arbitrarily combining the above variables.
本发明还提供了下式化合物、其立体异构体或其药学上可接受的盐，


The present invention also provides a compound of the following formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:


本发明还提供了下式化合物、其立体异构体或其药学上可接受的盐，



The present invention also provides a compound of the following formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:



本发明还提供了上述化合物、其立体异构体或其药学上可接受的盐在制备治疗炎症疾相关病药物中的应用。The present invention also provides the use of the above compound, its stereoisomer or its pharmaceutically acceptable salt in the preparation of drugs for treating inflammatory disease-related diseases.
技术效果Technical Effects
本发明化合物作为NLRP3抑制剂，展示了良好的NLRP3抑制活性，在治疗炎症相关的疾病中具有较大的应用前景；本发明化合物成药性好，在啮齿类和非啮齿类动物中口服暴露量高，种属之间口服吸收没有显著差异；本发明化合物在不同种属血浆中均表现出较高程度的结合率，在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人肝细胞中代谢稳定性好并具有良好的肝微粒体稳定性。The compounds of the present invention, as NLRP3 inhibitors, exhibit good NLRP3 inhibitory activity and have great application prospects in the treatment of inflammation-related diseases; the compounds of the present invention have good drugability, high oral exposure in rodents and non-rodents, and no significant difference in oral absorption between species; the compounds of the present invention show a high degree of binding rate in the plasma of different species, good metabolic stability in CD-1 mice, SD rats, beagles, crab-eating monkeys and human hepatocytes, and good liver microsomal stability.
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.
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 humans 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接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。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 the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.
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 reacted with a stoichiometric amount of an appropriate base or acid to prepare.
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.
术语“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。The terms "optional" or "optionally" mean 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.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基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。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
术语“任选被取代的”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 "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of what is chemically feasible.
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。 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.
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
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A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括 这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line For example, the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes The groups connected in this way are just that when one chemical bond is connected, the H at the site will be reduced by one and become the corresponding monovalent piperidinyl. Unless otherwise specified, the term "C 1-3 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.
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(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。Unless otherwise specified, the term "C 1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl 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, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
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C1-2、C1-3、C1-4、C1-5、C2-3、C2-4、C2、C3、C4、C5和C6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、-NHCH2CH2CH3、-NHCH2(CH3)2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 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2 , C 3 , C 4 , C 5 and C 6 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 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , etc.
除非另有规定，“C2-5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5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C2-5烯基包括C2-3、C2-4、C5、C4、C3和C2烯基 等；所述C2-5烯基可以是一价、二价或者多价。C2-5烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、丁间二烯基等。Unless otherwise specified, " C2-5 alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 5 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 C2-5 alkenyl includes C2-3 , C2-4 , C5 , C4 , C3 and C2 alkenyl. The C 2-5 alkenyl group may be monovalent, divalent or polyvalent. Examples of C 2-5 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like.
除非另有规定，“C2-5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5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。所述C2-5炔基包括C2-4、C2-3、C4、C3和C2炔基等。其可以是一价、二价或者多价。C2-5炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基等。Unless otherwise specified, "C 2-5 alkynyl" is used to represent a straight or branched hydrocarbon group consisting of 2 to 5 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. The C 2-5 alkynyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It may be monovalent, divalent or polyvalent. Examples of C 2-5 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, 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C1-2、C2-3、C3和C2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)等。Unless otherwise specified, the term "C 1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.
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 and the like.
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。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，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。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和-CH2-CH2-S(＝O)2-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。The term "heteroalkyl" by itself or in combination with another term refers to 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. 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 is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl 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, but the terms "alkoxy,""alkylamino," and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those alkyl groups attached to the remainder of the molecule through an oxygen, amino or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 (CH 3 ) 2 , -CH 2 -CH 2 -O-CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -CH 2 -CH 2 - NH -CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 , -S(＝O)-CH 3 and -CH 2 -CH 2 -S(＝O) 2 -CH 3 . Up to two heteroatoms may be consecutive, for example -CH 2 -NH-OCH 3 .
术语“C1-3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。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C1-3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，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。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和-CH2-CH2-S(＝O)2-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。The term "C 1-3 heteroalkyl" by itself or in combination with another term refers to 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. 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 is C 1-3 heteroalkyl. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom, amino group or sulfur atom, respectively. Examples of heteroalkyl groups include but are not limited to Limited to -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 (CH 3 ) 2 , -CH 2 -CH 2 -O-CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -CH 2 -CH 2 -NH-CH 3 , - CH 2 -CH 2 -N(CH 3 )-CH 3 , -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 , -S(=O)-CH 3 and -CH 2 -CH 2 -S(=O) 2 -CH 3 . Up to two heteroatoms may be consecutive, for example -CH 2 -NH-OCH 3 .
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.
除非另有规定，“C3-8环烷基”表示由3至8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C3-8环烷基包括C3-6、C4-5和C5-6环烷基等；其可以是一价、二价或者多价。C3-8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 3-8 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-8 cycloalkyl includes C 3-6 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
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，“C3-7环烷基”表示由3至7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C3-7环烷基包括C3-6、C4-6和C5-6环烷基等；其可以是一价、二价或者多价。C3-7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 3-7 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-7 cycloalkyl includes C 3-6 , C 4-6 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
除非另有规定，“C5-6环烷基”表示由5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C5-6环烷基包括C5和C6元环烷基；其可以是一价、二价或者多价。C5-6环烷基的实例包括，但不限于环戊基和环己基等。Unless otherwise specified, "C 5-6 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 5 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 5-6 cycloalkyl includes C5 and C6 cycloalkyl; it can be monovalent, divalent or polyvalent. Examples of C 5-6 cycloalkyl include, but are not limited to, cyclopentyl and cyclohexyl.
除非另有规定，“5-7元环烯基”表示由5至7个环原子组成的环烯基。所述的环包括单环，也包括螺环、并环和桥环等双环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述5-7元环包括5-6元环、6-7元环、5元、6元和7元环等。“5-7元环”包括例如苯基、吡啶基和哌啶基等。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "5-7 membered cycloalkenyl" means a cycloalkenyl group consisting of 5 to 7 ring atoms. The ring includes a monocyclic ring, and also includes bicyclic ring systems such as spirocyclic rings, fused rings and bridged rings. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N. The 5-7 membered ring includes a 5-6 membered ring, a 6-7 membered ring, a 5-membered ring, a 6-membered ring and a 7-membered ring. "5-7 membered ring" includes, for example, phenyl, pyridyl and piperidyl. The term "ring" also includes a ring system containing at least one ring, each of which independently meets the above definition.
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)。此外，就该“3-6元杂环烷基”而言，杂原子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4-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷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、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)或四氢呋喃基(包括四氢呋喃-2-基等)等。Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated monocyclic radical 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 are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). In addition, with respect to the "3-6 membered heterocycloalkyl", heteroatoms may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 4-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), and the like.
除非另有规定，“5-7杂环烷基”表示由5至7个环原子组成的杂环烷基。所述的环包括单环，也包括 螺环、并环和桥环等双环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述5-7元环包括5-6元、6-7元和6元等。术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "5-7 heterocycloalkyl" means a heterocycloalkyl group consisting of 5 to 7 ring atoms. The ring includes a monocyclic ring and also includes The term "heterocycloalkyl" includes piperidinyl, etc., but does not include phenyl. The term "ring" also includes a ring system containing at least one ring, each of which independently meets the above definition.
除非另有规定，“3-7杂环烷基”表示由3至7个环原子组成的杂环烷基。所述的环包括单环，也包括螺环、并环和桥环等双环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述3-7元环包括3-6元、3-5元、3-4元、4-7元、4-6元、4-5元、5-7元、4元、5元、6元和7元等。术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。除非另有规定，术语“5-6元杂环烷基”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元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-6元杂环烷基包括5元和6元杂环烷基。5-6元杂环烷基的实例包括但不限于吡咯烷基、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、六氢哒嗪基等。Unless otherwise specified, "3-7 heterocycloalkyl" means a heterocycloalkyl consisting of 3 to 7 ring atoms. The ring includes a monocyclic ring, and also includes bicyclic ring systems such as spirocyclic rings, cyclic rings and bridged rings. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N. The 3-7 membered ring includes 3-6, 3-5, 3-4, 4-7, 4-6, 4-5, 5-7, 4, 5, 6 and 7 members. The term "5-7 membered heterocycloalkyl" includes piperidinyl, etc., but does not include phenyl. The term "ring" also includes a ring system containing at least one ring, each of which "rings" independently meets the above definition. Unless otherwise specified, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated 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 heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, 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, etc.
除非另有规定，术语“5-12元杂环烷基”本身或者与其他术语联合分别表示由5至12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)。所述其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环，其中至少有一个环为芳香性的，其它环可以是任意环。此外，就该“5-12元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-12元杂环烷基包括5-10元、5-8元、5-7元、5-6元、5元和6元杂环烷基等。5-12元杂环烷基的实例包括但不限于吡咯烷基、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、高哌啶基或二氧杂环庚烷基等。Unless otherwise specified, the term "5-12 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 12 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 are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The term "5-12 membered heterocycloalkyl" includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, paracyclic and bridged rings, wherein at least one ring is aromatic, and the other rings can be any ring. In addition, with respect to the "5-12 membered heterocycloalkyl", heteroatoms can occupy the position where the heterocycloalkyl connects to the rest of the molecule. The 5-12 membered heterocycloalkyl includes 5-10 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 5-12 membered heterocycloalkyl groups include, but are not limited to, 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, homopiperidinyl or dioxepanyl, etc.
除非另有规定，术语“5-7元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至7个环原子组成的部分不饱和的环状基团，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，此体系的任意环都是非芳香性的。此外， 就该“5-7元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述5-7元杂环烯基包括5-6元、5元、6元和7元杂环烯基等。5-7元杂环烯基的实例包括但不限于 Unless otherwise specified, the term "5-7 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 7 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms 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, fused and bridged rings, and any ring of this system is non-aromatic. In addition, In the case of the "5-7 membered heterocycloalkenyl", a heteroatom may occupy the position at which the heterocycloalkenyl is attached to the rest of the molecule. The 5-7 membered heterocycloalkenyl includes 5-6 membered, 5 membered, 6 membered and 7 membered heterocycloalkenyl, etc. Examples of 5-7 membered heterocycloalkenyl include, but are not limited to
除非另有规定，本发明术语“C6-10芳环”和“C6-10芳基”可以互换使用，术语“C6-10芳环”或“C6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环或稠合双环体系，其中至少有一个环为芳香性的，其它环可以是任意环。其可以是一价、二价或者多价，C6-10芳基包括C6-9、C9、C10和C6芳基等。C6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)、 Unless otherwise specified, the terms "C 6-10 aromatic ring" and "C 6-10 aryl" of the present invention can be used interchangeably. The term "C 6-10 aromatic ring" or "C 6-10 aryl" means a cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated π electron system. It can be a monocyclic ring or a fused bicyclic ring system, wherein at least one ring is aromatic and the other rings can be any ring. It can be monovalent, divalent or polyvalent. C 6-10 aryl includes C 6-9 , C 9 , C 10 and C 6 aryl. Examples of C 6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.),
除非另有规定，本发明术语“C9-10芳环”和“C9-10芳基”可以互换使用，术语“C9-10芳环”或“C9-10芳基”表示由9至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中至少有一个环为芳香性的，其它环可以是任意环。其可以是一价、二价或者多价，C9-10芳基包括C9和C10芳基。C9-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)、 Unless otherwise specified, the terms "C 9-10 aromatic ring" and "C 9-10 aryl" in the present invention can be used interchangeably. The term "C 9-10 aromatic ring" or "C 9-10 aryl" means a cyclic hydrocarbon group composed of 9 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, wherein at least one ring is aromatic, and the other rings can be any ring. It can be monovalent, divalent or polyvalent. C 9-10 aryl includes C 9 and C 10 aryl. Examples of C 9-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.),
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，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。其可以是单环、稠合双环或稠合三环体系，其中至少有一个环为芳香性的，其它环可以是任意环。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)。5-10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5-10元杂芳基包括5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-10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、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包 括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" of the present invention can be used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 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. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein at least one ring is aromatic, and the other rings can be any rings. 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 5-10 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-10 membered heteroaryl includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl, etc. Examples of the 5-10 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), yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl), furyl (including 2-furyl and 3-furyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl), benzothiazolyl (including 5-benzothiazolyl), purinyl, benzimidazolyl (including 2-benzimidazolyl), benzoxazolyl, indolyl (including 5-indolyl), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl), quinoxalinyl (including quinolinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolinyl (including 3-quinolinyl and 6-quinolinyl, 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" of the present invention can be used interchangeably, and the term "5-6 membered heteroaryl" means 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. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be 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 through 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，本发明术语“9-10元杂芳环”和“9-10元杂芳基”可以互换使用，术语“9-10元杂芳基”是表示由9至10个环原子组成的具有共轭π电子体系的环状基团，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。其可以是单环、稠合双环或稠合三环体系，其中至少有一个环为芳香性的，其它环可以是任意环。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)。9-10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9-10元杂芳基包括9元和10元杂芳基。所述9-10元杂芳基的实例包括但不限于苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。Unless otherwise specified, the terms "9-10 membered heteroaromatic ring" and "9-10 membered heteroaryl" of the present invention can be used interchangeably. The term "9-10 membered heteroaryl" refers to a cyclic group consisting of 9 to 10 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. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein at least one ring is aromatic, and the other rings can be any rings. 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 9-10 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 9-10 membered heteroaryl includes 9-membered and 10-membered heteroaryl. Examples of the 9-10 membered heteroaryl include, but are not limited to, benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).
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、6-7元环、6-8元环、和6-10元环等。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。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 on the ring is n to n+m, for example, 3-12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, and 12-membered rings, and also include any range from n to n+m, for example, 3-12-membered rings include 3-6-membered rings, 3-9-membered rings, 5-6-membered rings, 5-7-membered rings, 6-7-membered rings, 6-8-membered rings, and 6-10-membered rings, etc. 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 synthesis methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRC)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关 数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRC) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: Scan and collect relevant After obtaining the data, the direct method (Shelxs97) was further used to analyze the crystal structure to confirm the absolute configuration.
本发明采用下述缩略词：CO2代表二氧化碳；DCM代表二氯甲烷；MeOH代表甲醇；ATP代表三磷酸腺苷；LPS代表脂多糖；CBA代表细胞因子微球检测技术；PMA代表巴豆醇-12-十四烷酸酯-13-乙酸酯；NEAA代表非必须氨基酸；FBS代表胎牛血清；IL-1β代表白介素-1β；Human IL-1βFlex Set代表人白介素-1β检测试剂盒。The present invention adopts the following abbreviations: CO2 represents carbon dioxide; DCM represents dichloromethane; MeOH represents methanol; ATP represents adenosine triphosphate; LPS represents lipopolysaccharide; CBA represents cytokine microsphere assay technology; PMA represents crotonyl-12-tetradecanoate-13-acetate; NEAA represents non-essential amino acids; FBS represents fetal bovine serum; IL-1β represents interleukin-1β; Human IL-1βFlex Set represents human interleukin-1β detection kit.
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.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1：各类受试药品在不同给药剂量下2小时和6小时动物血清IL-1β水平柱形图。Figure 1: Bar graph of animal serum IL-1β levels at 2 hours and 6 hours after administration of various test drugs at different dosages.
具体实施方式DETAILED DESCRIPTION
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，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，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present invention. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
参考例1
Reference Example 1
步骤1:将化合物中间体1-1(317.8mg,1.4mmol)和中间体1-2(0.2g,1.4mmol)溶于叔戊醇(5mL)和水(1mL)，加入氢氧化钾(168.0mg,3.0mmol)、5-(二叔丁基磷)-1,3,5-三苯基-1氢-[1,4]二吡唑(141.2mg,278.6μmol)和三(二苄亚基丙酮)钯(127.6mg,139.3μmol)。氮气保护下90℃搅拌12小时。反应完毕后用水(50mL)淬灭反应并用乙酸乙酯(50mL*3)萃取，有机相干燥浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1),得中间体1。MS ESI计算值[M+H]+290。Step 1: Dissolve the compound intermediate 1-1 (317.8 mg, 1.4 mmol) and intermediate 1-2 (0.2 g, 1.4 mmol) in tert-amyl alcohol (5 mL) and water (1 mL), add potassium hydroxide (168.0 mg, 3.0 mmol), 5-(di-tert-butylphosphine)-1,3,5-triphenyl-1 hydrogen-[1,4]dipyrazole (141.2 mg, 278.6 μmol) and tris(dibenzylideneacetone)palladium (127.6 mg, 139.3 μmol). Stir at 90 ° C for 12 hours under nitrogen protection. After the reaction is completed, quench the reaction with water (50 mL) and extract with ethyl acetate (50 mL*3). After the organic phase is dried and concentrated, the crude product is purified by column chromatography (dichloromethane: methanol = 10:1) to obtain intermediate 1. MS ESI calculated value [M+H] + 290.
参考例2
Reference Example 2
步骤1:将中间体2-1(1.0g,6.2mmol)和中间体2-2(857.4mg,7.5mmol)混合，反应于130℃下加热搅拌1小时，反应完毕后用水(30mL)淬灭，用氢氧化钠溶液(1M)调节到pH＝7,然后用二氯甲烷(30mL*2)萃取，有机相干燥浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5：1),然后经超临界流体色谱分离(色谱柱: DAICEL CHIRALPAK IG(250mm*50mm,10μm)；流动相:A:CO2 B:乙醇(0.1％氨水)洗脱梯度:A:B＝35:35；流速:200mL/min；柱温:38℃；柱压:100Bar；样品含量：90％)得中间体2。MS ESI[M+H]+241。Step 1: Intermediate 2-1 (1.0 g, 6.2 mmol) and intermediate 2-2 (857.4 mg, 7.5 mmol) were mixed, and the reaction was heated and stirred at 130°C for 1 hour. After the reaction was completed, it was quenched with water (30 mL), adjusted to pH = 7 with sodium hydroxide solution (1 M), and then extracted with dichloromethane (30 mL * 2). After the organic phase was dried and concentrated, the crude product was purified by column chromatography (dichloromethane: methanol = 5: 1), and then separated by supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 μm); mobile phase: A: CO 2 B: ethanol (0.1% ammonia water); elution gradient: A: B = 35:35; flow rate: 200 mL/min; column temperature: 38°C; column pressure: 100 Bar; sample content: 90%) to obtain intermediate 2. MS ESI [M+H] + 241.
实施例1
Example 1
步骤1:将化合物1-1(4.0g,18.2mmol)溶于乙酸(40mL)，加入三氯化铁(322.0mg,2.0mmol)和液溴(4.4g,27.4mmol)。氮气保护下20℃搅拌2小时。反应完毕后将反应液浓缩，粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0)得化合物1-2。Step 1: Dissolve compound 1-1 (4.0 g, 18.2 mmol) in acetic acid (40 mL), add ferric chloride (322.0 mg, 2.0 mmol) and liquid bromine (4.4 g, 27.4 mmol). Stir at 20 ° C for 2 hours under nitrogen protection. After the reaction is completed, the reaction solution is concentrated, and the crude product is purified by column chromatography (petroleum ether: ethyl acetate = 1:0) to obtain compound 1-2.
步骤2:将化合物1-2(1.5g,5.02mmol)溶于N,N-二甲基甲酰胺(8mL)中，加入碳酸钾(1.39g,10.05mmol)和碘甲烷(1.07g,7.53mmol)，60℃搅拌2小时。反应完毕后用水(20mL)淬灭反应并用乙酸乙酯(20mL*3)萃取，有机相干燥浓缩后，粗品经柱层析纯化(石油醚)得化合物1-3。1H NMR(400MHz,CDCl3)δppm 7.61-7.66(m,1H)7.25-7.27(m,1H)7.24(s,1H)3.95(s,3H)。Step 2: Compound 1-2 (1.5 g, 5.02 mmol) was dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (1.39 g, 10.05 mmol) and iodomethane (1.07 g, 7.53 mmol) were added, and stirred at 60°C for 2 hours. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3). After the organic phase was dried and concentrated, the crude product was purified by column chromatography (petroleum ether) to obtain compound 1-3. 1 H NMR (400 MHz, CDCl 3 ) δppm 7.61-7.66 (m, 1H) 7.25-7.27 (m, 1H) 7.24 (s, 1H) 3.95 (s, 3H).
步骤3:将化合物1-3(0.8g,2.6mmol)、双联频哪醇硼酸酯(800.0mg,3.2mmol)和醋酸钾(502.0mg,5.1mmol)悬浮于二氧六环(6mL)中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(200.0mg,273.3μmol)，氮气保护下100℃搅拌3小时，反应完毕后用水(10mL)淬灭反应并用乙酸乙酯(30mL*3)萃取，有机相干燥浓缩后，粗品经柱层析(石油醚)得化合物1-4。1H NMR(400MHz,DMSO-d6)δppm 7.71(d,J＝8.07Hz,1H),7.44(d,J＝8.19,1H),7.33(s,1H),3.83(s,3H),1.28(s,12H)。Step 3: Compound 1-3 (0.8 g, 2.6 mmol), bis-pinacol borate (800.0 mg, 3.2 mmol) and potassium acetate (502.0 mg, 5.1 mmol) were suspended in dioxane (6 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (200.0 mg, 273.3 μmol) was added. The mixture was stirred at 100 °C for 3 hours under nitrogen protection. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was dried and concentrated, and the crude product was purified by column chromatography (petroleum ether) to obtain compound 1-4. 1 H NMR (400MHz, DMSO-d 6) δppm 7.71 (d, J = 8.07 Hz, 1H), 7.44 (d, J = 8.19, 1H), 7.33 (s, 1H), 3.83 (s, 3H), 1.28 (s, 12H).
步骤4:将化合物1-4(270.0mg,749.7μmol)、中间体1(217.2mg,749.7μmol)溶于二氧六环(10mL)和水(2mL)中，加入碳酸钾(207.2mg,1.5mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(128.7mg,157.6μmol)，反应于氮气保护下100℃搅拌4小时，反应完毕后用水(10mL)淬灭反应并用乙酸乙酯(30mL*3)萃取，有机相干燥浓缩后，粗品经制备型HPLC分离(色谱柱:Phenomenex Synergi Polar-RP 100*25mm*4μm；流动相:[水(三氟乙酸)-乙腈]；乙腈％:27％-57％,9min)得化合物1-5。1H NMR(400MHz,DMSO-d6)δppm 10.71(s,1H)，9.18(s,1H),7.58-7.65(m,2H),7.48-7.56(m,2H),7.15-7.22(m,1H),6.92-6.98(m,2H),3.87(s,3 H),3.27(s,3H),2.02(s,3H).MS ESI[M+H]+488。Step 4: Compound 1-4 (270.0 mg, 749.7 μmol) and intermediate 1 (217.2 mg, 749.7 μmol) were dissolved in dioxane (10 mL) and water (2 mL), potassium carbonate (207.2 mg, 1.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (128.7 mg, 157.6 μmol) were added, and the reaction was stirred at 100 ° C for 4 hours under nitrogen protection. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL*3). After the organic phase was dried and concentrated, the crude product was separated by preparative HPLC (chromatographic column: Phenomenex Synergi Polar-RP 100*25mm*4μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile%: 27%-57%, 9min) to obtain compound 1-5. 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.71 (s, 1H), 9.18 (s, 1H), 7.58-7.65 (m, 2H), 7.48-7.56 (m, 2H), 7.15-7.22 (m, 1H), 6.92-6.98 (m, 2H), 3.87 (s, 3 H),3.27(s,3H),2.02(s,3H).MS ESI[M+H] + 488.
步骤5:将化合物1-5(90.0mg,184.6μmol)溶于二氯甲烷(1mL)中，在0℃加入三溴化硼(2.6g,10.4mmol)，反应于25℃搅拌16小时，反应完毕后用水(5mL)和甲醇(5mL)淬灭，浓缩至干，粗品经薄层制备色谱(DCM:MeOH＝10:1)分离纯化得到化合物1。1H NMR(400MHz,DMSO-d6)δppm 10.71(s,1H),10.66(s,1H),9.16(s,1H),7.60(s,1H),7.40-7.50(m,3H),7.18(d,J＝8.38,1H),6.93-6.97(m,2H),3.27(s,3H),2.10(s,3H)。MS ESI[M+H]+474。Step 5: Compound 1-5 (90.0 mg, 184.6 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (2.6 g, 10.4 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, the mixture was quenched with water (5 mL) and methanol (5 mL), concentrated to dryness, and the crude product was separated and purified by thin layer preparative chromatography (DCM: MeOH = 10: 1) to obtain compound 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.71 (s, 1H), 10.66 (s, 1H), 9.16 (s, 1H), 7.60 (s, 1H), 7.40-7.50 (m, 3H), 7.18 (d, J = 8.38, 1H), 6.93-6.97 (m, 2H), 3.27 (s, 3H), 2.10 (s, 3H). MS ESI[M+H] + 474.
实施例2
Example 2
步骤1:将化合物1-4(0.3g,833.0μmol),中间体2(220.6mg,916.3μmol)溶于二氧六环(10mL)和水(2mL)中，加入碳酸钾(230.3mg,1.7mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(142.97mg,175.07μmol)，反应于氮气保护下100℃搅拌0.5小时，反应完毕后用水(10mL)淬灭反应并用乙酸乙酯(30mL*3)萃取，有机相干燥浓缩后，粗品经薄层制备色谱(DCM:MeOH＝5:1)分离得到化合物2-1.1H NMR(400MHz,CDCl3)δppm 7.45-7.48(m,2H),7.31(d,J＝1.50Hz,1H),6.55(s,1H),5.11-5.46(m,1H),4.04-4.26(m,1H),3.83(s,3H),2.37-2.75(m,2H),2.30-2.37(m,3H),2.06(d,J＝0.75Hz,3H),1.56-1.90(m,8H)。MS ESI[M+H]+439。Step 1: Compound 1-4 (0.3 g, 833.0 μmol) and intermediate 2 (220.6 mg, 916.3 μmol) were dissolved in dioxane (10 mL) and water (2 mL), potassium carbonate (230.3 mg, 1.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (142.97 mg, 175.07 μmol) were added, and the reaction was stirred at 100 ° C for 0.5 hours under nitrogen protection. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (30 mL*3). After the organic phase was dried and concentrated, the crude product was separated by thin layer preparative chromatography (DCM: MeOH = 5: 1) to obtain compound 2-1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.45-7.48(m,2H),7.31(d,J＝1.50Hz,1H),6.55(s,1H),5.11-5.46(m,1H),4.04-4.26(m,1H),3.83(s,3H),2.37-2.75(m,2H),2.30-2.37(m,3H), 2.06(d,J=0.75Hz,3H),1.56-1.90(m,8H). MS ESI[M+H] +439 .
步骤2:将化合物2-1(90.0mg,184.6μmol)溶于二氯甲烷(1mL)中，在0℃加入三溴化硼(2.6g,10.4mmol)，反应于25℃搅拌16小时，反应完毕后用水(5mL)和甲醇(5mL)淬灭，浓缩至干，粗品经HPLC制备分离(色谱柱:YMC Triart C18 150*25mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:12％-42％,10min)得到化合物2。1H NMR(400MHz,CD3OD)δppm 7.40(s,2H),7.37(d,J＝1.25Hz,1H),6.88(s,1H),4.28-4.39(m,1H),3.53-3.69(m,1H),3.04(br d,J＝7.38Hz,2H),2.85(s,3H),2.08-2.17(m,5H),1.94(br d,J＝1.00Hz,1H),1.57-1.76(m,1H),1.26-1.34(m,3H)。MS ESI-[M+H]+425。Step 2: Compound 2-1 (90.0 mg, 184.6 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (2.6 g, 10.4 mmol) was added at 0°C. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, it was quenched with water (5 mL) and methanol (5 mL), concentrated to dryness, and the crude product was separated by HPLC (chromatographic column: YMC Triart C18 150*25mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 12%-42%, 10 min) to obtain compound 2. 1 H NMR (400MHz, CD 3 OD) δppm 7.40 (s, 2H), 7.37 (d, J = 1.25Hz, 1H), 6.88 (s, 1H), 4.28-4.39 (m, 1H), 3.53-3.69 (m, 1H), 3.04 (br d, J = 7.38Hz, 2H), 2.85 (s, 3 H), 2.08-2.17 (m, 5H), 1.94 (br d, J = 1.00Hz, 1H), 1.57-1.76 (m, 1H), 1.26-1.34 (m, 3H). MS ESI-[M+H] +425 .
参考例3
Reference Example 3
步骤1:将化合物1-4(15.4g,42.7mmol)的二氯甲烷(100mL)溶液冷却到0℃，缓慢滴加三溴化硼(16.0g,64.0mmol)，0℃搅拌0.5小时，反应完毕后，在0℃下，用冷却过的饱和碳酸钠水溶液(100mL) 淬灭，室温下搅拌0.5小时，静置分层，水相用2N盐酸水溶液(～20mL)调节pH＝2，用二氯甲烷(100mL*2)萃取，有机相用无水硫酸钠干燥浓缩后，粗品加入石油醚(20mL)中室温打浆0.5小时，过滤后得化合物2。MS ESI计算值C6H6BF5O3S[M+H]+265，实测值265。Step 1: Cool a solution of compound 1-4 (15.4 g, 42.7 mmol) in dichloromethane (100 mL) to 0°C, slowly add boron tribromide (16.0 g, 64.0 mmol) dropwise, and stir at 0°C for 0.5 hours. After the reaction is complete, add a cooled saturated aqueous sodium carbonate solution (100 mL) at 0°C. The mixture was quenched, stirred at room temperature for 0.5 hours, allowed to stand for stratification, the aqueous phase was adjusted to pH=2 with 2N hydrochloric acid aqueous solution (-20 mL), extracted with dichloromethane (100 mL*2), the organic phase was dried over anhydrous sodium sulfate and concentrated, the crude product was added to petroleum ether (20 mL) and slurried at room temperature for 0.5 hours, and filtered to obtain compound 2. MS ESI calculated value C 6 H 6 BF 5 O 3 S [M+H] + 265, found value 265.
参考例4
Reference Example 4
步骤1:将化合物中间体4-1(5.0g,21.3mmol)和中间体4-2(2.9g,23.5mmol)溶于乙腈中，然后加入碳酸钠(3.4g,32.0mmol),反应于60℃搅拌4小时，反应完毕后过滤旋干，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1～5:1)得中间体4-3。MS ESI计算值C15H22N2O3[M+H]+279，实测值279。Step 1: Dissolve the intermediate 4-1 (5.0 g, 21.3 mmol) and the intermediate 4-2 (2.9 g, 23.5 mmol) in acetonitrile, then add sodium carbonate (3.4 g, 32.0 mmol), react at 60°C and stir for 4 hours, filter and spin dry after the reaction, and purify the crude product by column chromatography (dichloromethane: methanol = 10:1 to 5:1) to obtain the intermediate 4-3. MS ESI calculated value C 15 H 22 N 2 O 3 [M+H] + 279, found value 279.
步骤2:将中间体4-3(5.9g,21.20mmol)溶于甲醇(30mL)中，加入10％干钯碳(～1g),反应于氢气(15Psi)氛围下，25℃搅拌1小时，反应完毕后过滤，滤液旋干得中间体4。MS ESI计算值C7H16N2O[M+H]+145，实测值145。Step 2: Dissolve intermediate 4-3 (5.9 g, 21.20 mmol) in methanol (30 mL), add 10% dry palladium carbon (~1 g), react under hydrogen (15 Psi) atmosphere, stir at 25 ° C for 1 hour, filter after the reaction, and spin dry the filtrate to obtain intermediate 4. MS ESI calculated value C 7 H 16 N 2 O [M + H] + 145, found value 145.
实施例3&4
Embodiment 3 & 4
步骤1:将化合物3-1(1.0g,4.9mmol)和中间体2-2(723.9mg,6.3mmol)混匀,加热至130℃保温0.5小时，反应完毕后用水(50mL)和二氯甲烷(50mL)淬灭，用氢氧化钠溶液(1M,～8mL)调节到pH＝7,并用二氯甲烷(50mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5:1)得化合物3-2和4-2的混合物。MS ESI计算值C12H15ClN4S[M+H]+283，实测值283。Step 1: Compound 3-1 (1.0 g, 4.9 mmol) and intermediate 2-2 (723.9 mg, 6.3 mmol) were mixed and heated to 130°C for 0.5 hours. After the reaction was completed, the mixture was quenched with water (50 mL) and dichloromethane (50 mL), adjusted to pH = 7 with sodium hydroxide solution (1 M, ~8 mL), and extracted with dichloromethane (50 mL*2). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain a mixture of compounds 3-2 and 4-2. MS ESI calculated value C 12 H 15 ClN 4 S [M + H] + 283, found value 283.
步骤2:将化合物3-2和4-2的混合物(60mg,227.3μmol),中间体3(64.3mg,227.3μmol)溶于二氧六环(2mL)和水(1mL)中，加入碳酸钾(173.5mg,1.2mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(91.8mg,125.5μmol)，反应于90℃搅拌2小时，反应完毕后用水(50mL)淬灭反应并用乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经(色谱柱:Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:10％-40％,10min)分别得化合物3和化合物4的盐酸盐。Step 2: A mixture of compounds 3-2 and 4-2 (60 mg, 227.3 μmol) and intermediate 3 (64.3 mg, 227.3 μmol) were dissolved in dioxane (2 mL) and water (1 mL), potassium carbonate (173.5 mg, 1.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (91.8 mg, 125.5 μmol) were added, and the reaction was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by (chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain the hydrochloride of compound 3 and compound 4, respectively.
化合物3的盐酸盐：1H NMR(400MHz,CD3OD)δppm 8.42-8.47(m,1H),7.79(7d,J＝8.5Hz,1H),7.70(d,J＝5.3Hz,1H),7.61(dd,J＝2.0,8.5Hz,1H),7.57(d,J＝2.0Hz,1H),4.74-4.60(m,1H),3.92(d,J＝9.0Hz,1H), 3.60(d,J＝11.5Hz,1H),2.92-3.15(m,5H),1.85-2.41(m,4H)。MS ESI计算值C18H19F5N4OS2[M+H]+467，实测值467。Hydrochloride of compound 3: 1 H NMR (400 MHz, CD 3 OD) δppm 8.42-8.47 (m, 1H), 7.79 (7d, J = 8.5 Hz, 1H), 7.70 (d, J = 5.3 Hz, 1H), 7.61 (dd, J = 2.0, 8.5 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 4.74-4.60 (m, 1H), 3.92 (d, J = 9.0 Hz, 1H), 3.60 (d, J=11.5 Hz, 1H), 2.92-3.15 (m, 5H), 1.85-2.41 (m, 4H). MS ESI calcd for C 18 H 19 F 5 N 4 OS 2 [M+H] + 467, found 467.
化合物4的盐酸盐1H NMR(400MHz,CD3OD)δppm 8.53-8.63(m,1H),8.26(d,J＝5.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.53-7.65(m,2H),4.63(s,1H),3.91(s,1H),3.61(d,J＝11.8Hz,1H),3.06-3.29(m,2H),3.00(s,3H),2.04-2.44(m,4H)。MS ESI计算值C18H19F5N4OS2[M+H]+467，实测值467。 1 H NMR (400 MHz, CD 3 OD) δ ppm of the hydrochloride salt of compound 4 8.53-8.63 (m, 1H), 8.26 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.53-7.65 (m, 2H), 4.63 (s, 1H), 3.91 (s, 1H), 3.61 (d, J = 11.8 Hz, 1H), 3.06-3.29 (m, 2H), 3.00 (s, 3H), 2.04-2.44 (m, 4H). MS ESI calculated value for C 18 H 19 F 5 N 4 OS 2 [M+H] + 467, found value 467.
实施例5
Example 5
步骤1:将化合物5-1(921.7mg,4.9mmol)和中间体2-2(723.9mg,6.3mmol)混匀,加热至130℃保温0.5小时，反应完毕后用水(50mL)二氯甲烷(50mL)淬灭，用氢氧化钠溶液(1M,～8mL)调节到pH＝7,并用二氯甲烷(50mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5:1)得化合物5-2。MS ESI计算值C12H15ClN4O[M+H]+267，实测值267。Step 1: Compound 5-1 (921.7 mg, 4.9 mmol) and intermediate 2-2 (723.9 mg, 6.3 mmol) were mixed and heated to 130°C for 0.5 hours. After the reaction was completed, the mixture was quenched with water (50 mL) and dichloromethane (50 mL). The pH was adjusted to 7 with sodium hydroxide solution (1 M, ~8 mL), and the mixture was extracted with dichloromethane (50 mL*2). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain compound 5-2. MS ESI calculated value C 12 H 15 ClN 4 O[M+H] + 267, found value 267.
步骤2:将化合物5-2(30.3mg,113.6μmol),中间体3(30.0mg,113.6μmol)溶于二氧六环(5mL)和水(2mL)中，加入碳酸钾(47.1mg,340.9mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(25.0mg,34.1μmol)，反应于90℃搅拌2小时，反应完毕后用水(50mL)淬灭反应并用乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经(色谱柱:Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:15％-45％,10min)得化合物5的盐酸盐。1H NMR(400MHz,CD3OD)δppm 8.46(d,J＝1.5Hz,1H),8.08(d,J＝7.8Hz,1H),7.48-7.60(m,3H),4.56(s,1H),3.92(s,1H),3.60(d,J＝10.8Hz,1H),2.92-3.21(m,5H),1.89-2.44(m,4H)。MS ESI计算值C18H19F5N4O2S[M+H]+451，实测值451。Step 2: Compound 5-2 (30.3 mg, 113.6 μmol) and intermediate 3 (30.0 mg, 113.6 μmol) were dissolved in dioxane (5 mL) and water (2 mL), potassium carbonate (47.1 mg, 340.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (25.0 mg, 34.1 μmol) were added, and the reaction was stirred at 90 ° C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by (chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-45%, 10min) to obtain the hydrochloride of compound 5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.46 (d, J = 1.5 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.48-7.60 (m, 3H), 4.56 (s, 1H), 3.92 (s, 1H), 3.60 (d, J = 10.8 Hz, 1H), 2.92-3.21 (m, 5H), 1.89-2.44 (m, 4H). MS ESI calculated value for C 18 H 19 F 5 N 4 O 2 S [M+H] + 451, found 451.
实施例6
Example 6
步骤1:将化合物中间体2-1(1.0g,6.1mmol)和化合物6-1(777.2mg,6.8mmol)混匀,加热至130℃保温0.5小时，反应完毕后用水(50mL)和二氯甲烷(50mL)淬灭，用氢氧化钠溶液(1M,～8mL)调节到pH＝7,并用二氯甲烷(50mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5:1)得化合物6-2。MS ESI计算值C9H12ClN3O2[M+H]+230，实测值230。 Step 1: Compound intermediate 2-1 (1.0 g, 6.1 mmol) and compound 6-1 (777.2 mg, 6.8 mmol) were mixed and heated to 130°C for 0.5 hours. After the reaction was completed, the mixture was quenched with water (50 mL) and dichloromethane (50 mL), adjusted to pH = 7 with sodium hydroxide solution (1 M, ~8 mL), and extracted with dichloromethane (50 mL*2). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain compound 6-2. MS ESI calculated value C 9 H 12 ClN 3 O 2 [M+H] + 230, found value 230.
步骤2:将化合物6-2(30.0mg,113.6μmol),中间体3(26.1mg,113.6μmol)溶于二氧六环(2mL)和水(1mL)中，加入碳酸钾(47.1mg,340.9μmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(46.4mg,56.8μmol)，反应于90℃搅拌2小时，反应完毕后用水(50mL)淬灭反应并用乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经(色谱柱:Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:1％-30％,10min)得化合物6的盐酸盐。Step 2: Compound 6-2 (30.0 mg, 113.6 μmol) and intermediate 3 (26.1 mg, 113.6 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and potassium carbonate (47.1 mg, 340.9 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.4 mg, 56.8 μmol) were added. The reaction was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by (chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 1%-30%, 10 min) to obtain the hydrochloride of compound 6.
1H NMR(400MHz,CD3OD)δppm 7.51-7.55(m,1H),7.50(d,J＝2.0Hz,1H),7.48(s,1H),7.44(d,J＝1.8Hz,1H),4.41(brs,1H),4.11-4.21(m,2H),3.91(d,J＝7.8Hz,1H),3.77(dd,J＝2.4,9.9Hz,1H),3.54(s,3H),3.19(s,1H)。MS ESI计算值C15H16F5N3O3S[M+H]+414，实测值414。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.51-7.55 (m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 4.41 (brs, 1H), 4.11-4.21 (m, 2H), 3.91 (d, J = 7.8 Hz, 1H), 3.77 (dd, J = 2.4, 9.9 Hz, 1H), 3.54 (s, 3H), 3.19 (s, 1H). MS ESI calculated value for C 15 H 16 F 5 N 3 O 3 S [M+H] + 414, found 414.
实施例7
Example 7
步骤1:将化合物3-1(500.0mg,2.4mmol)和中间体4(457.1mg,3.2mmol)混匀,加热至130℃保温0.5小时，反应完毕后用水(50mL)二氯甲烷(50mL)淬灭，用氢氧化钠溶液(1M,～8mL)调节到pH＝7,并用二氯甲烷(50mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5:1)得化合物7-1。MS ESI计算值C9H12ClN3O2[M+H]+230，实测值230。Step 1: Compound 3-1 (500.0 mg, 2.4 mmol) and intermediate 4 (457.1 mg, 3.2 mmol) were mixed and heated to 130°C for 0.5 hours. After the reaction was completed, the mixture was quenched with water (50 mL) and dichloromethane (50 mL). The pH was adjusted to 7 with sodium hydroxide solution (1 M, ~8 mL), and the mixture was extracted with dichloromethane (50 mL*2). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain compound 7-1. MS ESI calculated value C 9 H 12 ClN 3 O 2 [M+H] + 230, found value 230.
步骤2:将化合物7-1(94.8mg,303.1μmol)，中间体3(80.0mg,303.1μmol)溶于二氧六环(8mL)和水(3mL)中，加入碳酸钾(125.66mg,909.18μmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(66.52mg,90.92μmol)，反应于90℃搅拌2小时，反应完毕后用水(50mL)淬灭反应并用乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经薄层色谱法分离(二氯甲烷：甲醇＝10:1)得化合物7。1H NMR(400MHz,CD3OD)δppm 7.89(d,J＝5.3Hz,1H),7.68(d,J＝8.8Hz,1H),7.47(d,J＝5.5Hz,1H),7.25-7.36(m,2H),4.40-4.57(m,1H),3.51-3.75(m,2H),3.21(td,J＝1.6,3.3Hz,1H),3.14(d,J＝10.0Hz,1H),2.72(d,J＝10.8Hz,1H),2.45-2.67(m,2H),2.21-243(m,2H),1.87-2.00(m,1H),1.62-1.82(m,2H)。MS ESI计算值C19H21F5N4O2S2[M+H]+497，实测值497。Step 2: Compound 7-1 (94.8 mg, 303.1 μmol) and intermediate 3 (80.0 mg, 303.1 μmol) were dissolved in dioxane (8 mL) and water (3 mL), potassium carbonate (125.66 mg, 909.18 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (66.52 mg, 90.92 μmol) were added, and the reaction was stirred at 90 ° C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by thin layer chromatography (dichloromethane: methanol = 10:1) to obtain compound 7. 1 H NMR (400MHz, CD 3 OD) δppm 7.89 (d, J = 5.3Hz, 1H), 7.68 (d, J = 8.8Hz, 1H), 7.47 (d, J = 5.5Hz, 1H), 7.25-7.36 (m, 2H), 4.40-4.57 (m, 1H), 3.51-3.75 (m, 2H), 3.21(td,J＝1.6,3.3Hz,1H),3.14(d,J＝10.0Hz,1H),2.72(d,J＝10.8Hz,1H) ,2.45-2.67(m,2H),2.21-243(m,2H),1.87-2.00(m,1H),1.62-1.82(m,2H) . MS ESI calcd for C19H21F5N4O2S2 [M + H ] +497 , found497 .
实施例8
Example 8
步骤1:将化合物8-1(1.2g,14.1mmol)和四氢吡咯(1.0g,14.1mmol)混匀,0℃加入碳酸钾(1.9g,14.1mmol)，0℃下反应1小时后升温至25℃反应2小时。向反应液中加入二氯甲烷(30mL)和无水硫酸钠(10.0g)，过滤，滤液旋干得化合物8-2，粗品直接用于下一步。Step 1: Compound 8-1 (1.2 g, 14.1 mmol) and tetrahydropyrrole (1.0 g, 14.1 mmol) were mixed, potassium carbonate (1.9 g, 14.1 mmol) was added at 0°C, reacted at 0°C for 1 hour, then heated to 25°C for 2 hours. Dichloromethane (30 mL) and anhydrous sodium sulfate (10.0 g) were added to the reaction solution, filtered, and the filtrate was dried to obtain compound 8-2, which was used directly in the next step.
步骤2:将化合物8-2(1.9g,13.6mmol)溶于二氯甲烷(50mL),0℃分批加入中间体8-3(2.1g,13.7mmol)，升至室温搅拌2小时。加入水(50mL)淬灭反应并用二氯甲烷(50mL)萃取。有机相经无水硫酸钠干燥后过滤，滤液旋干所得粗品经柱层析纯化(石油醚：乙酸乙酯＝5：1)得化合物8-4。MS ESI计算值C6H4Cl2N2O[M+H]+191，实测值191。Step 2: Compound 8-2 (1.9 g, 13.6 mmol) was dissolved in dichloromethane (50 mL), and intermediate 8-3 (2.1 g, 13.7 mmol) was added in batches at 0°C, and the mixture was heated to room temperature and stirred for 2 hours. Water (50 mL) was added to quench the reaction and extracted with dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried and the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 8-4. MS ESI calculated value C 6 H 4 Cl 2 N 2 O [M + H] + 191, found value 191.
步骤3:将化合物8-4(350.0mg,1.8mmol)和中间体2-2(272.0mg,2.4mmol)混匀,加热至130℃保温0.5小时，反应完毕后用水(50mL)二氯甲烷(50mL)淬灭，用氢氧化钠溶液(1M,～8mL)调节到pH＝7,并用二氯甲烷(50mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1)得化合物8-5。MS ESI计算值C12H17ClN4O[M+H]+269，实测值269。Step 3: Compound 8-4 (350.0 mg, 1.8 mmol) and intermediate 2-2 (272.0 mg, 2.4 mmol) were mixed and heated to 130°C for 0.5 hours. After the reaction was completed, the mixture was quenched with water (50 mL) and dichloromethane (50 mL). The pH was adjusted to 7 with sodium hydroxide solution (1 M, ~8 mL), and the mixture was extracted with dichloromethane (50 mL*2). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 8-5. MS ESI calculated value C 12 H 17 ClN 4 O[M+H] + 269, found value 269.
步骤4:将化合物8-5(48.3mg,179.9μmol),中间体3(47.5mg,179.9μmol)溶于二氧六环(4mL)和水(2mL)中，加入碳酸钾(74.6mg,539.6μmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(29.4mg,35.9μmol)，反应于90℃搅拌2小时，反应完毕后用水(50mL)淬灭反应并用乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经薄层色谱法分离(二氯甲烷：甲醇＝10:1)得化合物8。Step 4: Compound 8-5 (48.3 mg, 179.9 μmol) and intermediate 3 (47.5 mg, 179.9 μmol) were dissolved in dioxane (4 mL) and water (2 mL), and potassium carbonate (74.6 mg, 539.6 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (29.4 mg, 35.9 μmol) were added. The reaction was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by thin layer chromatography (dichloromethane: methanol = 10:1) to obtain compound 8.
1H NMR(400MHz,CD3OD)δppm 7.68(brs,1H),7.54(brs,1H),7.49(s,1H),5.27(brs,4H),4.44-4.66(m,1H),3.84(brs,1H),3.57(d,J＝11.3Hz,1H),3.40(d,J＝11.0Hz,1H),2.83-3.20(m,5H),1.94-2.42(m,4H)。MS ESI计算值C18H21F5N4O2S[M+H]+453，实测值453。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.68 (brs, 1H), 7.54 (brs, 1H), 7.49 (s, 1H), 5.27 (brs, 4H), 4.44-4.66 (m, 1H), 3.84 (brs, 1H), 3.57 (d, J=11.3 Hz, 1H), 3.40 (d, J=11.0 Hz, 1H), 2.83-3.20 (m, 5H), 1.94-2.42 (m, 4H). MS ESI calculated value for C 18 H 21 F 5 N 4 O 2 S [M+H] + 453, found 453.
实施例9
Embodiment 9
步骤1:将化合物8-4(350.0mg,1.8mmol)和中间体4(343.5mg,2.4mmol)混匀,加热至130℃保温 0.5小时，反应完毕后用水(50mL)二氯甲烷(50mL)淬灭，用氢氧化钠溶液(1M,～8mL)调节到pH＝7,并用二氯甲烷(50mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1)得化合物9-1。MS ESI计算值C13H19ClN4O2[M+H]+299，实测值299。Step 1: Mix compound 8-4 (350.0 mg, 1.8 mmol) and intermediate 4 (343.5 mg, 2.4 mmol) and heat to 130 °C. 0.5 hours, after the reaction is completed, quench with water (50 mL) and dichloromethane (50 mL), adjust the pH to 7 with sodium hydroxide solution (1M, ~8 mL), and extract with dichloromethane (50 mL*2), dry the organic phase over sodium sulfate, filter and concentrate, and purify the crude product by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 9-1. MS ESI calculated value C 13 H 19 ClN 4 O 2 [M+H] + 299, found value 299.
步骤2:将化合物9-1(135.8mg,454.6μmol),中间体3(120.0mg,454.6μmol)溶于二氧六环(4mL)和水(2mL)中，加入碳酸钾(188.5mg,1.4μmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(74.3mg,90.9μmol)，反应于90℃搅拌2小时，反应完毕后用水(50mL)淬灭反应并用乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经薄层色谱法分离(二氯甲烷：甲醇＝10:1)得化合物9。1H NMR(400MHz,CD3OD)δppm 7.69(brs,1H),7.54(brs,1H),7.49(s,1H),5.27(brs,5H),4.56(s,1H),3.95(brs,4H),3.70(d,J＝9.3Hz,1H),3.37(brs,2H),2.94-3.17(m,2H),1.96-2.36(m,4H)。MS ESI计算值C19H23F5N4O3S[M+H]+483，实测值483。Step 2: Compound 9-1 (135.8 mg, 454.6 μmol) and intermediate 3 (120.0 mg, 454.6 μmol) were dissolved in dioxane (4 mL) and water (2 mL), potassium carbonate (188.5 mg, 1.4 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (74.3 mg, 90.9 μmol) were added, and the reaction was stirred at 90 ° C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by thin layer chromatography (dichloromethane: methanol = 10:1) to obtain compound 9. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.69 (brs, 1H), 7.54 (brs, 1H), 7.49 (s, 1H), 5.27 (brs, 5H), 4.56 (s, 1H), 3.95 (brs, 4H), 3.70 (d, J=9.3 Hz, 1H), 3.37 (brs, 2H), 2.94-3.17 (m, 2H), 1.96-2.36 (m, 4H). MS ESI calculated value for C 19 H 23 F 5 N 4 O 3 S [M+H] + 483, found 483.
实施例10
Example 10
步骤1:将化合物10-1(521.8mg,2.2mmol)和中间体2-1(300.0mg,1.8mmol)溶于二甲基亚砜(2mL)中，加入二异丙基乙胺,加热至130℃保温2小时，反应完毕后用水(50mL)淬灭，用二氯甲烷(50mL)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1)得化合物10-2。MS ESI计算值C15H21ClF2N4O2[M+H]+363，实测值363。Step 1: Compound 10-1 (521.8 mg, 2.2 mmol) and intermediate 2-1 (300.0 mg, 1.8 mmol) were dissolved in dimethyl sulfoxide (2 mL), diisopropylethylamine was added, and the mixture was heated to 130°C for 2 hours. After the reaction was completed, the mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL), and the organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 10-2. MS ESI calculated value C 15 H 21 ClF 2 N 4 O 2 [M+H] + 363, found value 363.
步骤2:将化合物10-2(130.0mg,358.3μmol)溶于甲醇(10mL)中，加入盐酸/乙酸乙酯(20mL，4M)，反应于25℃搅拌2小时。将反应液浓缩后得化合物10-3，直接用于下一步。MS ESI计算值C10H13ClF2N4[M+H]+263，实测值263。Step 2: Compound 10-2 (130.0 mg, 358.3 μmol) was dissolved in methanol (10 mL), and hydrochloric acid/ethyl acetate (20 mL, 4 M) was added, and the reaction was stirred at 25° C. for 2 hours. The reaction solution was concentrated to obtain compound 10-3, which was directly used in the next step. MS ESI calculated value C 10 H 13 ClF 2 N 4 [M+H] + 263, found value 263.
步骤3:将化合物10-3(0.5g,2.3mmol)和溴乙醇(94.2mg,753.8μmol)溶于乙腈(20mL)中，然后加入碳酸钠(217.8mg,2.0mmol),反应于60℃搅拌4小时，反应完毕后过滤旋干，得化合物10-4。MS ESI计算值C12H17ClF2N4O[M+H]+307，实测值307。Step 3: Compound 10-3 (0.5 g, 2.3 mmol) and bromoethanol (94.2 mg, 753.8 μmol) were dissolved in acetonitrile (20 mL), and then sodium carbonate (217.8 mg, 2.0 mmol) was added, and the mixture was stirred at 60° C. for 4 hours. After the reaction was completed, the mixture was filtered and dried to obtain compound 10-4. MS ESI calculated value C 12 H 17 ClF 2 N 4 O[M+H] + 307, found value 307.
步骤4:将化合物10-4(55.1mg,179.8μmol),中间体3(47.4mg,179.8μmol)溶于二氧六环(4mL)和水 (2mL)中，加入碳酸钾(74.5mg,539.5μmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(29.7mg,35.9μmol)，反应于90℃搅拌2小时，反应完毕后用水(50mL)淬灭反应并用乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经薄层色谱法分离(二氯甲烷：甲醇＝10:1)得化合物10。Step 4: Dissolve compound 10-4 (55.1 mg, 179.8 μmol) and intermediate 3 (47.4 mg, 179.8 μmol) in dioxane (4 mL) and water. To the mixture was added potassium carbonate (74.5 mg, 539.5 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29.7 mg, 35.9 μmol), and the reaction was stirred at 90°C for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by thin layer chromatography (dichloromethane: methanol = 10:1) to obtain compound 10.
1H NMR(400MHz,CD3OD)δppm 7.63(brs,2H),7.55(d,J＝6.3Hz,1H),7.49(d,J＝1.8Hz,1H),4.66(s,1H),3.97(brs,4H),3.63-3.84(m,1H),3.38-3.52(m,2H),2.81(d,J＝9.0Hz,1H),2.36(s,3H),2.05(s,2H)。MS ESI计算值C18H21F7N4O2S[M+H]+491，实测值491。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.63 (brs, 2H), 7.55 (d, J = 6.3 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 4.66 (s, 1H), 3.97 (brs, 4H), 3.63-3.84 (m, 1H), 3.38-3.52 (m, 2H), 2.81 (d, J = 9.0 Hz, 1H), 2.36 (s, 3H), 2.05 (s, 2H). MS ESI calculated value for C 18 H 21 F 7 N 4 O 2 S [M+H] + 491, found 491.
实施例11
Embodiment 11
步骤1:将中间体4(884.3mg,6.3mmol)，化合物中间体2-1(1.0g,6.1mmol)混合，反应于130℃搅拌10分钟，反应完毕后用水(30mL)和二氯甲烷(50mL*3)萃取，用氢氧化钠溶液(1M)调节到pH＝7，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5:1)得化合物11-1。MS ESI计算值C12H19ClN4O[M+H]+271，实测值271。Step 1: Intermediate 4 (884.3 mg, 6.3 mmol) and compound intermediate 2-1 (1.0 g, 6.1 mmol) were mixed and stirred at 130°C for 10 minutes. After the reaction was completed, the mixture was extracted with water (30 mL) and dichloromethane (50 mL*3), and the pH was adjusted to 7 with sodium hydroxide solution (1 M). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain compound 11-1. MS ESI calculated value C 12 H 19 ClN 4 O[M+H] + 271, found value 271.
步骤2:将化合物11-1(50.0mg,184.7μmol)和化合物1-4(66.5mg,184.7μmol)溶于二氧六环(2mL)和水(1mL)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(67.6mg,92.3μmol)和碳酸钾(51.0mg,369.3μmol)氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1)得化合物11-2。MS ESI计算值C19H25F5N4O2S[M+H]+469，实测值469。Step 2: Compound 11-1 (50.0 mg, 184.7 μmol) and compound 1-4 (66.5 mg, 184.7 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (67.6 mg, 92.3 μmol) and potassium carbonate (51.0 mg, 369.3 μmol) were added and stirred at 100 ° C for 0.5 hours under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3), the organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 11-2. MS ESI calculated value C 19 H 25 F 5 N 4 O 2 S [M + H] + 469, found value 469.
步骤3:将化合物11-2(70.0mg,149.4μmol)溶于二氯甲烷(10mL)中，0℃下加入三溴化硼(1M,1.5mL)，反应于0℃搅拌10分钟，反应完毕后用水(5mL)和甲醇(8mL)淬灭反应，浓缩后粗品经色谱柱分离(Xtimate C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:15％-33％,10min)得化合物11的盐酸盐。1H NMR(400MHz,CD3OD)δppm 7.51-7.66(m,3H)，7.47(d,J＝1.76Hz,1H)，4.40(d,J＝11.54Hz,1H)，3.96(d,J＝4.77Hz,3H)，3.70(d,J＝11.80Hz,1H)，3.37(brs,2H)，3.04-3.15(m,1H)，2.98(br t,J＝11.54Hz,1H)，2.35(s,3H)，2.29(d,J＝11.29Hz,1H)，2.12-2.21(m,1H)，2.05(d,J＝13.05Hz,1H)，1.66-1.81(m,1H)。MS ESI计算值C18H23F5N4O2S[M+H]+454，实测值455。Step 3: Compound 11-2 (70.0 mg, 149.4 μmol) was dissolved in dichloromethane (10 mL), and boron tribromide (1 M, 1.5 mL) was added at 0°C. The reaction was stirred at 0°C for 10 minutes. After the reaction was completed, the reaction was quenched with water (5 mL) and methanol (8 mL). After concentration, the crude product was separated by chromatographic column (Xtimate C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-33%, 10 min) to obtain the hydrochloride of compound 11. 1 H NMR (400MHz, CD 3 OD) δppm 7.51-7.66 (m, 3H), 7.47 (d, J = 1.76Hz, 1H), 4.40 (d, J = 11.54Hz, 1H), 3.96 (d, J = 4.77Hz, 3H), 3.70 (d, J = 11.80Hz, 1H), 3.37 (br s,2H), 3.04-3.15(m,1H), 2.98(br t,J＝11.54Hz,1H), 2.35(s,3H), 2.29(d,J＝11.29Hz,1H), 2.12-2.21(m,1H), 2.05(d,J＝13.05Hz,1H), 1.66-1.81(m,1 H). MS ESI calcd for C18H23F5N4O2S [M + H ] +454 , found455 .
实施例12
Example 12
步骤1:将化合物中间体2-1(1.0g,6.1mmol)，化合物12-1(706.0mg,6.1mmol)混合，反应于130℃搅拌10分钟，反应完毕后用水(30mL)二氯甲烷(50mL*3)萃取，用氢氧化钠溶液(1M)调节到pH＝7,有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5:1)得化合物12-2。MS ESI计算值C11H16ClN3O[M+H]+242，实测值242。Step 1: Compound intermediate 2-1 (1.0 g, 6.1 mmol) and compound 12-1 (706.0 mg, 6.1 mmol) were mixed and stirred at 130°C for 10 minutes. After the reaction was completed, the mixture was extracted with water (30 mL) and dichloromethane (50 mL*3), and the pH was adjusted to 7 with sodium hydroxide solution (1 M). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain compound 12-2. MS ESI calculated value C 11 H 16 ClN 3 O[M+H] + 242, found value 242.
步骤2:将化合物12-2(30.0mg,124.1μmol)，化合物1-4(44.0mg,124.1μmol)溶于二氧六环(2mL)和水(1mL)，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(18.1mg,24.8μmol)和碳酸钾(34.1mg,248.2μmol)氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1)得化合物12-3。MS ESI计算值C18H22F5N3O2S[M+H]+440，实测值440。Step 2: Compound 12-2 (30.0 mg, 124.1 μmol) and compound 1-4 (44.0 mg, 124.1 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18.1 mg, 24.8 μmol) and potassium carbonate (34.1 mg, 248.2 μmol) were added and stirred at 100 °C for 0.5 hours under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3), the organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 12-3. MS ESI calculated value C 18 H 22 F 5 N 3 O 2 S [M + H] + 440, found value 440.
步骤3:将化合物12-3(20.0mg,45.5μmol)溶于二氯甲烷(10mL)中，在0℃加入三溴化硼(1M,455.1μL)反应于0℃搅拌0.5小时，反应完毕后用水(5mL)和甲醇(8mL)淬灭。浓缩后粗品经色谱柱分离(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:10％-40％,10min)得化合物12。Step 3: Compound 12-3 (20.0 mg, 45.5 μmol) was dissolved in dichloromethane (10 mL), and boron tribromide (1 M, 455.1 μL) was added at 0°C and stirred at 0°C for 0.5 hours. After the reaction was completed, the mixture was quenched with water (5 mL) and methanol (8 mL). After concentration, the crude product was separated by chromatographic column (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain compound 12.
1H NMR(400MHz,CD3OD)δppm 7.46(s,2H)，7.40(s,1H)，7.35(s,1H)，3.60-3.69(m,1H)，4.14Hz,1H)，3.52(td,J＝9.85,1H),2.29(s,3H),2.09(d,J＝7.78Hz,2H),1.83(d,J＝7.28Hz,2H),1.40-1.53(m,4H)。MS ESI计算值C17H20F5N3O2S[M+H]+426，实测值426。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.46 (s, 2H), 7.40 (s, 1H), 7.35 (s, 1H), 3.60-3.69 (m, 1H), 4.14 Hz, 1H), 3.52 (td, J=9.85, 1H), 2.29 (s, 3H), 2.09 (d, J=7.78 Hz, 2H), 1.83 (d, J=7.28 Hz, 2H), 1.40-1.53 (m, 4H). MS ESI calculated value for C 17 H 20 F 5 N 3 O 2 S [M+H] + 426, found 426.
实施例13
Example 13
步骤1:将化合物13-1(0.2g,1.1mmol)，中间体4(152.7mg,1.1mmol)混合，反应于130℃搅拌10分钟，反应完毕后用水(30mL)二氯甲烷(50mL*3)萃取，用氢氧化钠溶液(1M)调节到pH＝7,有机相经硫酸钠干燥，过滤浓缩后，经色谱柱分离(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:1％-30％,10min)得化合物13-2。MS ESI计算值C14H21ClN4O[M+H]+297，实测值297。Step 1: Compound 13-1 (0.2 g, 1.1 mmol) and intermediate 4 (152.7 mg, 1.1 mmol) were mixed and stirred at 130°C for 10 minutes. After the reaction was completed, the mixture was extracted with water (30 mL) and dichloromethane (50 mL*3), and the pH was adjusted to 7 with sodium hydroxide solution (1 M). The organic phase was dried over sodium sulfate, filtered and concentrated, and separated by a chromatographic column (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 1%-30%, 10 min) to obtain compound 13-2. MS ESI calculated value C 14 H 21 ClN 4 O[M+H] + 297, found value 297.
步骤2:将化合物13-2(33.7mg,113.6μmol)，中间体3(30.0mg,113.6μmol)溶于二氧六环(2mL)和水(1mL)加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(41.5mg,56.8μmol)和碳酸钾(34.4mg,227.3μmol,) 氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经色谱柱分离(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:10％-40％,10min)得化合物13的盐酸盐。Step 2: Compound 13-2 (33.7 mg, 113.6 μmol) and intermediate 3 (30.0 mg, 113.6 μmol) were dissolved in dioxane (2 mL) and water (1 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (41.5 mg, 56.8 μmol) and potassium carbonate (34.4 mg, 227.3 μmol,) were added. The mixture was stirred at 100°C for 0.5 hours under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was separated by a chromatographic column (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain the hydrochloride of compound 13.
1H NMR(400MHz,CD3OD)δppm 7.67(d,J＝8.78Hz,1H)，7.53(d,J＝8.28Hz,1H)，7.50(d,J＝1.76Hz,1H)，4.57(d,J＝10.79Hz,1H)，3.88-4.03(m,3H)，3.70(d,J＝11.80Hz,1H)，3.35-3.43(m,2H)，3.27(brs,1H)，3.07-3.17(m,5H)，2.97-3.06(m,1H)，2.31-2.39(m,2H)，2.27(d,J＝12.05Hz,1H)，2.13-2.20(m,1H)，2.07(d,J＝13.05Hz,1H)，1.78-1.90(m,1H)。MS ESI计算值C20H25F5N4O2S[M+H]+481，实测值481。 1 H NMR (400MHz, CD 3 OD) δppm 7.67 (d, J = 8.78Hz, 1H), 7.53 (d, J = 8.28Hz, 1H), 7.50 (d, J = 1.76Hz, 1H), 4.57 (d ,J＝10.79Hz,1H), 3.88-4.03(m,3H), 3.70(d,J＝11.80Hz,1H), 3.35-3.43(m,2H), 3.27 (brs, 1H), 3.07-3.17 (m, 5H), 2.97-3.06 (m, 1H), 2.31-2.39 (m, 2H), 2.27 (d, J＝12.05 Hz, 1H), 2.13-2.20 ( m, 1H), 2.07 (d, J = 13.05 Hz, 1H), 1.78-1.90 (m, 1H). MS ESI calculated for C 20 H 25 F 5 N 4 O 2 S [M+H] + 481, found Value: 481.
实施例14
Embodiment 14
步骤1:将化合物中间体2-1(0.23g,1.84mmol)，化合物14-1(162.24mg,1.84mmol)混合均匀，反应于130℃搅拌10分钟，反应完毕后用水(30mL)和二氯甲烷(50mL*3)淬灭，用氢氧化钠溶液(1M，～2ml)调节到pH＝7,有机相硫酸钠干燥浓缩后，经色谱柱分离(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:1％-30％,10min)得化合物14-2。MS ESI计算值C9H15ClN4[M+H]+215，实测值215。Step 1: Compound intermediate 2-1 (0.23 g, 1.84 mmol) and compound 14-1 (162.24 mg, 1.84 mmol) were mixed evenly, stirred at 130°C for 10 minutes, quenched with water (30 mL) and dichloromethane (50 mL*3) after the reaction was completed, adjusted to pH=7 with sodium hydroxide solution (1M, ~2 ml), dried and concentrated over sodium sulfate, and separated by chromatographic column (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 1%-30%, 10min) to obtain compound 14-2. MS ESI calculated value C 9 H 15 ClN 4 [M+H] + 215, found value 215.
步骤2:将化合物14-2(40.7mg,189.4μmol)，中间体3(50.0mg,189.4μmol)溶于二氧六环(2mL)和水(1mL)加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(69.3mg,94.7μmol)和碳酸钾(52.3mg,378.8μmol)氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相浓缩后，粗品经色谱柱分离(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:5％-35％,10min)得化合物14的盐酸盐。Step 2: Compound 14-2 (40.7 mg, 189.4 μmol) and intermediate 3 (50.0 mg, 189.4 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (69.3 mg, 94.7 μmol) and potassium carbonate (52.3 mg, 378.8 μmol) were added. The mixture was stirred at 100 °C for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). After the organic phase was concentrated, the crude product was separated by chromatographic column (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 5%-35%, 10 min) to obtain the hydrochloride of compound 14.
1H NMR(400MHz,CD3OD)δppm 7.58-7.63(m,2H),7.51-7.56(m,1H),7.47(d,J＝2.01Hz,1H),3.93(t,J＝6.02Hz,2H),3.53(t,J＝6.02Hz,2H),3.02(s,6H),2.36(s,3H)。MS ESI计算值C15H19F5N4OS[M+H]+399，实测值399。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.58-7.63 (m, 2H), 7.51-7.56 (m, 1H), 7.47 (d, J = 2.01 Hz, 1H), 3.93 (t, J = 6.02 Hz, 2H), 3.53 (t, J = 6.02 Hz, 2H), 3.02 (s, 6H), 2.36 (s, 3H). MS ESI calculated value for C 15 H 19 F5N 4 OS [M+H] + 399, found 399.
实施例15
Embodiment 15
步骤1:将化合物中间体2-1(0.3g,1.84mmol)和化合物15-1(138.23mg,1.84mmol)混合均匀并于130℃保温10分钟，反应完毕后用水(30mL)二氯甲烷(50mL*3)萃取，用氢氧化钠溶液(1M，2mL)调节到pH＝7,有机相经硫酸钠干燥，过滤浓缩后，粗品经柱色谱分离(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:1％-30％,10min)得化合物15-2。MS ESI计算值C8H12ClN3O[M+H]+202，实测值202。Step 1: Compound intermediate 2-1 (0.3 g, 1.84 mmol) and compound 15-1 (138.23 mg, 1.84 mmol) were mixed evenly and kept at 130°C for 10 minutes. After the reaction was completed, the mixture was extracted with water (30 mL) and dichloromethane (50 mL*3), and the pH was adjusted to 7 with sodium hydroxide solution (1 M, 2 mL). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by column chromatography (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 1%-30%, 10min) to obtain compound 15-2. MS ESI calculated value C 8 H 12 ClN 3 O[M+H] + 202, found value 202.
步骤2:将化合物15-2(38.2mg,189.4μmol)，中间体3(50.0mg,189.4μmol)溶于二氧六环(2mL)和水(1mL)加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(69.3mg,94.7μmol)和碳酸钾(52.4mg,378.8μmol)氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱色谱分离(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:5％-35％,10min)得化合物15的盐酸盐。Step 2: Compound 15-2 (38.2 mg, 189.4 μmol) and intermediate 3 (50.0 mg, 189.4 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (69.3 mg, 94.7 μmol) and potassium carbonate (52.4 mg, 378.8 μmol) were added. The mixture was stirred at 100 °C for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by column chromatography (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 5%-35%, 10 min) to obtain the hydrochloride of compound 15.
1H NMR(400MHz,CD3OD)δppm 7.45-7.49(m,3H)，7.41(s,1H),4.08(dd J＝6.27,1H),3.49-3.56(m,1H),3.40(d,J＝13.93,1H),2.31(s,3H),1.31(d,J＝6.27Hz,3H)。MS ESI计算值C14H16F5N3O2S[M+H]+386，实测值386。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.45-7.49 (m, 3H), 7.41 (s, 1H), 4.08 (dd J=6.27, 1H), 3.49-3.56 (m, 1H), 3.40 (d, J=13.93, 1H), 2.31 (s, 3H), 1.31 (d, J=6.27 Hz, 3H). MS ESI calculated value for C 14 H 16 F 5 N 3 O 2 S [M+H] + 386, found 386.
实施例16
Example 16
步骤1:将化合物中间体4-1(1.0g,4.3mmol)和化合物16-1(1.2g,8.5mmol)溶于乙腈(20mL)中，然后加入碳酸钠(678.6mg,6.4mmol)，反应于60℃搅拌4小时，反应完毕后过滤旋干，粗品经柱层析纯化 (二氯甲烷：甲醇＝10:1到5:1)得化合物16-2。MS ESI计算值C16H24N2O3[M+H]+293，实测值293。Step 1: Dissolve the intermediate compound 4-1 (1.0 g, 4.3 mmol) and compound 16-1 (1.2 g, 8.5 mmol) in acetonitrile (20 mL), then add sodium carbonate (678.6 mg, 6.4 mmol), stir at 60 ° C for 4 hours, filter and dry after the reaction, and purify the crude product by column chromatography (dichloromethane:methanol=10:1 to 5:1) to obtain compound 16-2. MS ESI calculated value for C 16 H 24 N 2 O 3 [M+H] + 293, found value 293.
步骤2:将化合物16-2(1.0g,3.4mmol)溶于甲醇(30mL)中，加入10％干钯碳(～1.0g),反应于氢气(15Psi)保护下25℃搅拌1小时，反应完毕后反应完毕后过滤，滤液旋干得化合物16-3。MS ESI计算值C8H18N2O[M+H]+159，实测值159。Step 2: Compound 16-2 (1.0 g, 3.4 mmol) was dissolved in methanol (30 mL), 10% dry palladium carbon (~1.0 g) was added, and the mixture was stirred at 25°C for 1 hour under the protection of hydrogen (15 Psi). After the reaction was completed, the mixture was filtered and the filtrate was dried to obtain compound 16-3. MS ESI calculated value C 8 H 18 N 2 O [M+H] + 159, found value 159.
步骤3:将化合物16-3(582.4mg,3.6mmol)与中间体2-1(0.6g,3.7mmol)混合均匀，反应于130℃保温10分钟，反应完毕后用水(30mL)和二氯甲烷(50mL*3)淬灭，用氢氧化钠溶液(1M,2mL)调节pH＝7,有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5:1)得化合物16-4。MS ESI计算值C13H21ClN4O[M+H]+285，实测值285。Step 3: Compound 16-3 (582.4 mg, 3.6 mmol) and intermediate 2-1 (0.6 g, 3.7 mmol) were mixed evenly, and the reaction was kept at 130°C for 10 minutes. After the reaction was completed, the mixture was quenched with water (30 mL) and dichloromethane (50 mL*3), and the pH was adjusted to 7 with sodium hydroxide solution (1 M, 2 mL). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain compound 16-4. MS ESI calculated value C 13 H 21 ClN 4 O[M+H] + 285, found value 285.
步骤4:将化合物16-4(30.7mg,107.9μmol)和中间体3(28.4mg,107.9μmol)溶于二氧六环(2mL)和水(1mL)，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(39.4mg,53.9μmol)和碳酸钾(29.8mg,215.8μmol)氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品柱色谱纯化(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:5％-35％,10min)得化合物16的盐酸盐。Step 4: Compound 16-4 (30.7 mg, 107.9 μmol) and intermediate 3 (28.4 mg, 107.9 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (39.4 mg, 53.9 μmol) and potassium carbonate (29.8 mg, 215.8 μmol) were added. The mixture was stirred at 100 °C for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 5%-35%, 10 min) to obtain the hydrochloride of compound 16.
1H NMR(400MHz,CD3OD)δppm 7.50-7.63(m,3H)，7.48(d,J＝1.51Hz,1H)，4.38(brs,1H)，3.91(brs,1H)，3.81(brs,2H)，3.67(d,J＝11.54Hz,1H)，3.44(s,5H)，3.08(br t,J＝11.17Hz,1H)，2.97(brs,1H)，2.68(brs,1H)，2.35(s,3H)，2.28(d,J＝7.03Hz,1H)，2.11-2.20(m,1H)，2.05(d,J＝13.30Hz,1H)，1.73(d,J＝11.29Hz,1H)。MS ESI计算值C19H25F5N4O2S[M+H]+469，实测值469。 1 H NMR (400MHz, CD 3 OD) δppm 7.50-7.63 (m, 3H), 7.48 (d, J = 1.51Hz, 1H), 4.38 (brs, 1H), 3.91 (brs, 1H), 3.81 (brs, 2H), 3.67(d,J＝11.54Hz,1H), 3.44(s,5H), 3.08(br t, J = 11.17 Hz, 1H), 2.97 (brs, 1H), 2.68 (brs, 1H), 2.35 (s, 3H), 2.28 (d, J = 7.03 Hz, 1H), 2.11-2.20 (m, 1H ), 2.05 (d, J = 13.30 Hz, 1H), 1.73 (d, J = 11.29 Hz, 1H). MS ESI calculated value for C 19 H 25 F 5 N 4 O 2 S [M+H] + 469, found Value: 469.
实施例17
Embodiment 17
步骤1:将中间体1-2(0.2g,1.4mmol)，化合物17-1(275.8mg,1.4mmol)溶于叔戊醇(5mL)和水(1mL)中，然后加入氢氧化钾(168.1mg,3.0mmol)和5-(二叔丁基磷)-1,3,5-三苯基-1氢-[1,4]二吡唑(141.2mg,278.6μmol)，三(二亚苄基丙酮)二钯(127.6mg,139.3μmol)，反应于90℃搅拌1小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝20:1)得化合物17-2。MS ESI计算值C11H9ClN6[M+H]+261，实测值261。Step 1: Dissolve intermediate 1-2 (0.2 g, 1.4 mmol) and compound 17-1 (275.8 mg, 1.4 mmol) in tert-amyl alcohol (5 mL) and water (1 mL), then add potassium hydroxide (168.1 mg, 3.0 mmol) and 5-(di-tert-butylphosphino)-1,3,5-triphenyl-1 hydrogen-[1,4]dipyrazole (141.2 mg, 278.6 μmol), tris(dibenzylideneacetone)dipalladium (127.6 mg, 139.3 μmol), react at 90 ° C and stir for 1 hour. After the reaction is completed, extract with water (50 mL) and ethyl acetate (50 mL*3), dry the organic phase over sodium sulfate, filter and concentrate, and purify the crude product by column chromatography (dichloromethane: methanol = 20:1) to obtain compound 17-2. MS ESI calcd for C11H9ClN6 [ M + H] +261 , found261.
步骤2:将化合物17-2(19.7mg,75.7μmol)，中间体3(20.0mg,75.7μmol)溶于二氧六环(2mL)和水(1mL)，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(27.7mg,37.8μmol)和碳酸钾(20.9mg,151.5μmol)， 反应于氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经色谱柱分离纯化(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:15％-45％,10min)得化合物17的盐酸盐。1H NMR(400MHz,CD3OD)δppm 9.82(s,1H)，9.61(s,1H)，8.20-8.26(m,1H)，8.12-8.18(m,1H)，7.86(s,1H)，7.69(d,J＝8.03Hz,1H)，7.58(d,J＝7.28Hz,1H)，7.53(s,1H)，2.44(s,3H)。MS ESI计算值C17H13F5N6OS[M+H]+445，实测值445。Step 2: Compound 17-2 (19.7 mg, 75.7 μmol) and intermediate 3 (20.0 mg, 75.7 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.7 mg, 37.8 μmol) and potassium carbonate (20.9 mg, 151.5 μmol) were added. The reaction was stirred at 100° C. for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was separated and purified by chromatographic column (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-45%, 10 min) to obtain the hydrochloride of compound 17. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.82 (s, 1H), 9.61 (s, 1H), 8.20-8.26 (m, 1H), 8.12-8.18 (m, 1H), 7.86 (s, 1H), 7.69 (d, J=8.03 Hz, 1H), 7.58 (d, J=7.28 Hz, 1H), 7.53 (s, 1H), 2.44 (s, 3H). MS ESI calculated value for C 17 H 13 F 5 N 6 OS [M+H] + 445, found 445.
实施例18
Embodiment 18
步骤1:将化合物18-1(0.2g,1.3mmol)和中间体2-2(153.0mg,1.3mmol)混合均匀，，反应于130℃保10分钟，反应完毕后用水(30mL)和二氯甲烷(50mL*3)淬灭，用氢氧化钠溶液(1M,5mL)调节pH＝7,有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝5:1)得化合物18-2。MS ESI计算值C10H15ClN4[M+H]+227，实测值227。Step 1: Compound 18-1 (0.2 g, 1.3 mmol) and intermediate 2-2 (153.0 mg, 1.3 mmol) were mixed evenly, and the reaction was maintained at 130°C for 10 minutes. After the reaction was completed, the mixture was quenched with water (30 mL) and dichloromethane (50 mL*3), and the pH was adjusted to 7 with sodium hydroxide solution (1 M, 5 mL). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain compound 18-2. MS ESI calculated value C 10 H 15 ClN 4 [M+H]+227, found value 227.
步骤2:将化合物18-2(34.3mg,151.5μmol)，中间体3(40.0mg,151.5μmol)溶于二氧六环(2mL)和水(1mL),加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(55.44mg,75.76μmol)和碳酸钾(41.8mg,303.0μmol)，反应于氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱色谱分离纯化(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:15％-45％,10min)得化合物18的盐酸盐。1H NMR(400MHz,CD3OD)δppm8.40(d,J＝9.54Hz,1H)，7.83-7.93(m,1H)，7.73(d,J＝9.03Hz,1H)，7.50(s,2H)，4.34-4.49(m,1H)，3.84(d,J＝9.03Hz,1H)，3.58(d,J＝11.04Hz,1H)，3.01-3.23(m,2H)，2.98(s,2H)，2.90-2.95(m,1H)，2.93(s,1H)，2.30(d,J＝12.55Hz,1H)，2.05-2.20(m,2H)，1.66-1.81(m,1H)。MS ESI计算值C16H19F5N4OS[M+H]+411，实测值411。Step 2: Compound 18-2 (34.3 mg, 151.5 μmol) and intermediate 3 (40.0 mg, 151.5 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (55.44 mg, 75.76 μmol) and potassium carbonate (41.8 mg, 303.0 μmol) were added. The reaction was stirred at 100 ° C for 0.5 hour under nitrogen protection. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3), and the organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was separated and purified by column chromatography (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-45%, 10min) to obtain the hydrochloride of compound 18. 1 H NMR(400MHz,CD 3 OD)δppm8.40(d,J＝9.54Hz,1H)，7.83-7.93(m,1H)，7.73(d,J＝9.03Hz,1H)，7.50(s,2H)，4.34-4.49(m,1H)，3.84(d,J＝9.03Hz,1H)，3.58(d,J＝11.04Hz,1H)，3.01-3.23(m,2H)，2.98(s,2H)，2.90-2.95(m,1H)，2.93(s,1H)，2.30(d,J＝12.55Hz,1H)，2.05-2.20(m,2H)，1.66-1.81(m,1H)。 MS ESI calcd for C16H19F5N4OS [M+ H ] +411 , found411 .
实施例19
Embodiment 19
步骤1:将化合物19-1(1.0g,5.4mmol)溶于甲醇(10mL)中，然后加入碘甲烷(1.5g,10.8mmol)，碳酸钠(1.2g,10.8mmol)，反应于25℃搅拌2小时，反应完毕后用水(150mL)和乙酸乙酯(150mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(石油醚：乙酸乙酯＝10:1)得化合物19-2。MS ESI计算值C8H10N2O4[M+H]+199，实测值199。Step 1: Compound 19-1 (1.0 g, 5.4 mmol) was dissolved in methanol (10 mL), and then iodomethane (1.5 g, 10.8 mmol) and sodium carbonate (1.2 g, 10.8 mmol) were added, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, the mixture was extracted with water (150 mL) and ethyl acetate (150 mL*3), and the organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 19-2. MS ESI calculated value C 8 H 10 N 2 O 4 [M+H] + 199, found value 199.
步骤2:将化合物19-2(1.0g,5.2mmol)溶于甲醇(10mL)中，加入水合肼(1.0g,20.7mmol)，反应于100℃搅拌12小时，反应完毕后反应完毕后过滤，收集滤饼，干燥后得化合物19-3。MS ESI计算值C6H6N4O2[M+H]+167，实测值167。Step 2: Compound 19-2 (1.0 g, 5.2 mmol) was dissolved in methanol (10 mL), hydrazine hydrate (1.0 g, 20.7 mmol) was added, the mixture was stirred at 100°C for 12 hours, and the mixture was filtered after completion of the reaction, the filter cake was collected, and compound 19-3 was obtained after drying. MS ESI calculated value C 6 H 6 N 4 O 2 [M+H] + 167, found value 167.
步骤3:将化合物19-3(0.2g,1.2mmol)与三氯氧磷(9.9g,64.5mmol)混合，反应于100℃搅拌12小时，反应完毕后用碳酸氢钠水溶液(150mL)乙酸乙酯(100mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，得化合物19-4。MS ESI计算值C6H4Cl2N4[M+H]+203，实测值203。Step 3: Compound 19-3 (0.2 g, 1.2 mmol) was mixed with phosphorus oxychloride (9.9 g, 64.5 mmol), and the mixture was stirred at 100°C for 12 hours. After the reaction was completed, the mixture was extracted with sodium bicarbonate aqueous solution (150 mL) and ethyl acetate (100 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated to obtain compound 19-4. MS ESI calculated value: C 6 H 4 C l2 N 4 [M+H] + 203, found value: 203.
步骤4:将化合物19-4(70.0mg,344.7μmol)，中间体2-2(39.3mg,344.7μmol)混合均匀，反应于130℃保温10分钟，反应完毕后用水(30mL)和二氯甲烷(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱色谱分离(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:1％-30％,10min)得化合物19-5。MS ESI计算值C12H17ClN6[M+H]+281，实测值281。Step 4: Compound 19-4 (70.0 mg, 344.7 μmol) and intermediate 2-2 (39.3 mg, 344.7 μmol) were mixed evenly, and the mixture was kept at 130°C for 10 minutes. After the reaction was completed, the mixture was extracted with water (30 mL) and dichloromethane (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated by column chromatography (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 1%-30%, 10 min) to obtain compound 19-5. MS ESI calculated value C 12 H 17 ClN 6 [M+H] + 281, found value 281.
步骤5:将化合物19-5(18.1mg,64.4μmol)中间体3(17.0mg,64.4μmol)溶于二氧六环(2mL)和水(1mL),加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(23.56mg,32.20μmol)和碳酸钾(17.8mg,128.8μmol)，反应于氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经色谱柱(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:5％-35％,10min)得化合物19的盐酸盐。Step 5: Compound 19-5 (18.1 mg, 64.4 μmol) and intermediate 3 (17.0 mg, 64.4 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (23.56 mg, 32.20 μmol) and potassium carbonate (17.8 mg, 128.8 μmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 0.5 hours. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by chromatography (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 5%-35%, 10 min) to obtain the hydrochloride of compound 19.
1H NMR(400MHz,CD3OD)δppm 8.58(s,1H)，7.72(d,J＝8.53Hz,1H)，7.60(d,J＝8.53Hz,1H)，7.52(s,1H)，3.90(d,J＝11.54Hz,1H)，3.75(s,3H)，3.55-3.66(m,1H)，3.06(br t,J＝11.92Hz,2H)，2.99(s,3H)，2.33(brs,1H)，2.18(brs,1H)，2.06(s,1H)，1.94-2.02(m,2H)，1.82(d,J＝11.29Hz,1H)。MS ESI 计算值C18H21F5N6OS[M+H]+465，实测值465。 1 H NMR (400MHz, CD 3 OD) δppm 8.58 (s, 1H), 7.72 (d, J = 8.53Hz, 1H), 7.60 (d, J = 8.53Hz, 1H), 7.52 (s, 1H), 3.90 (d,J＝11.54Hz,1H), 3.75(s,3H), 3.55-3.66(m,1H), 3.06(br t,J＝11.92Hz,2H), 2.99(s,3H), 2.33(brs ,1H), 2.18(brs,1H), 2.06(s,1H), 1.94-2.02(m,2H), 1.82(d,J=11.29Hz,1H). MS ESI Calculated for C18H21F5N6OS [M + H ] +465 , found465 .
实施例20
Embodiment 20
步骤1:将化合物20-1(0.5g,2.3mmol)和溴乙醇(314.8mg,2.5mmol)溶于乙腈(10mL)中，然后加入碳酸钠(364.2mg,3.4mmol)，反应于60℃搅拌4小时，反应完毕后过滤，滤液浓缩得化合物20-2。MS ESI计算值C12H23FN2O3[M+H]+263，实测值263。Step 1: Compound 20-1 (0.5 g, 2.3 mmol) and bromoethanol (314.8 mg, 2.5 mmol) were dissolved in acetonitrile (10 mL), and then sodium carbonate (364.2 mg, 3.4 mmol) was added, and the mixture was stirred at 60°C for 4 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain compound 20-2. MS ESI calculated value: C 12 H 23 FN 2 O 3 [M+H] + 263, found value: 263.
步骤2:将化合物20-2(0.6g,2.2mmol)溶于乙酸乙酯(10mL)中，加入盐酸乙酸乙酯(4M,0.6mL),反应于25℃搅拌1小时，反应完毕后过滤，收集滤饼，干燥后得化合物20-3的盐酸盐。MS ESI计算值C5H11FN2[M+H]+119，实测值119。Step 2: Compound 20-2 (0.6 g, 2.2 mmol) was dissolved in ethyl acetate (10 mL), and ethyl acetate hydrochloride (4 M, 0.6 mL) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction was completed, the mixture was filtered, and the filter cake was collected and dried to obtain the hydrochloride salt of compound 20-3. MS ESI calculated value C 5 H 11 FN 2 [M+H] + 119, found value 119.
步骤3:将化合物20-3的盐酸盐(454.0mg,2.3mmol)，碳酸钾(410.9mg,2.9mmol)溶于四氢呋喃(12mL)和水(10mL)中，在0℃滴加氯甲酸苄酯(409.7mg,2.4mmol)，反应于25℃搅拌1小时，反应完毕后用水(150mL)和乙酸乙酯(100mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，得化合物20-4。MS ESI计算值C13H17FN2O2[M+H]+253，实测值253。Step 3: The hydrochloride of compound 20-3 (454.0 mg, 2.3 mmol) and potassium carbonate (410.9 mg, 2.9 mmol) were dissolved in tetrahydrofuran (12 mL) and water (10 mL), and benzyl chloroformate (409.7 mg, 2.4 mmol) was added dropwise at 0°C, and the reaction was stirred at 25°C for 1 hour. After the reaction was completed, the mixture was extracted with water (150 mL) and ethyl acetate (100 mL*3), and the organic phase was dried over sodium sulfate, filtered and concentrated to obtain compound 20-4. MS ESI calculated value C 13 H 17 FN 2 O 2 [M+H] + 253, found value 253.
步骤4:将化合物20-4(0.6g,2.0mmol)溶于甲醇(10mL)中，加入10％干钯碳(0.1g),反应于氢气(15Psi)保护下25℃搅拌1小时，反应完毕后过滤，滤液浓缩至干得化合物20-3。MS ESI计算值C5H11FN2[M+H]+119，实测值119。Step 4: Compound 20-4 (0.6 g, 2.0 mmol) was dissolved in methanol (10 mL), 10% dry palladium on carbon (0.1 g) was added, and the mixture was stirred at 25°C for 1 hour under the protection of hydrogen (15 Psi). After the reaction was completed, the mixture was filtered and the filtrate was concentrated to dryness to obtain compound 20-3. MS ESI calculated value C 5 H 11 FN 2 [M+H] + 119, found value 119.
步骤5:将化合物20-3(0.1g,739.8μmol)，中间体2-1(120.6mg,739.8μmol)混合均匀，反应于130℃搅拌10分钟，反应完毕后用水(30mL)二氯甲烷(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝50:1)得化合物20-5。MS ESI计算值C12H18ClFN4O[M+H]+289，实测值289。Step 5: Compound 20-3 (0.1 g, 739.8 μmol) and intermediate 2-1 (120.6 mg, 739.8 μmol) were mixed evenly, reacted at 130°C with stirring for 10 minutes, extracted with water (30 mL) and dichloromethane (50 mL*3) after the reaction was completed, the organic phase was dried over sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (dichloromethane: methanol = 50:1) to obtain compound 20-5. MS ESI calculated value C 12 H 18 ClFN 4 O [M + H] + 289, found value 289.
步骤5:将化合物20-5(20.0mg,69.2μmol)，中间体3(18.2mg,69.2μmol)溶于二氧六环(2mL)和水(1 mL),加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(25.3mg,34.6μmol)和碳酸钾(19.1mg,138.5μmol)，反应于氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱色谱(色谱柱:Xtimate C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:5％-45％,10min)得化合物20的盐酸盐。Step 5: Compound 20-5 (20.0 mg, 69.2 μmol) and intermediate 3 (18.2 mg, 69.2 μmol) were dissolved in dioxane (2 mL) and water (1 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.3 mg, 34.6 μmol) and potassium carbonate (19.1 mg, 138.5 μmol), react at 100 ° C under nitrogen protection and stir for 0.5 hour, after the reaction is completed, extract with water (50 mL) and ethyl acetate (50 mL*3), the organic phase is dried over sodium sulfate, filtered and concentrated, and the crude product is subjected to column chromatography (chromatographic column: Xtimate C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 5%-45%, 10min) to obtain the hydrochloride of compound 20.
1H NMR(400MHz,CD3OD)δppm 7.59-7.64(m,2H)，7.53-7.57(m,1H)，7.49(d,J＝2.01Hz,1H)，5.25-5.44(m,1H)，4.72(br t,J＝11.92Hz,1H)，3.93-4.07(m,4H)，3.38-3.50(m,1H)3.44(brs,2H)，3.18(brs,1H)，2.63(brs,1H)，2.36(s,3H)，1.97-2.19(m,1H)。MS ESI计算值C18H22F6N4O2S[M+H]+473，实测值473。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.59-7.64 (m, 2H), 7.53-7.57 (m, 1H), 7.49 (d, J=2.01 Hz, 1H), 5.25-5.44 (m, 1H), 4.72 (br t, J=11.92 Hz, 1H), 3.93-4.07 (m, 4H), 3.38-3.50 (m, 1H) 3.44 (brs, 2H), 3.18 (brs, 1H), 2.63 (brs, 1H), 2.36 (s, 3H), 1.97-2.19 (m, 1H). MS ESI calculated value for C 18 H 22 F 6 N 4 O 2 S [M+H]+473, found value 473.
实施例21
Embodiment 21
步骤1:将化合物21-1(277.2mg,1.4mmol)，中间体1-2(0.2g,1.4mmol)溶于叔戊醇(5mL)和水(1mL)中，然后加入氢氧化钾(168.1mg,3.0mmol)和5-(二叔丁基磷)-1,3,5-三苯基-1氢-[1,4]二吡唑(141.2mg,278.6μmol)，三(二亚苄基丙酮)二钯(127.5mg,139.3μmol)，反应于90℃搅拌1小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:15％-45％,10min)得化合物21-2。MS ESI计算值C13H12ClN3O[M+H]+262，实测值262。Step 1: Compound 21-1 (277.2 mg, 1.4 mmol) and intermediate 1-2 (0.2 g, 1.4 mmol) were dissolved in tert-amyl alcohol (5 mL) and water (1 mL), and then potassium hydroxide (168.1 mg, 3.0 mmol) and 5-(di-tert-butylphosphino)-1,3,5-triphenyl-1 hydrogen-[1,4]dipyrazole (141.2 mg, 278.6 μmol), tris(dibenzylideneacetone)dipalladium (127.5 mg, 139.3 μmol) were added, and the mixture was stirred at 90 ° C for 1 hour. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3), and the organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-45%, 10min) to obtain compound 21-2. MS ESI calculated value C 13 H 12 ClN 3 O[M+H] + 262, found value 262.
步骤2:将化合物21-2(30.0mg,121.1μmol)，中间体3(33.6mg,127.1μmol)溶于二氧六环(2mL)和水(1mL),加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(22.1mg,30.2μmol)和碳酸钾(33.4mg,242.2μmol),反应于氮气保护下100℃搅拌0.5小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱色谱分离纯化(Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:15％-45％,10min)得化合物21的盐酸盐。Step 2: Compound 21-2 (30.0 mg, 121.1 μmol) and intermediate 3 (33.6 mg, 127.1 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.1 mg, 30.2 μmol) and potassium carbonate (33.4 mg, 242.2 μmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 0.5 hour. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was separated and purified by column chromatography (Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-45%, 10 min) to obtain the hydrochloride of compound 21.
1H NMR(400MHz,CD3OD)δppm 7.52-7.57(m,3H)，7.48-7.51(m,1H)，7.41-7.47(m,3H)，5.13(s,4H)，2.36(s,3H)。MS ESI计算值C18H14F5N3O2S[M+H]+446，实测值446。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.52-7.57 (m, 3H), 7.48-7.51 (m, 1H), 7.41-7.47 (m, 3H), 5.13 (s, 4H), 2.36 (s, 3H). MS ESI calculated value for C1 8 H 14 F 5 N 3 O 2 S [M+H] + 446, found 446.
实施例22
Embodiment 22
步骤1:将化合物22-1(77.7mg,674.8μmol)，中间体2-1(0.1g,613.4μmol)溶于四氢呋喃(2mL)中，在0℃加入钠氢(60％，98.1mg,2.4mmol)，反应于0℃搅拌1小时，反应完毕后用水(50mL)和乙酸乙酯(50mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后得化合物22-2。MS ESI计算值C11H16ClN3O[M+H]+242，实测值242。Step 1: Compound 22-1 (77.7 mg, 674.8 μmol) and intermediate 2-1 (0.1 g, 613.4 μmol) were dissolved in tetrahydrofuran (2 mL), sodium hydrogen sulfide (60%, 98.1 mg, 2.4 mmol) was added at 0°C, and the reaction was stirred at 0°C for 1 hour. After the reaction was completed, the mixture was extracted with water (50 mL) and ethyl acetate (50 mL*3), and the organic phase was dried over sodium sulfate, filtered and concentrated to obtain compound 22-2. MS ESI calculated value C 11 H 16 ClN 3 O[M+H] + 242, found value 242.
步骤2:将化合物22-2(32.7mg,124.1μmol)，中间体3(30.0mg,124.1μmol)溶于二氧六环(2mL)和水(1mL),加入[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)(22.7mg,31.0μmol)和碳酸钾(34.3mg,248.2μmol)氮气保护下100℃搅拌0.5小时，反应完毕后过滤，滤液旋干，粗品经色谱柱分离纯化(Xtimate C18150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:15％-45％,10min)得化合物22的盐酸盐。Step 2: Dissolve compound 22-2 (32.7 mg, 124.1 μmol) and intermediate 3 (30.0 mg, 124.1 μmol) in dioxane (2 mL) and water (1 mL), add [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (22.7 mg, 31.0 μmol) and potassium carbonate (34.3 mg, 248.2 μmol) and stir at 100 °C under nitrogen protection for 0.5 hour. After the reaction is completed, filter and dry the filtrate. The crude product is separated and purified by chromatographic column (Xtimate C18150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-45%, 10 min) to obtain the hydrochloride of compound 22.
1H NMR(400MHz,CD3OD)δppm 8.31(brs,1H),8.05(d,J＝7.88Hz,1H),7.41(brs,2H),4.04(d,J＝12.51Hz,1H),3.53-3.66(m,1H),3.48(d,J＝13.26Hz,1H),3.04-3.25(m,2H),2.94(s,2H),2.46-2.56(m,3H),2.15-2.43(m,3H),1.99(d,J＝14.13Hz,2H)。MS ESI计算值C17H20F5N3O2S[M+H]+426，实测值426。 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.31 (brs, 1H), 8.05 (d, J = 7.88 Hz, 1H), 7.41 (brs, 2H), 4.04 (d, J = 12.51 Hz, 1H), 3.53-3.66 (m, 1H), 3.48 (d, J = 13.26 Hz, 1H), 3.04-3.25 (m, 2H), 2.94 (s, 2H), 2.46-2.56 (m, 3H), 2.15-2.43 (m, 3H), 1.99 (d, J = 14.13 Hz, 2H). MS ESI calculated value for C 17 H 20 F 5 N 3 O 2 S [M+H] + 426, found 426.
实施例23
Embodiment 23
步骤1:将化合物中间体1-2(10.0g,60.9mmol)的乙腈(50mL)溶液加入到亚硝酸叔丁酯(9.4g,91.4mmol)和CuBr2(16.3g,73.1mmol)的乙腈(100mL)溶液中,25℃搅拌3小时，反应完毕后用稀盐酸(1M，50mL)淬灭，用乙酸乙酯(150mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(石油醚：乙酸乙酯＝10:1)得化合物23-1。MS ESI计算值C4HN2Cl2Br[M+H]+/[M+H+2]+227/229，实测值227/229。Step 1: Add a solution of compound intermediate 1-2 (10.0 g, 60.9 mmol) in acetonitrile (50 mL) to a solution of tert-butyl nitrite (9.4 g, 91.4 mmol) and CuBr 2 (16.3 g, 73.1 mmol) in acetonitrile (100 mL), stir at 25°C for 3 hours, quench with dilute hydrochloric acid (1 M, 50 mL) after the reaction is complete, extract with ethyl acetate (150 mL*2), dry the organic phase over sodium sulfate, filter and concentrate, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 23-1. MS ESI calculated value C 4 HN 2 Cl 2 Br[M+H] + /[M+H+2] + 227/229, found value 227/229.
步骤2:将化合物23-1(9.0g,39.5mmol)、乙烯基三氟硼酸钾(6.3g,47.3mmol)、碳酸钾(16.3g,118.4 mmol)加入到四氢呋喃(150mL)和水(30mL)中，氮气保护下加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(1.61g,1.97mmol)，反应于80℃搅拌3小时，反应完毕后用水(50mL)和乙酸乙酯(150mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(石油醚：乙酸乙酯＝5:1)得化合物23-2。MS ESI计算值C6H4N2Cl2[M+H]+175，实测值175。Step 2: Compound 23-1 (9.0 g, 39.5 mmol), potassium vinyl trifluoroborate (6.3 g, 47.3 mmol), potassium carbonate (16.3 g, 118.4 mmol) was added to tetrahydrofuran (150 mL) and water (30 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.61 g, 1.97 mmol) was added under nitrogen protection, and the reaction was stirred at 80°C for 3 hours. After the reaction was completed, it was extracted with water (50 mL) and ethyl acetate (150 mL*2), and the organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 23-2. MS ESI calculated value C 6 H 4 N 2 Cl 2 [M+H] + 175, found value 175.
步骤3:将化合物23-2(3.0g,17.1mmol)、氢氟酸吡啶(6.8g,68.5mmol)溶于二氯甲烷(30mL)中，在-20度下加入二溴海因(5.8g,20.5mmol)，反应于25℃搅拌12小时，反应完毕后用冰水(50mL)淬灭反应并用乙酸乙酯(70mL*3)萃取，有机相经硫酸钠干燥，过滤浓缩后得粗品化合物23-3直接用于下一步。MS ESI计算值C6H4N2Cl2FBr[M+H]+/[M+H+2]+273/275，实测值273/275。Step 3: Compound 23-2 (3.0 g, 17.1 mmol) and pyridine hydrofluoride (6.8 g, 68.5 mmol) were dissolved in dichloromethane (30 mL), dibromohydantoin (5.8 g, 20.5 mmol) was added at -20 degrees, and the reaction was stirred at 25°C for 12 hours. After the reaction was completed, the reaction was quenched with ice water (50 mL) and extracted with ethyl acetate (70 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated to obtain crude compound 23-3, which was directly used in the next step. MS ESI calculated value C 6 H 4 N 2 Cl 2 FBr [M + H] + / [M + H + 2] + 273/275, found value 273/275.
步骤4:将粗品化合物23-3(4.7g)溶于二氯甲烷(50mL)中，加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(3.13g,20.59mmol)，反应于25℃搅拌1小时，反应完毕后用稀盐酸(1M,50mL)淬灭反应并用二氯甲烷(50mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(石油醚：乙酸乙酯＝5:1)得化合物23-4。MS ESI计算值C6H3N2Cl2F[M+H]+193，实测值193。Step 4: Dissolve the crude compound 23-3 (4.7 g) in dichloromethane (50 mL), add 1,8-diazabicyclo[5.4.0]undec-7-ene (3.13 g, 20.59 mmol), stir at 25°C for 1 hour, quench with dilute hydrochloric acid (1M, 50 mL) after the reaction is complete, extract with dichloromethane (50 mL*2), dry the organic phase over sodium sulfate, filter and concentrate, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 23-4. MS ESI calculated value C 6 H 3 N 2 Cl 2 F[M+H] + 193, found value 193.
步骤5:将化合物23-4(300.0mg,1.6mmol)和中间体2-2(177.5mg,1.6mmol)混合，加热到180℃下反应5分钟，反应完毕后，反应物用稀盐酸(1M，5mL)溶解，二氯甲烷(10mL)稀释，水相用氢氧化钠(1M，5mL)调节到pH＝10，用二氯甲烷(10mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1)得化合物24-5。MS ESI计算值C12H15N4Cl[M+H]+251，实测值251。Step 5: Compound 23-4 (300.0 mg, 1.6 mmol) and intermediate 2-2 (177.5 mg, 1.6 mmol) were mixed and heated to 180°C for 5 minutes. After the reaction was completed, the reactants were dissolved with dilute hydrochloric acid (1M, 5 mL), diluted with dichloromethane (10 mL), the aqueous phase was adjusted to pH = 10 with sodium hydroxide (1M, 5 mL), extracted with dichloromethane (10 mL*2), the organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain compound 24-5. MS ESI calculated value C 12 H 15 N 4 Cl [M + H] + 251, found value 251.
步骤6:将化合物24-5(39.6mg,158.2μmol)、中间体3(41.7mg,158.2μmol)、碳酸钾(65.6mg,474.7μmol)溶于二氧六环(3mL)和水(1mL)中，氮气保护下加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(11.5mg,15.8μmol)，反应于100℃搅拌1小时，反应完毕后用水(10mL)淬灭反应并用乙酸乙酯(10mL*2)萃取，有机相经硫酸钠干燥，过滤浓缩后，粗品经制备HPLC纯化(色谱柱:Phenomenex C18 150*40mm*5μm；流动相:[水(0.05％HCl)-乙腈]；乙腈％:15％-45％,10min)得化合物24的盐酸盐。Step 6: Compound 24-5 (39.6 mg, 158.2 μmol), intermediate 3 (41.7 mg, 158.2 μmol), and potassium carbonate (65.6 mg, 474.7 μmol) were dissolved in dioxane (3 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (11.5 mg, 15.8 μmol) was added under nitrogen protection. The reaction was stirred at 100 °C for 1 hour. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL*2). The organic phase was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC (chromatographic column: Phenomenex C18 150*40mm*5μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 15%-45%, 10 min) to obtain the hydrochloride of compound 24.
1H NMR(400MHz,CD3OD)δppm 8.85(s,1H),8.74(brs,1H),7.88(d,J＝6.5Hz,1H),7.59(d,J＝7.8Hz,1H),7.56(s,1H),7.21(brs,1H),5.46(brs,1H),3.82-3.99(m,1H),3.54-3.80(m,2H),3.18-3.39(m,3H),2.83-3.07(m,3H),2.07-2.55(m,4H。MS ESI计算值C18H19OSF5N4[M+H]+435，实测值435。 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.85 (s, 1H), 8.74 (brs, 1H), 7.88 (d, J=6.5 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.21 (brs, 1H), 5.46 (brs, 1H), 3.82-3.99 (m, 1H), 3.54-3.80 (m, 2H), 3.18-3.39 (m, 3H), 2.83-3.07 (m, 3H), 2.07-2.55 (m, 4H. MS ESI calcd for C 18 H 19 OSF 5 N 4 [M+H] + 435, found 435.
生物测试数据：Biological test data:
实验例1：利用THP-1细胞检测NLRP3抑制剂的IC50实验Experimental Example 1: IC 50 experiment of NLRP3 inhibitors using THP-1 cells
供实验用的本发明化合物其化学名称和结构式见各化合物的制备实施例。The chemical names and structural formulas of the compounds of the present invention used in the experiments are given in the preparation examples of the compounds.
1.实验原理：本实验利用人源的单核细胞系THP1，来研究NLRP3抑制剂对细胞IL-1β分泌的抑制活性(IC50)。利用PMA(巴豆醇-12-十四烷酸酯-13-乙酸酯)分化单核细胞系THP1变成成熟的巨噬细胞，然后利 用Toll样受体TLR4的激动剂LPS(脂多糖)来对细胞进行刺激，激活炎症小体NLRP3的转录活性，以及IL-1β前体pro-IL-1β的表达。在此时，加入NLRP3的抑制剂，然后再加入ATP来使得NLRP3进一步成熟和活化，并激活下游的caspase-1。活化的caspase-1可以对pro-IL-1β进行酶切加工成为可被分泌的成熟IL-1β。NLRP3抑制剂可以有效抑制ATP诱导的NLRP3的成熟和活化，以及下游caspase-1的活化，从而抑制IL-1β的成熟和分泌。1. Experimental principle: This experiment uses human monocytic cell line THP1 to study the inhibitory activity (IC50) of NLRP3 inhibitors on cellular IL-1β secretion. PMA (crotyl alcohol-12-tetradecanoate-13-acetate) is used to differentiate the monocytic cell line THP1 into mature macrophages, and then The cells were stimulated with LPS (lipopolysaccharide), an agonist of Toll-like receptor TLR4, to activate the transcriptional activity of the inflammasome NLRP3 and the expression of the IL-1β precursor pro-IL-1β. At this time, an inhibitor of NLRP3 was added, and then ATP was added to further mature and activate NLRP3 and activate downstream caspase-1. Activated caspase-1 can enzymatically process pro-IL-1β into mature IL-1β that can be secreted. NLRP3 inhibitors can effectively inhibit the maturation and activation of NLRP3 induced by ATP, as well as the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1β.
2.实验材料：2. Experimental materials:
2.1本实验所用试剂的信息如表1所示：2.1 The information of reagents used in this experiment is shown in Table 1:
表1.试剂的信息
Table 1. Reagent information
2.2本实验所用仪器的信息如表2所示：2.2 The information of the instruments used in this experiment is shown in Table 2:
表2.仪器的信息
Table 2. Instrument information
2.3实验步骤：2.3 Experimental steps:
(1)将THP1细胞的密度调整到5*105细胞/mL，然后加入PMA，并且将终浓度调整为100ng/mL，200μL/孔接种至96孔平底板，37℃、5％CO2刺激过夜(尽量<16小时)。(1) Adjust the density of THP1 cells to 5*10 5 cells/mL, then add PMA and adjust the final concentration to 100 ng/mL, inoculate 200 μL/well into a 96-well flat-bottom plate, and stimulate overnight (try to <16 hours) at 37°C and 5% CO 2 .
(2)第二天，将上清弃掉，然后小心用杜氏磷酸盐缓冲液清洗两次(200μL/次)。 (2) The next day, the supernatant was discarded and the cells were carefully washed twice with Dulbecco's phosphate buffer (200 μL/time).
(3)用LPS刺激细胞，LPS终浓度为：100ng/mL，200μL/孔加入96孔板，37℃、5％CO2培养3h。(3) Cells were stimulated with LPS at a final concentration of 100 ng/mL. 200 μL/well was added to a 96-well plate and cultured at 37°C and 5% CO2 for 3 h.
(4)将测试化合物加入孔内，筛选浓度分别为：5μM、1μM、200nM、40nM、8nM、1.6nM、0.32nM、0.064nM。在37℃、5％CO2培养箱内孵育1h。(4) Add the test compound into the wells, and the screening concentrations are: 5 μM, 1 μM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM. Incubate in a 37°C, 5% CO 2 incubator for 1 hour.
(5)每孔加入ATP，终浓度为5mM，37℃、5％CO2培养过夜(>18小时)。(5) Add ATP to each well to a final concentration of 5 mM and incubate overnight (>18 hours) at 37°C, 5% CO2 .
(6)第三天，取出上清5μL，稀释10倍，并利用CBA检测上清中IL-1β的含量。(6) On the third day, 5 μL of the supernatant was removed and diluted 10-fold. The IL-1β content in the supernatant was detected using CBA.
3.实验结果：3. Experimental results:
化合物活性结果见表3。The activity results of the compounds are shown in Table 3.
表3.本发明化合物的抑制活性结果
Table 3. Inhibitory activity results of the compounds of the present invention
实验结论：本发明化合物具备良好的NLRP3抑制活性。Experimental conclusion: The compounds of the present invention have good NLRP3 inhibitory activity.
实验例2：药代动力学评价Experimental Example 2: Pharmacokinetic Evaluation
实验目的：测试化合物在小鼠体内药代动力学Experimental purpose: Test the pharmacokinetics of compounds in mice
实验材料：C57BL/6J小鼠(雄性，6-8周龄)Experimental materials: C57BL/6J mice (male, 6-8 weeks old)
实验操作：将试验化合物溶解后得的澄清溶液分别经尾静脉注射和灌胃(溶媒为10％DMSO/10％solutol/80％水)给予雌性C57BL/6J小鼠体内(过夜禁食，6-8周龄)。给予受试化合物或对照化合物后，静脉注射组在 0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组在0.25，0.5，1，2，4，6，8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlinTMVersion 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。测试结果如下表4所示。Experimental procedure: The clear solution obtained after dissolving the test compound was injected into the female C57BL/6J mice (fasted overnight, 6-8 weeks old) via tail vein injection and oral gavage (the solvent was 10% DMSO/10% solutol/80% water). 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, and the oral administration group at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, respectively, from the mandibular vein blood was collected and centrifuged to obtain plasma. The blood drug concentration was determined by LC-MS/MS, and the relevant pharmacokinetic parameters were calculated by the non-compartmental linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software. The test results are shown in Table 4 below.
表4.本发明化合物的药代动力学测试结果

ND：未确定(末端消除相不完整从而参数无法确定)Table 4. Pharmacokinetic test results of the compounds of the present invention

ND: Not determined (the terminal elimination phase is incomplete and the parameters cannot be determined)
实验结论：本发明化合物成药性好，口服利用度高。Experimental conclusion: The compound of the present invention has good drugability and high oral availability.
实验例3：大鼠药代动力学评价Experimental Example 3: Pharmacokinetic Evaluation in Rats
实验目的：测试化合物在大鼠体内药代动力学Experimental purpose: To test the pharmacokinetics of compounds in rats
实验材料：SD大鼠(雄性，6-10周龄)Experimental materials: SD rats (male, 6-10 weeks old)
实验操作：将试验化合物溶解后得的澄清溶液分别经尾静脉注射(溶媒为10％DMSO/10％solutol/80％水)和灌胃(溶媒为5％DMSO/10％solutol/85％水)给予雄性SD大鼠体内(不禁食，6-8周龄)。给予受试化合物或对照化合物，一定时间后，分别从下颌静脉采血并离心后获得血浆。另外，化合物2灌胃组还采集了脑脊液。化合物11盐酸盐静脉注射组在0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组在0.25，0.5，1，2，4，8和24小时。化合物2静脉注射组在0.0833，0.5，1，2，4，8，24和48小时，灌胃组在0.25，1，2，4，8，24和48小时。采用LC-MS/MS法测定血药和脑脊液浓度，使用WinNonlinTMVersion 6.3药动学软件， 以非房室模型线性对数梯形法计算相关药代动力学参数。测试结果如下表5所示。Experimental procedure: The clear solution obtained after dissolving the test compound was injected into male SD rats (no fasting, 6-8 weeks old) via tail vein injection (solvent is 10% DMSO/10% solutol/80% water) and gavage (solvent is 5% DMSO/10% solutol/85% water). After a certain period of time after administration of the test compound or control compound, blood was collected from the mandibular vein and centrifuged to obtain plasma. In addition, cerebrospinal fluid was also collected from the compound 2 gavage group. The compound 11 hydrochloride intravenous injection group was at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, and the gavage group was at 0.25, 0.5, 1, 2, 4, 8 and 24 hours. The compound 2 intravenous injection group was at 0.0833, 0.5, 1, 2, 4, 8, 24 and 48 hours, and the gavage group was at 0.25, 1, 2, 4, 8, 24 and 48 hours. The plasma and cerebrospinal fluid concentrations were determined by LC-MS/MS, using WinNonlin TM Version 6.3 pharmacokinetic software. The relevant pharmacokinetic parameters were calculated using the non-compartmental linear logarithmic trapezoidal method. The test results are shown in Table 5 below.
表5.大鼠的药代动力学测试结果

ND：未确定(末端消除相不完整从而参数无法确定)；“/”：未检测或未计算；Table 5. Pharmacokinetic test results in rats

ND: not determined (the terminal elimination phase is incomplete and the parameters cannot be determined); "/": not detected or calculated;
实验结论：本发明化合物成药性好，大鼠灌胃给药生物利用度高。化合物11的盐酸盐大鼠灌胃给药后系统暴露量随剂量同比例增长。化合物2大鼠灌胃给药后在脑脊液中有较高的暴露量，且脑-血浆游离药物比值(Kp,uu,CSF)较高，展现了较高的穿透血脑屏障的能力。Experimental conclusion: The compounds of the present invention have good drugability and high bioavailability after oral administration to rats. The systemic exposure of the hydrochloride salt of compound 11 increased in proportion to the dose after oral administration to rats. Compound 2 had a higher exposure in the cerebrospinal fluid after oral administration to rats, and a higher brain-plasma free drug ratio (K p,uu, CSF), showing a higher ability to penetrate the blood-brain barrier.
实验例4：犬药代动力学评价 Experimental Example 4: Pharmacokinetic Evaluation in Dogs
实验目的：测试化合物在比格犬体内药代动力学Experimental purpose: To test the pharmacokinetics of compounds in beagle dogs
实验材料：比格犬(雄性，9-11月龄)Experimental materials: Beagle dogs (male, 9-11 months old)
实验操作：将试验化合物溶解后得的澄清溶液分别经尾静脉注射和灌胃(溶媒为10％DMSO/10％solutol/80％水)给予雄性比格犬体内(禁食，9-11月龄)。给予受试化合物或对照化合物后，静脉注射组在0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组在0.25，0.5，1，2，4，8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlinTMVersion 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。测试结果如下表6所示。Experimental procedure: The clear solution obtained after dissolving the test compound was injected into the tail vein and administered to male beagle dogs (fasted, 9-11 months old) via gavage (the solvent was 10% DMSO/10% solutol/80% water). After administration of the test compound or the control compound, blood was collected from the mandibular vein at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours for the intravenous injection group and at 0.25, 0.5, 1, 2, 4, 8 and 24 hours for the gavage group, and plasma was obtained after centrifugation. The blood drug concentration was determined by LC-MS/MS, and the relevant pharmacokinetic parameters were calculated by the non-compartmental linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software. The test results are shown in Table 6 below.
表6.化合物11盐酸盐大鼠的药代动力学测试结果
Table 6. Pharmacokinetic test results of compound 11 hydrochloride in rats
实验结论：本发明化合物成药性好，犬口服给药后利用度高。Experimental conclusion: The compound of the present invention has good drugability and high utilization after oral administration to dogs.
实验例5：体内抗炎效果评价Experimental Example 5: Evaluation of in vivo anti-inflammatory effect
实验目的：评价本发明化合物对LPS诱导的C57BL/6小鼠PD模型中抗炎效果实验材料：C57BL/6小鼠(雌性，6-8周龄，浙江维通利华实验动物技术有限公司)Experimental purpose: To evaluate the anti-inflammatory effect of the compound of the present invention on LPS-induced C57BL/6 mouse PD model Experimental materials: C57BL/6 mice (female, 6-8 weeks old, Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.)
实验步骤：C57BL/6小鼠随机分为6组，每组5只，灌胃给予溶媒(5％DMSO/10％solutol/85％水)或者1、3、10mg/kg的化合物11盐酸盐，1小时之后，模型小鼠腹腔注射10mg/kg LPS大肠杆菌055:B5(Sigma-Aldrich，#L2880)或PBS。在2小时和6小时收集动物血清，用于检测细胞因子IL-1β(BD，560232)水平。实验分组方案如下表7所示：Experimental procedures: C57BL/6 mice were randomly divided into 6 groups, 5 mice in each group, and given vehicle (5% DMSO/10% solutol/85% water) or 1, 3, 10 mg/kg of compound 11 hydrochloride by gavage. One hour later, the model mice were intraperitoneally injected with 10 mg/kg LPS Escherichia coli 055:B5 (Sigma-Aldrich, #L2880) or PBS. Animal serum was collected at 2 hours and 6 hours for the detection of cytokine IL-1β (BD, 560232) levels. The experimental grouping scheme is shown in Table 7 below:
表7.LPS模型分组方案

Table 7. LPS model grouping scheme

实验结果：如图1所示，LPS刺激后，模型动物IL-1β水平显著升高；给药后2h，化合物11盐酸盐在1、3、10mg/kg给药剂量下可以抑制IL-1β水平，且呈剂量依赖性；给药后6h，化合物11盐酸盐在10mg/kg给药剂量对IL-1β抑制效果显著。Experimental results: As shown in Figure 1, after LPS stimulation, the IL-1β level of the model animal increased significantly; 2 hours after administration, compound 11 hydrochloride could inhibit the IL-1β level at doses of 1, 3, and 10 mg/kg, and was dose-dependent; 6 hours after administration, compound 11 hydrochloride had a significant inhibitory effect on IL-1β at a dose of 10 mg/kg.
注释：t-test；*p<0.05；**p<0.01；***p<0.001；****p<0.0001。Notes: t-test; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.
实验结论：本发明化合物在小鼠LPS模型中展示良好的抗炎效果，具有治疗炎性疾病的潜力。Experimental conclusion: The compounds of the present invention exhibited good anti-inflammatory effects in the mouse LPS model and have the potential to treat inflammatory diseases.
实验例6：血浆蛋白结合实验(PPB)Experimental Example 6: Plasma protein binding assay (PPB)
实验目的：利用平衡透析法测定本发明化合物在人、CD-1小鼠、SD大鼠、比格犬和食蟹猴血浆中的蛋白结合率。Experimental purpose: To determine the protein binding rate of the compound of the present invention in the plasma of human, CD-1 mouse, SD rat, beagle dog and cynomolgus monkey by equilibrium dialysis method.
实验步骤：Experimental steps:
取各种属(人/CD-1小鼠/SD大鼠/比格犬/食蟹猴)的空白血浆995μL，加入5μL受试化合物工作溶液(400μM)或华法林工作溶液(400μM)，使血浆样品中受试化合物与华法林终浓度均为2μM。将样品充分混合。有机相DMSO的终浓度为0.5％；移取50μL受试化合物和华法林血浆样品到样品接收板中(三个平行)，立即加入相应体积的对应空白血浆或PBS缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1:1，然后向这些样品中加入500μL终止液，此样品将作为T0样品用于回收率及稳定性测定。将T0样品存储于2-8℃，等待与其它透析完的样品一起进行后续处理；将150μL受试化合物和华法林血浆样品加入到每个透析孔的给药端，在透析孔对应的接收端中加入150μL空白透析缓冲液。然后将透析板置于湿润的、5％ CO2的培养箱中，在37℃下、约100rpm振荡孵育4-hr。透析结束后，移取50μL透析后的缓冲液样品和透析后的血浆样品到新的样品接收板。在样品中加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1:1。所有样品经过蛋白沉淀后进行LC/MS/MS分析，并通过公式：％Unbound＝100*F/T,％Bound＝100-％Unbound,％Recovery＝100*(F+T)/T0计算蛋白结合率以及回收率(其中F是透析4h后透析液中化合物的峰面积比值；T是透析4h后血浆中化合物的峰面积比值；T0是零时刻血浆样品中化合物的峰面积比值)。实验结果如表8所示：Take 995 μL of blank plasma of various species (human/CD-1 mouse/SD rat/beagle dog/cynomolgus monkey), add 5 μL of test compound working solution (400 μM) or warfarin working solution (400 μM), so that the final concentration of test compound and warfarin in plasma sample is 2 μM. Mix the samples thoroughly. The final concentration of DMSO in organic phase is 0.5%; pipette 50 μL of test compound and warfarin plasma sample into the sample receiving plate (three parallels), immediately add the corresponding volume of blank plasma or PBS buffer, so that the final volume of each sample well is 100 μL, and the volume ratio of plasma: dialysis buffer is 1:1, then add 500 μL of stop solution to these samples, which will be used as T 0 samples for recovery and stability determination. Store the T0 sample at 2-8°C and wait for subsequent processing with other dialyzed samples; add 150 μL of the test compound and warfarin plasma sample to the dosing end of each dialysis well, and add 150 μL of blank dialysis buffer to the receiving end corresponding to the dialysis well. Then place the dialysis plate in a humidified, 5% CO2 incubator and incubate at 37°C, shaking at about 100 rpm for 4-hr. After the dialysis is completed, transfer 50 μL of the dialyzed buffer sample and the dialyzed plasma sample to a new sample receiving plate. Add the corresponding volume of blank plasma or buffer to the sample so that the final volume of each sample well is 100 μL, and the volume ratio of plasma:dialysis buffer is 1:1. All samples were subjected to LC/MS/MS analysis after protein precipitation, and the protein binding rate and recovery rate were calculated by the formula: %Unbound=100*F/T, %Bound=100-%Unbound, %Recovery=100*(F+T)/T 0 (where F is the peak area ratio of the compound in the dialysate after 4 hours of dialysis; T is the peak area ratio of the compound in the plasma after 4 hours of dialysis; T 0 is the peak area ratio of the compound in the plasma sample at time zero). The experimental results are shown in Table 8:
表8.血浆蛋白结合率测试结果(％Unbound)


“/”：未检测；Table 8. Plasma protein binding test results (% Unbound)


“/”: not detected;
实验结论：本发明化合物在不同种属血浆中均表现出较高程度的结合率。Experimental conclusion: The compounds of the present invention exhibit a high degree of binding rate in the plasma of different species.
实验例7：化合物对体外细胞色素P450酶抑制评价Experimental Example 7: Evaluation of the Inhibition of Cytochrome P450 Enzymes by Compounds in Vitro
实验目的：测定受试化合物对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的抑制作用。Experimental purpose: To determine the inhibitory effect of the test compounds on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).
实验步骤：Experimental steps:
首先将受试化合物(10.0mM)进行梯度稀释，制备工作液(100×最终浓度)，且工作液浓度分别为：5.00、1.50、0.500、0.150、0.0500、0.0150和0.00500mM，同时准备P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)各阳性抑制剂及其特异性底物混合物的工作液；将保存在低于-60℃冰箱的人肝微粒体置于冰上解冻，待人肝微粒体全部溶解，用Potassium phosphate buffer(PB)进行稀释，制备一定浓度工作液(0.253mg/ml)。First, the test compound (10.0 mM) was graded diluted to prepare the working solution (100× final concentration), and the working solution concentrations were 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150 and 0.00500 mM, respectively. At the same time, the working solution of each positive inhibitor of P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their specific substrate mixtures were prepared; human liver microsomes stored in a refrigerator below -60°C were thawed on ice, and after the human liver microsomes were completely dissolved, they were diluted with Potassium phosphate buffer (PB) to prepare a working solution of a certain concentration (0.253 mg/ml).
先将20.0μL底物混合液加至反应板中(Blank孔中加入20.0μL PB)，然后将158μL人肝微粒体工作液加入反应板中，将反应板置于冰上，待用；此时将2.00μL各个浓度的受试化合物(N＝1)及特异性抑制剂(N＝2)加入对应孔中，无抑制剂(受试化合物或阳性抑制剂)组加入对应的有机溶剂，作为对照组样品(受试化合物对照样品为1:1DMSO:MeOH，阳性对照样品均为1:9DMSO:MeOH)；在37℃水浴预孵育10min后，将20.0μL辅酶因子(NADPH)溶液加入反应板中，置于37℃水浴孵育反应10min；加入400μL预冷的乙腈溶液(含200ng/mL Tolbutamide和Labetalol的内标)终止反应；将反应板置于摇床，振荡10min混匀；然后在4℃、4000rpm条件下离心20min；取200μL上清加至100μL水中，进行样品稀释；最后封板，振荡10min混匀，进行LC/MS/MS检测。First, add 20.0μL of substrate mixture to the reaction plate (add 20.0μL PB to the Blank well), then add 158μL of human liver microsome working solution to the reaction plate, and place the reaction plate on ice for later use; at this time, add 2.00μL of test compounds (N=1) and specific inhibitors (N=2) of various concentrations to the corresponding wells, and add the corresponding organic solvent to the group without inhibitor (test compound or positive inhibitor) as the control group sample (the test compound control sample is 1:1 DMSO:MeOH, and the positive control samples are all 1:9 DMSO:MeOH); incubate in a 37°C water bath. After pre-incubation for 10 minutes, add 20.0 μL of coenzyme factor (NADPH) solution to the reaction plate and incubate in a 37°C water bath for 10 minutes; add 400 μL of pre-cooled acetonitrile solution (containing 200 ng/mL Tolbutamide and Labetalol as internal standards) to terminate the reaction; place the reaction plate on a shaker and oscillate for 10 minutes to mix; then centrifuge at 4°C and 4000 rpm for 20 minutes; take 200 μL of supernatant and add it to 100 μL of water for sample dilution; finally, seal the plate, oscillate for 10 minutes to mix, and perform LC/MS/MS detection.
用各探针底物代谢物的生成速率体现各CYP同工酶的活性。设定不加供试品或阳性抑制剂的溶剂对照孵育体系中各同工酶的活性为100％，将含不同浓度供试品或阳性抑制剂时探针底物代谢产物的生成速率与溶剂对照样品代谢产物的生成速率相比再乘以100％作为各同工酶的剩余活性百分比。以剩余活性百分比为纵坐标，抑制剂浓度为横坐标，使用XL fit软件中三参数或四参数进行非线性回归分析，计算得到供试品及各阳性抑制剂的IC50值。当XL fit软件拟合得到的IC50大于最高给药浓度(50μM)或无法拟合得到IC50时，则IC50值标记为“>50μM”。实验结果如表9所示。The generation rate of each probe substrate metabolite reflects the activity of each CYP isozyme. The activity of each isozyme in the solvent control incubation system without the test sample or positive inhibitor was set to 100%. The generation rate of the probe substrate metabolite when containing different concentrations of the test sample or positive inhibitor was compared with the generation rate of the metabolite of the solvent control sample and then multiplied by 100% as the residual activity percentage of each isozyme. With the residual activity percentage as the ordinate and the inhibitor concentration as the abscissa, the three-parameter or four-parameter nonlinear regression analysis in the XL fit software was used to calculate the IC 50 values of the test sample and each positive inhibitor. When the IC 50 fitted by the XL fit software is greater than the highest administration concentration (50μM) or the IC 50 cannot be fitted, the IC 50 value is marked as ">50μM". The experimental results are shown in Table 9.
表9.细胞色素P450同工酶半数抑制浓度IC50(μM)

Table 9. Half maximal inhibitory concentration IC 50 (μM) of cytochrome P450 isozymes

实验结论：本发明化合物对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4酶无明显抑制作用。Experimental conclusion: The compounds of the present invention have no obvious inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes.
实验例8：肝细胞代谢稳定性实验(HMS)Experimental Example 8: Hepatocyte Metabolic Stability Study (HMS)
实验目的：测试本发明化合物在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人的肝细胞的稳定性。Experimental purpose: To test the stability of the compounds of the present invention in the hepatocytes of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and humans.
实验步骤：将198μL的肝细胞混悬液(0.51×106cells/mL)加入到已预热的孵育板中，培养液对照组加入198μL不含肝细胞的孵育培养液至T0-MC和T120-MC孵育板中，所有孵育板在37℃培养箱中预孵育10分钟。然后加入2μL供试品和对照化合物工作液，混匀，立即将孵育板放入培养箱内的摇板机中，调节转数约为650rpm，启动计时器开始反应。每个化合物的每个时间点准备2个重复样本。孵育条件为37℃、饱和湿度、含5％CO2。测试体系中，供试品的终浓度为1μM，对照品的终浓度为3μM，肝细胞的终浓度为0.5×106cells/mL，总有机溶剂的终浓度为0.96％，其中DMSO的终浓度为0.1％。相应时间点孵育结束时，取出孵育板，取出25μL化合物和对照化合物与细胞的混合液加入到含有125μL终止液(含有200ng/mL甲苯磺丁脲的乙腈甲醇溶液(v：v，5：95))的样品板中。对于Blank样品板，直接加入25μL不含肝细胞的孵育培养液。所有样品板封膜后在摇板机上以600rpm摇10分钟后，3220×g离心20分钟。供试品上清液用超纯水以1：1的比例稀释，对照品上清液用超纯水以1：3的比例稀释。所有样品混匀后用LC-MS/MS的方法进行分析。实验结果如表10所示：Experimental steps: 198 μL of hepatocyte suspension (0.51×10 6 cells/mL) was added to the preheated incubation plate. For the culture medium control group, 198 μL of incubation medium without hepatocytes was added to the T0-MC and T120-MC incubation plates. All incubation plates were pre-incubated in a 37°C incubator for 10 minutes. Then 2 μL of the test sample and control compound working solution were added, mixed well, and the incubation plate was immediately placed in the shaker in the incubator, the speed was adjusted to about 650 rpm, and the timer was started to start the reaction. Two replicate samples were prepared for each compound at each time point. The incubation conditions were 37°C, saturated humidity, and 5% CO 2 . In the test system, the final concentration of the test sample was 1 μM, the final concentration of the control sample was 3 μM, the final concentration of the hepatocytes was 0.5×10 6 cells/mL, the final concentration of the total organic solvent was 0.96%, and the final concentration of DMSO was 0.1%. At the end of the incubation at the corresponding time point, the incubation plate was removed, and 25 μL of the mixture of the compound and the control compound and cells was taken out and added to the sample plate containing 125 μL of the stop solution (acetonitrile methanol solution containing 200 ng/mL tolbutamide (v:v, 5:95)). For the Blank sample plate, 25 μL of incubation culture medium without hepatocytes was directly added. After all sample plates were sealed and shaken on a shaker at 600 rpm for 10 minutes, they were centrifuged at 3220×g for 20 minutes. The supernatant of the test sample was diluted with ultrapure water at a ratio of 1:1, and the supernatant of the control sample was diluted with ultrapure water at a ratio of 1:3. All samples were mixed and analyzed by LC-MS/MS. The experimental results are shown in Table 10:
表10.HMS测试
Table 10. HMS test
CLint(liver)：肝固有清除率CLint(liver): liver intrinsic clearance
实验结论：本发明化合物在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人肝细胞中代谢稳定性好。Experimental conclusion: The compounds of the present invention have good metabolic stability in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and human hepatocytes.
实验例9：肝微粒体代谢稳定性实验(MMS)Experimental Example 9: Liver Microsome Metabolic Stability Study (MMS)
实验目的：测试本发明化合物在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人的肝微粒体中的稳定性。Experimental purpose: To test the stability of the compounds of the present invention in liver microsomes of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and humans.
实验操作：准备2块96孔孵育板，分别命名为T60孵育板和NCF60孵育板。在T60孵育板和NCF60孵育板上分别加入445μL微粒体工作液(肝微粒体蛋白浓度为0.56mg/mL)，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。预孵育结束后，在T60孵育板和NCF60孵育板上分别加入5μL供试品或对照化合物工作液，混匀。在NCF60孵育板上每孔添加50μL磷酸钾盐缓冲液启动反应；在T0终止板中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)和6uL的NADPH再生体系工作液，从T60孵育板中取出54μL样品至T0终止板(T0样品产生)。在Blank板中只添加54μL微粒体工作液、6uL的NADPH再生体系工作液和180μL的终止液。Experimental operation: Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate. Add 445 μL of microsomal working solution (liver microsomal protein concentration is 0.56 mg/mL) to the T60 incubation plate and NCF60 incubation plate, respectively, and then place the above incubation plates in a 37°C water bath for preincubation for about 10 minutes. After the preincubation, add 5 μL of the test sample or control compound working solution to the T60 incubation plate and the NCF60 incubation plate, respectively, and mix well. Add 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate to start the reaction; add 180 μL of stop solution (acetonitrile solution containing 200 ng/mL tolbutamide and 200 ng/mL labetalol) and 6 uL of NADPH regeneration system working solution to the T0 stop plate, and take 54 μL of sample from the T60 incubation plate to the T0 stop plate (T0 sample generation). Only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution and 180 μL of stop solution were added to the Blank plate.
在T60孵育板上每孔添加44μL NADPH再生体系工作液启动反应。因此，在供试品或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)。孵育适当时间(如5、15、30、45和60分钟)后，分别在每个终止板的样品孔中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)，之后从T60孵育板或NCF60孵育板中取出60μL样品以终止反应。所有样品板摇匀并在3220×g离心20分钟，然后每孔取80μL上清液稀释到240μL纯水中用于液相色谱串联质谱分析。实验结果如表11所示：Add 44 μL of NADPH regeneration system working solution to each well of the T60 incubation plate to start the reaction. Therefore, in the sample of the test or control compound, the final reaction concentration of the compound, testosterone, diclofenac and propafenone is 1 μM, the concentration of liver microsomes is 0.5 mg/mL, and the final concentrations of DMSO and acetonitrile in the reaction system are 0.01% (v/v) and 0.99% (v/v), respectively. After incubation for an appropriate time (such as 5, 15, 30, 45 and 60 minutes), add 180 μL of stop solution (containing 200 ng/mL tolbutamide and 200 ng/mL labetalol in acetonitrile) to each sample well of the termination plate, and then take out 60 μL of sample from the T60 incubation plate or NCF60 incubation plate to terminate the reaction. All sample plates were shaken and centrifuged at 3220×g for 20 minutes, and then 80 μL of supernatant was diluted into 240 μL of pure water for liquid chromatography tandem mass spectrometry analysis. The experimental results are shown in Table 11:
表11.MMS测试结果

“/”：未检测；Clint(liver)：肝固有清除率Table 11. MMS test results

“/”: not measured; Clint(liver): liver intrinsic clearance
实验结论：本发明化合物具有良好的肝微粒体稳定性。 Experimental conclusion: The compound of the present invention has good liver microsome stability.

Claims (21)

  1. 式(Ⅱ)所示化合物、其立体异构体或其药学上可接受的盐，
    The compound represented by formula (II), its stereoisomer or its pharmaceutically acceptable salt,
    其中，in,
    X为OH、NH2、NHCOCH3或CH2OH；X is OH, NH 2 , NHCOCH 3 or CH 2 OH;
    R1为H、F、Cl、Br、I、C1-3烷基、C1-3杂烷基、C2-5烯基或C3-6环烷基，其中，所述C1-3烷基、C1-3杂烷基、C2-5烯基和C3-6环烷基各自独立地任选地被1、2或3个Ra取代；R 1 is H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl or C 3-6 cycloalkyl, wherein the C 1-3 alkyl, C 1-3 heteroalkyl, C 2-5 alkenyl and C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3 Ra ;
    R2为H、F、Cl、Br、I、CN、C1-3烷基、C2-5烯基、C2-5炔基、C1-3烷氧基、C3-6环烷基或3-6元杂环烷基，其中，所述C1-3烷基、C2-5烯基、C2-5炔基、C1-3烷氧基、C3-6环烷基和3-6元杂环烷基各自独立地任选地被1、2或3个Rb取代； R2 is H, F, Cl, Br, I, CN, C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-3 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-3 alkoxy, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 Rb ;
    L为单键、-NH(CH2)n-或-O-；L is a single bond, -NH(CH 2 ) n - or -O-;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    R3为C1-6烷基、C3-8环烷基、5-12元杂环烷基、C6-10芳基或5-10元杂芳基，其中，所述C1-6烷基、C3-8环烷基、5-12元杂环烷基、C6-10芳基和5-10元杂芳基各自独立地任选地被1、2或3个Rc取代； R3 is C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 Rc ;
    环A为 Ring A is
    为单价或双键； is a single bond or a double bond;
    T为N或C；T is N or C;
    环B为5-7元环烯基、5-7元杂环烯基或5-6元杂芳基；Ring B is a 5-7 membered cycloalkenyl group, a 5-7 membered heterocycloalkenyl group or a 5-6 membered heteroaryl group;
    各Ra分别独立地为H、F、Cl、Br、I、CN、OH或C1-3烷氧基；Each Ra is independently H, F, Cl, Br, I, CN, OH or C1-3 alkoxy;
    各Rb分别独立地为H、F、Cl、Br、I、CN、OH或C1-3烷基；Each R b is independently H, F, Cl, Br, I, CN, OH or C 1-3 alkyl;
    各Rc分别独立地为H、F、Cl、Br、I、CN、OH、C1-6烷基、C1-6烷氧基或C1-6烷氨基，所述C1-6烷基、C1- 6烷氧基和C1-6烷氨基各自独立地任选地被1、2或3个R取代；Each R c is independently H, F, Cl, Br, I , CN, OH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, and the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
    各R分别独立地为F、Cl、Br、I、OH、SRa1、-C(＝O)ORa1、-C(＝O)NH2、-S(＝O)Ra1、-S(＝O)2Ra1或C1-3烷氧基；Each R is independently F, Cl, Br, I, OH, SR a1 , -C(=O)OR a1 , -C(=O)NH 2 , -S(=O)R a1 , -S(=O) 2 R a1 or C 1-3 alkoxy;
    各Ra1分别独立地为C1-3烷基，所述C1-3烷基任选被1、2或3个F取代；Each R a1 is independently C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F;
    所述C1-3杂烷基、3-6元杂环烷基、5-7元杂环烯基、5-12元杂环烷基、5-6元杂芳基和5-10元杂芳基中 “杂”选自1、2和3个独立为O、NH、S或N的杂原子或杂原子团；The C 1-3 heteroalkyl, 3-6 membered heterocycloalkyl, 5-7 membered heterocycloalkenyl, 5-12 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-10 membered heteroaryl "Hetero" is selected from 1, 2 and 3 heteroatoms or heteroatoms independently selected from O, NH, S or N;
    条件是所述化合物不选自所示结构、其立体异构体或其药学上可接受的盐： Provided that the compound is not selected from the structure shown, its stereoisomers or pharmaceutically acceptable salts thereof:
  2. 根据权利要求1所示化合物、其立体异构体或其药学上可接受的盐，其中，各R分别独立地为H、F、OH或-OCH3。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R is independently H, F, OH or -OCH 3 .
  3. 根据权利要求1所示化合物、其立体异构体或其药学上可接受的盐，其中，各Ra分别独立地为H或F。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each Ra is independently H or F.
  4. 根据权利要求1所示化合物、其立体异构体或其药学上可接受的盐，其中，各Rb分别独立地为H、F或CH3。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R b is independently H, F or CH 3 .
  5. 根据权利要求1所示化合物、其立体异构体或其药学上可接受的盐，其中，各Rc分别独立地为H、F、OH、C1-3烷基、C1-3烷氧基或C1-3烷氨基，所述C1-3烷基、C1-3烷氧基和C1-3烷氨基任选独立地被1、2或3个R取代。The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R c is independently H, F, OH, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, and the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are optionally independently substituted by 1, 2 or 3 R.
  6. 根据权利要求5所示化合物、其立体异构体或其药学上可接受的盐，其中，各Rc分别独立地为H、F、OH、-CH3、-CH2CH2OH、-CH2CH2OCH3或-N(CH3)2。The compound according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R c is independently H, F, OH, -CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 or -N(CH 3 ) 2 .
  7. 根据权利要求1所示的化合物、其立体异构体或其药学上可接受的盐，其中，R1为H、F、Cl、Br、I或CH3。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 is H, F, Cl, Br, I or CH 3 .
  8. 根据权利要求1所示的化合物、其立体异构体或其药学上可接受的盐，其中，R2为H、CN、CH3、-CH＝CH2、-CH2CH＝CH2、-CH2CH2CH＝CH2、-CH2CH2CH2CH＝CH2、-OCH3、其中，所述CH3、-CH＝CH2、-CH2CH＝CH2、-CH2CH2CH＝CH2、-CH2CH2CH2CH＝CH2、-OCH3、各自独立地任选地被1、2或3个Rb取代。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 2 is H, CN, CH 3 , -CH＝CH 2 , -CH 2 CH＝CH 2 , -CH 2 CH 2 CH＝CH 2 , -CH 2 CH 2 CH 2 CH＝CH 2 , -OCH 3 , Wherein, the CH 3 , -CH=CH 2 , -CH 2 CH=CH 2 , -CH 2 CH 2 CH=CH 2 , -CH 2 CH 2 CH 2 CH=CH 2 , -OCH 3 , Each is independently optionally substituted with 1, 2 or 3 R b .
  9. 根据权利要求8所示的化合物、其立体异构体或其药学上可接受的盐，其中，R2为H、CN、CH3、-CH＝CH2、-CF＝CH2、-CH2CH＝CH2、-OCH3、 The compound according to claim 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 2 is H, CN, CH 3 , -CH=CH 2 , -CF=CH 2 , -CH 2 CH=CH 2 , -OCH 3 ,
  10. 根据权利要求1所示的化合物、其立体异构体或其药学上可接受的盐，其中，R3为C1-3烷基、C5-6环烷基、5-6元杂环烷基、C9-10芳基或9-10元杂芳基，其中，所述C1-3烷基、C5-6环烷基、5-6元杂环烷基、C9-10芳基和9-10元杂芳基各自独立地任选地被1、2或3个Rc取代。The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 is C 1-3 alkyl, C 5-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 9-10 aryl or 9-10 membered heteroaryl, wherein the C 1-3 alkyl, C 5-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 9-10 aryl and 9-10 membered heteroaryl are each independently optionally substituted by 1, 2 or 3 R c .
  11. 根据权利要求10所示的化合物、其立体异构体或其药学上可接受的盐，其中，R3为CH2CH3、CH2CH2CH3、环己烷基、四氢呋喃基、哌啶基、苯并四氢呋喃基、1,3-二氢-2H-苯并咪唑酮基或吡啶并三氮唑基，所述 CH2CH3、CH2CH2CH3、环己烷基、四氢呋喃基、哌啶基、苯并四氢呋喃基、1,3-二氢-2H-苯并咪唑酮基和吡啶并三氮唑基各自独立地任选地被1、2或3个Rc取代。The compound according to claim 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3 is CH 2 CH 3 , CH 2 CH 2 CH 3 , cyclohexyl, tetrahydrofuranyl, piperidinyl, benzotetrahydrofuranyl, 1,3-dihydro-2H-benzimidazolone or pyridotriazolyl, and the CH 2 CH 3 , CH 2 CH 2 CH 3 , cyclohexanyl, tetrahydrofuranyl, piperidinyl, benzotetrahydrofuranyl, 1,3-dihydro-2H-benzimidazolone and pyridotriazolyl are each independently optionally substituted with 1, 2 or 3 R c .
  12. 根据权利要求11所示的化合物、其立体异构体或其药学上可接受的盐，其中，R3为 The compound according to claim 11, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3 is
  13. 根据权利要求1所示化合物、其立体异构体或其药学上可接受的盐，其中，L为-NH-或-O-。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is -NH- or -O-.
  14. 根据权利要求1所示化合物、其立体异构体或其药学上可接受的盐，其中，环B为 The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring B is
  15. 根据权利要求1所示化合物、其立体异构体或其药学上可接受的盐，其中，环A为 The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring A is
  16. 根据权利要求1所示化合物、其立体异构体或其药学上可接受的盐，其中，结构单元为 The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unit for
  17. 根据权利要求1所述化合物、其立体异构体或其药学上可接受的盐，其中所述化合物具有式(II-1)或(II-2)所示结构：
    The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (II-1) or (II-2):
    其中，为单价或双键；环B、X、L、T、R1、R2和R3如权利要求1所定义。in, is a monovalent or double bond; Ring B, X, L, T, R 1 , R 2 and R 3 are as defined in claim 1.
  18. 根据权利要求17所述化合物、其立体异构体或其药学上可接受的盐，其中所述化合物具有式(P-1)、(P-2)或(P-3)所示结构：
    The compound according to claim 17, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (P-1), (P-2) or (P-3):
    其中，为单价或双键；环B、T、R1、R2和R3如权利要求17所定义。in, is a monovalent or double bond; Ring B, T, R 1 , R 2 and R 3 are as defined in claim 17.
  19. 一种化合物、其立体异构体或其药学上可接受的盐，其化合物选自：


    A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:


  20. 一种化合物、其立体异构体或其药学上可接受的盐，其化合物选自：



    A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:



  21. 根据权利要求1～20任意一项所述的化合物、其立体异构体或其药学上可接受的盐在制备治疗与炎症相关疾病的药物中的应用。 Use of the compound according to any one of claims 1 to 20, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating inflammation-related diseases.
PCT/CN2024/088358 2023-04-18 2024-04-17 Sulfur pentafluoride substituted aromatic ring compound and use thereof WO2024217462A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113784957A (en) * 2019-05-17 2021-12-10 诺华股份有限公司 NLRP3 inflammasome inhibitor
WO2022216971A1 (en) * 2021-04-07 2022-10-13 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting nlrp3

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113784957A (en) * 2019-05-17 2021-12-10 诺华股份有限公司 NLRP3 inflammasome inhibitor
WO2022216971A1 (en) * 2021-04-07 2022-10-13 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting nlrp3

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