Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to a class of sulfinimide compounds and applications thereof, in particular to compounds represented by formula (II) or pharmaceutically acceptable salts thereof.
• the Janus kinases (JAKs) family is a class of intracellular non-receptor tyrosine kinases, which are mainly responsible for regulating the signal transduction pathways mediated by cytokine receptors. And receptor activation, and participate in many types of cell proliferation, differentiation, apoptosis, angiogenesis and immune regulation and other important physiological processes.
• the Janus kinase family includes four different subtypes in mammals: JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2).
• TYK2 structure also consists of 7 homology domains (JAK homology domain, JH) composed of 4 conserved domains, including the C-terminal pseudo-kinase domain (JH2) and the kinase domain ( kinase domain, JH1), and N-terminal FERM (Four.1 protein, Ezrin, Radixin, Moesin) region and SH2 domain (srchomology 2 domain).
• TYK2 forms a dimer with JAK2 in the cell to mediate the signal transduction of IL-23 and IL-12, and can also form a dimer with JAK1 to mediate the response of type I interferon.
• These cytokines are associated with psoriasis, inflammatory It has been implicated in the pathogenesis of various inflammatory and autoimmune diseases such as intestinal disease (IBD) and systemic lupus erythematosus (SLE). By inhibiting TYK2, the signal transduction pathway of some inflammatory cytokines can be blocked to achieve the purpose of treating related diseases.
• Current TYK2 inhibitors mainly include orthosteric inhibitors that inhibit the kinase domain (JH1) and allosteric inhibitors that inhibit the pseudokinase domain (JH2).
• Orthosteric inhibitors represented by Pfizer's PF-06826647, are used to treat plaque and ulcerative colitis and other diseases, and are currently in phase II clinical trials.
• the allosteric inhibitors are represented by BMS-986165, and the clinical trials for the treatment of massive psoriasis have advanced to the third phase, with outstanding clinical effects and good safety. And systemic lupus erythematosus and other autoimmune diseases are in clinical research.
• Nimbus In addition to BMS-986165, Nimbus also has a number of TYK2 allosteric inhibitors in preclinical screening.
• the recently reported TYK2 allosteric inhibitor FTP-637 of Frontera acquired by Haisco is preparing to enter the first phase of clinical trials.
• the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,
• Ring A is a 6-membered heteroaryl group
• X 1 and X 2 are independently selected from N and CH;
• R 1 and R 2 are independently selected from C 1-3 alkyl groups optionally substituted by 1 , 2, 3 or 4 R a ;
• R 1 , R 2 and the S atom connected to them together form a 4-6 membered heterocycloalkyl group, and the 4-6 membered heterocyclyl group is optionally substituted by 1, 2, 3 or 4 R a ;
• Each R is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 alkyl and C 1-3 alkoxy;
• R 41 is selected from C 1-3 alkyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl, phenyl and 4-6 membered heterocycloalkyl, the C 1-3 alkyl, C 3 -8 cycloalkyl, 5-6 membered heteroaryl, phenyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2, 3 and 4 R c ;
• R 42 is selected from hydrogen and C 1-3 alkyl
• R 43 is selected from C 1-3 alkyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, the C 1-3 alkyl, C 3-8 ring Alkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2, 3 and 4 R;
• R is selected from hydrogen and C 1-3 alkyl ;
• R is selected from C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, -NH-C 1-3 alkyl and -NH-C 3-6 cycloalkyl , said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, -NH-C 1-3 alkyl and -NH-C 3-6 cycloalkyl are optionally replaced by 1, 2, 3 or 4 R d substitutions;
• R a , R b , R c and R d are independently selected from H, deuterium, fluorine, chlorine, bromine, iodine, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy;
• n is selected from 0, 1, 2 and 3.
• the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,
• Ring A is a 6-membered heteroaryl group
• X and X are independently selected from N and CH ;
• R 1 and R 2 are independently selected from C 1-3 alkyl groups optionally substituted by 1 , 2, 3 or 4 R a ;
• R 1 , R 2 and the S atom connected to them together form a 4-6 membered heterocyclic group, and the 4-6 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 R a ;
• Each R is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 alkyl and C 1-3 alkoxy;
• R is selected from C 1-3 alkyl and C 3-6 cycloalkyl, said C 1-3 alkyl and C 3-6 cycloalkyl are optionally substituted by 1, 2, 3 and 4 R c ;
• R is selected from hydrogen and C 1-3 alkyl ;
• R is selected from C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, -NH-C 1-3 alkyl and -NH-C 3-6 cycloalkyl , said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, -NH-C 1-3 alkyl and -NH-C 3-6 cycloalkyl are optionally replaced by 1, 2, 3 or 4 R d substitutions;
• R a , R b , R c and R d are independently selected from H, deuterium, fluorine, chlorine, bromine, iodine, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy;
• n 0, 1, 2 or 3.
• the above ring A is selected from Other variables are as defined herein.
• the above ring A is selected from Other variables are as defined herein.
• R 1 and R 2 are independently selected from methyl, ethyl and propyl, and the methyl, ethyl and propyl are optionally replaced by 1, 2, 3 or 4 R a is substituted, and other variables are as defined herein.
• R 1 and R 2 are independently selected from methyl and ethyl, and other variables are as defined in the present invention.
• R 1 and R 2 are independently selected from methyl, and other variables are as defined in the present invention.
• Each R a is substituted, and other variables are as defined in the present invention.
• R 1 , R 2 and the S atom connected to them together form said Optionally substituted by 1, 2, 3 or 4 R a , other variables are as defined herein.
• R a is selected from hydrogen, and other variables are as defined in the present invention.
• each X above is selected from N, and other variables are as defined in the present invention.
• each X above is selected from CH, and other variables are as defined in the present invention.
• each R 3 above is independently selected from hydrogen and fluorine, and other variables are as defined in the present invention.
• R 4 is selected from hydrogen, -C(O)R 41 , -C(O)NR 42 R 43 , said Optionally substituted with 1, 2 or 3 R b , other variables are as defined herein.
• R 4 is selected from hydrogen, -C(O)R 41 , said Optionally substituted with 1, 2 or 3 R b , other variables are as defined herein.
• R b is selected from hydrogen, deuterium, fluorine, CN, NH 2 , methyl, ethyl, methoxy and ethoxy, and other variables are as defined in the present invention.
• R b is selected from hydrogen, fluorine, CN and methyl, and other variables are as defined in the present invention.
• R b is selected from hydrogen, and other variables are as defined in the present invention.
• R b is selected from fluorine, and other variables are as defined in the present invention.
• R b is selected from CN, and other variables are as defined in the present invention.
• R b is selected from methyl, and other variables are as defined in the present invention.
• R b is selected from methoxy, and other variables are as defined in the present invention.
• the above-mentioned R is selected from methyl, ethyl, propyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, said Methyl, ethyl, propyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2, 3 and 4 R c , other variable as defined herein.
• R 41 is selected from methyl, ethyl, propyl and C 3-4 cycloalkyl, and the methyl, ethyl, propyl and C 3-4 cycloalkyl are any is optionally substituted by 1, 2, 3 and 4 Rc , other variables are as defined herein.
• the above-mentioned C 3-4 cycloalkyl is selected from cyclopropyl and cyclobutyl, and the cyclopropyl and cyclobutyl are optionally substituted by 1, 2, 3 and 4 R , other variables are as defined in the present invention.
• R 41 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, The methyl, ethyl, propyl, cyclopropyl, cyclobutyl, Optionally substituted with 1, 2, 3 and 4 Rc , other variables are as defined herein.
• R 41 is selected from cyclopropyl and cyclobutyl, and other variables are as defined in the present invention.
• R c is hydrogen, and other variables are as defined in the present invention.
• R 41 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, Other variables are as defined herein.
• R 42 is selected from hydrogen, and other variables are as defined in the present invention.
• the above-mentioned R is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and any of the methyl, ethyl, propyl, cyclopropyl and cyclobutyl is optionally substituted by 1, 2, 3 and 4 Rc , other variables are as defined herein.
• R 43 is selected from cyclopropyl, and other variables are as defined in the present invention.
• R 5 is selected from hydrogen, methyl and ethyl, and other variables are as defined in the present invention.
• R 5 is selected from hydrogen, and other variables are as defined in the present invention.
• R 5 is selected from methyl, and other variables are as defined in the present invention.
• the above R 6 is selected from methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH 3 , -NHCH 2 CH 3 , - NH-cyclopropyl and -NH-cyclobutyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -NHCH 3 , -NHCH 2 CH 3 , -NH-cyclopropyl and -NH-cyclobutyl are optionally substituted with 1, 2, 3 or 4 R d , other variables are as defined herein.
• R is selected from methyl, ethyl, -NHCH and cyclopropyl, and the methyl, ethyl, -NHCH and cyclopropyl are optionally replaced by 1 , 2, 3 or 4 Rd substitutions, other variables are as defined herein.
• R 6 is selected from methyl, ethyl and -NHCH 3 , and the methyl, ethyl and -NHCH 3 are optionally substituted by 1, 2, 3 or 4 R d , Other variables are as defined herein.
• R d is selected from hydrogen, and other variables are as defined in the present invention.
• R d is selected from deuterium, and other variables are as defined in the present invention.
• R d is selected from methoxy, and other variables are as defined in the present invention.
• the above-mentioned R 6 is selected from -CH 2 CD 3 , -CH 2 CH 3 , -NHCD 3 , -CH 3 , -CH 3 and cyclopropyl, and other variables are as described in the present invention definition.
• the above-mentioned R 6 is selected from -CH 2 CD 3 , -CH 2 CH 3 , -NHCD 3 and -CH 3 , and other variables are as defined in the present invention.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 and n are as defined in the present invention.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 and n are as defined in the present invention.
• R 1 , R 2 , R 3 , R 4 , R 5 , X 1 and n are as defined in the present invention.
• the above compounds are selected from the group consisting of,
• the present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Tyk2 JH2-related diseases.
• the present invention also provides a method for treating a disease related to Tyk2 JH2 in a subject in need, comprising providing the subject with an effective dose of the compound defined in any of the above technical schemes or a pharmaceutically acceptable salt thereof.
• the compound of the present invention has strong Tyk2 pseudokinase region (Tyk2 JH2) inhibitory activity.
• pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
• base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
• acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
• Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
• such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
• the compounds of the invention may exist in particular geometric or stereoisomeric forms.
• the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
• Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
• enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
• cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
• diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
• keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key and straight dashed keys
• tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
• proton tautomers also called prototropic tautomers
• prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
• Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
• keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
• the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
• the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
• the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
• Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
• a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
• the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
• compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
• radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
• heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
• the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
• deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
• the term “D” or “2H” refers to another stable form of hydrogen , the isotope “deuterium”, also known as deuterium.
• substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
• any variable eg, R
• its definition is independent at each occurrence.
• said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
• substituents and/or variations thereof are permissible 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.
• substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
• 6-membered heteroaryl ring and “6-membered heteroaryl” are used interchangeably, and the term “6-membered heteroaryl” means a single ring consisting of 6 ring atoms with a conjugated ⁇ -electron system A group whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2). A 6-membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
• the 6-membered heteroaryl group examples include but are not limited to pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
• C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
• the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (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), and the like.
• C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
• the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
• Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
• 4-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings.
• a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
• the 4-6-membered heterocycloalkyl group includes 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like.
• 4-6 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.), 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, isothiazolidin,
• 5-10 membered heteroaryl ring and “5-10 membered heteroaryl” can be used interchangeably in the present invention, and the term “5-10 membered heteroaryl” means that there are 5 to 10 rings
• the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
• the 5-10 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
• the 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5-membered and 6-membered heteroaryl groups and the like.
• Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, 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
• the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
• the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
• the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
• Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, 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.
• C 3-8 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 8 carbon atoms, which includes monocyclic and bicyclic systems, wherein bicyclic systems include spiro rings, fused rings and bridge ring.
• the C 3-8 cycloalkyl group includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl group, etc.; Can be monovalent, divalent or multivalent.
• Examples of C 3-8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
• C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed 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 may be monovalent, divalent or multivalent.
• Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• C 3-4 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 4 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 and C 4 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
• Examples of C 3-4 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl.
• the term "leaving group” refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
• representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
• protecting group includes, but is not limited to, "amino protecting group", “hydroxyl protecting group” or “mercapto protecting group”.
• amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
• Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
• acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
• hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxy group.
• Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
• alkyl groups such as methyl, ethyl, and tert-butyl
• acyl groups such as alkanoyl (such as acetyl)
• arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (P
• 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, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
• the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves 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 (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
• SXRD single crystal X-ray diffraction
• the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
• the light source is CuK ⁇ radiation
• the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
• methylmagnesium bromide (3M, ether solution, 36.87mL) was added to a solution of compound 1-2 (13g, 55.30mmol) in tetrahydrofuran (130mL), and stirred at 0°C for 2 hours.
• the reaction solution was quenched with saturated ammonium chloride aqueous solution (60 mL), diluted with water (100 mL), then extracted with ethyl acetate (100 mL ⁇ 2), and the combined organic phases were washed with brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate,
• the crude product was obtained by filtration and concentrated under reduced pressure.
• Dissolve compound 1-9 (2g, 10.34mmol) in dioxane (40mL), add dimethylsulfinimide (1.01g, 10.86mmol), cesium carbonate (6.74g, 20.68mmol), three (Dibenzylideneacetone)dipalladium (946.85mg, 1.03mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.20g, 2.07mmol), nitrogen replacement three times Afterwards, the temperature was raised to 110° C., and stirred for 4 hours under the protection of nitrogen.
• compound 2-1 (1g, 6.41mmol) was dissolved in phosphorus oxychloride (5mL), triethylamine (648.25mg, 6.41mmol, 891.68 ⁇ L) was added, and the mixture was stirred at 110°C for 120 minutes .
• the reaction solution was directly concentrated under reduced pressure, then diluted by adding 1,2-dichloroethane (40 mL) and concentrated under reduced pressure again to obtain crude product 2-2, which was directly used in the next reaction.
• compound 2-2 (1.35g, 6.38mmol) was dissolved in tetrahydrofuran (15mL), and deuterated methylamine hydrochloride (225.19mg, 3.19mmol) and N,N-diisopropylethyl Amine (2.48g, 19.15mmol, 3.34mL), the mixture was stirred at 20°C for 16 hours.
• compound 2-3 55.06 mg, 263.38 ⁇ mol
• compound 1-12 70 mg, 239.43 ⁇ mol
• tetrahydrofuran 3 mL
• lithium methyldisilazide 1M, 718.30 ⁇ L
• Aqueous ammonium chloride solution 10 mL was added to the reaction solution at 0° C. to quench, diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic phases were washed with saturated brine (5 mL ⁇ 2).
• reaction solution was quenched with saturated aqueous ammonium chloride (10 mL) in an ice-water bath, diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic phases were washed with saturated brine (5 mL ⁇ 2 ), and finally the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
• the crude product was stirred with ethyl acetate (2 mL) at 20° C. for 0.5 hour, filtered and dried to obtain compound 3-4.
• the reaction solution was diluted with dichloromethane (50 mL), extracted with water (5 mL ⁇ 3), the organic phase was washed with saturated brine (5 mL ⁇ 3), and finally the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Crude.
• compound 1-11 (318.72 mg, 1.22 mmol) was added to a solution of compound 8-6 (290 mg, 1.16 mmol) in dioxane (8 mL), mixed well, and potassium phosphonate (494.21 mg, 2.33mmol) in water (2mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (85.18mg, 116.41 ⁇ mol), stirred at 100°C for 2 hours.
• compound 1-8 (82.24 mg, 316.60 ⁇ mol), cesium carbonate (187.55 mg, 575.64 ⁇ mol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (35.84mg, 57.56 ⁇ mol) and tris(dibenzylideneacetone)dipalladium (26.36mg, 28.78 ⁇ mol), 110°C Stirring was continued for 3 hours.
• high performance liquid chromatography column chromatography
• the crude product was prepared and separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%-70%, 9min), to obtain compound 14 .
• reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with brine (5 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
• the crude product was prepared and separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 37%-67%, 9min) to obtain compound 15 .
• MS m/z 513[M+H] + ;
• isopropylmagnesium chloride (2M, 8.81mL) was added dropwise to a solution of compound 17-1 (2g, 8.81mmol) in tetrahydrofuran (10mL), and after stirring at -65°C for 1 hour, compound was added dropwise 17-2 (1.6 g, 12.02 mmol) was dissolved in tetrahydrofuran (5 mL). The mixture was stirred at 20° C. for 2 hours. TLC showed that the starting material was completely reacted.
• reaction solution was quenched with saturated ammonium chloride solution (10mL), diluted with water (10mL), extracted with ethyl acetate (20mL ⁇ 3), the organic phases were combined, washed with saturated brine (5mL ⁇ 3), anhydrous sodium sulfate Dry, filter and concentrate under reduced pressure to give the crude product.
• reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), the combined organic phases were washed with saturated brine (5 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
• the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated brine (5 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
• the crude product was purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 29%-59%, 10min) to obtain compound 17.
• compound 1-12 120 mg, 410.46 ⁇ mol
• cesium carbonate (267.47mg, 820.922 ⁇ mmol)
• tris(dibenzylideneacetone)dipalladium 48.19mg, 52.62 ⁇ mol
• (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl 25.56mg , 41.05 ⁇ mol
• high performance liquid chromatography column chromatography (column: Waters Xbridge 150*25mm* 5 ⁇ m; mobile phase: [water (ammonia, 0.05% v/v)-acetonitrile]; acetonitrile %: 22%-52%, 9 min) to obtain compound 18.
• high performance liquid chromatography column chromatography (column: Waters Xbridge 150*25mm* 5 ⁇ m; mobile phase: [water (ammonia, 0.05% v/v)-acetonitrile]; acetonitrile %: 27%-57%, 9 min) to obtain compound 19.
• high performance liquid chromatography Column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (ammonia water, 0.05% v/v)-acetonitrile]; acetonitrile%: 23%-53%, 9min
• the reaction solution was diluted with water (20 mL) and ethyl acetate (20 mL ⁇ 3) was added to obtain the organic phase, which was washed with brine (10 mL ⁇ 2) and dried over anhydrous sodium sulfate.
• the crude product was prepared and separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 34%-64%, 8min), to obtain compound 23 .
• Dissolve 1-7 (1 g, 4.83 mmol), 1-12 (1.27 g, 4.35 mmol) in isopropanol (15 mL), add 0.3 mL of concentrated hydrochloric acid, and stir at 70°C for 16 hours.
• the reaction solution was filtered, and the filter cake was collected and washed with isopropanol to obtain a crude product.
• Step 1 Synthesis of compound 25 24-1 (100 mg, 216.00 ⁇ mol), nicotinamide (52.76 mg, 432.00, ⁇ mol), cesium carbonate (140.75 mg, 432.00 ⁇ mol), 2,2-bis(diphenylphosphino) -1,1-binaphthalene (25.00 mg, 43.20 ⁇ mol) and tris(dibenzylideneacetone) dipalladium chloroform complex (19.78 mg, 21.60 ⁇ mol) in dioxane (1.5mL) were replaced with nitrogen three times, 110 Stir at °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product.
• the crude product was prepared and separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 41%-71%, 8min), to obtain compound 27 .
• the crude product was prepared and separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 26%-56%, 8min.), to obtain the compound 28.
• the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), the combined organic phases were washed with brine (5 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
• the reaction solution was diluted with water (15 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phase was washed with water (20 mL ⁇ 3) and saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and reduced Concentrate under reduced pressure to obtain the crude product.
• the crude product was prepared and separated by high performance liquid chromatography (column: Waters Xbrigde C18 150*50mm*10 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%-70%, 10min), to obtain the compound 32.
• the reaction solution was diluted with water (10mL), extracted with ethyl acetate (20mL ⁇ 3), and the organic phases were combined and washed with brine (5mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
• the crude product was prepared and separated by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 45%-75%, 8min), to obtain compound 33 .
• reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), the combined organic phases were washed with brine (5 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
• the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), the combined organic phases were washed with brine (5 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
• hPBMC Human peripheral blood mononuclear cells
• the Balb/c mice After the Balb/c mice arrive at the facility, they will undergo at least 3 days of adaptation/quarantine. After the adaptation/quarantine is over, the veterinarian or designated personnel will check the health status of the Balb/c mice to assess whether the animals are suitable for experimental research. All Balb/c mice were fasted overnight before dosing, and fed again 4 hours after dosing. In the experiment, the candidate compound was formulated into a homogeneous solution, and given to Balb/c mice for single intravenous injection and oral administration.
• the vehicle for intravenous injection is a clear solution of 80% polyethylene glycol 400/20% water
• the animals were weighed before administration, and the administration volume was calculated according to the body weight.
• Whole blood samples were collected within 24 hours by jugular vein puncture, and all blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, put it in dry ice quickly, and then store it at -60°C or lower for LC-MS/MS analysis.
• WinNonlin software package Version 6.3 and above
• the PK parameters include (if the data permits) but are not limited to the peak concentration (Cmax), Peak time (Tmax), elimination half-life (T1/2), area under the plasma concentration-time curve (AUC), mean residence time (MRT), bioavailability, etc.
• Cmax peak concentration
• Tmax Peak time
• T1/2 elimination half-life
• AUC area under the plasma concentration-time curve
• MRT mean residence time
• bioavailability bioavailability
• Vd volume of distribution
• Cl clearance rate
• T 1/2 half-life
• AUC exposure (area under the curve)
• C max maximum concentration
• T max time to peak concentration
• F% bioavailability
• IV intravenous
• PO oral
• the compound of the present invention shows excellent pharmacokinetic properties, low clearance rate and high oral bioavailability.

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