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WO2023011359A1 - 桥环类化合物及其应用 - Google Patents

桥环类化合物及其应用 Download PDF

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Publication number
WO2023011359A1
WO2023011359A1 PCT/CN2022/109073 CN2022109073W WO2023011359A1 WO 2023011359 A1 WO2023011359 A1 WO 2023011359A1 CN 2022109073 W CN2022109073 W CN 2022109073W WO 2023011359 A1 WO2023011359 A1 WO 2023011359A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkyl
present
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PCT/CN2022/109073
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English (en)
French (fr)
Inventor
毛魏魏
余柱
韦昌青
钱文远
胡世尘
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 WO2023011359A1 publication Critical patent/WO2023011359A1/zh

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

  • the invention relates to a bridged ring compound and its application in the preparation of medicines for treating related diseases. It specifically relates to the compound represented by formula (I) and its pharmaceutically acceptable salt.
  • IBD Inflammatory bowel disease
  • CD Crohn's disease
  • UC ulcerative colitis
  • Common symptoms include diarrhea, bloody stools, and abdominal pain.
  • the clinical course proceeds in intermittent, alternating cycles of exacerbations and remissions, and patients with ulcerative colitis are at increased risk of developing colorectal cancer (Dennis et al. N Engl J Med, 2011, 365, 1713-1725).
  • Excessive inflammatory responses in the gastrointestinal tract are mediated by inflammatory cytokines such as TNF ⁇ , IFN- ⁇ , IL-1, IL-6, IL-12, IL-21, and IL-23, and are Cells of the adaptive immune system play a role, including T and B lymphocytes, epithelial cells, macrophages and dendritic cells (Neurath, M.F. Nat. Rev. Immunol. 2014, 14, 329).
  • the Janus kinase (JAK) family: JAK1, JAK2, JAK3 and Tyk2 are non-receptor tyrosine kinases that play a key role in the transduction response of many of the above-mentioned cytokines.
  • cytokines Upon ligation of cytokines to receptors, associated JAK homo- or heterodimers are phosphorylated and activated, resulting in subsequent recruitment, phosphorylation, and activation of signal transducers and activators of transcription (STAT) family transcription factors .
  • STAT signal transducers and activators of transcription
  • pSTATs Phosphorylated STATs translocate to the nucleus and induce gene transcription of several chemokines, cytokines, and proteases associated with IBD pathogenesis.
  • AEs adverse events
  • Common systemic adverse events (AEs) in phase 2 and phase 3 clinical trials of tovacitinib in IBD include decreased hemoglobin, decreased absolute neutrophil count (ANC), increased total cholesterol (low-density and high-density lipids), and Infection (Sandborn, W.J. et al., N. Engl. J.
  • JAK1-selective inhibitors such as filgotinib and upadacitinib
  • filgotinib and upadacitinib are currently being used in phase 3 clinical trials in CD and UC.
  • upadacitinib dose 15 mg twice daily for rheumatoid arthritis also has a boxed warning from the FDA about the risk of thrombosis (Upadacitinib Instructions).
  • Another approach is to maximize gut tissue exposure of JAK inhibitors while avoiding possible systemic exposure.
  • JAK inhibitors may have adverse systemic immunosuppressive effects due to the modulatory effects of the JAK/STAT pathway on the immune system. There is thus a need to provide new JAK inhibitors that have their effects at the focal site without significant systemic effects. Specifically, it has advantages in the treatment of gastrointestinal inflammatory diseases, such as UC and CD.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is R 11 ,
  • D 1 is O or CH 2 ;
  • T1 is N or CH
  • R 11 is H, CN or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 2 is H or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
  • R 4 is H or C 1-3 alkyl
  • E 1 and E 2 are independently O or NH;
  • E 3 is CH 2 or O
  • R 31 , R 32 and R 34 are independently C 1-3 alkyl
  • R 33 is H or C 1-3 alkyl
  • q 1 or 2;
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • r 0, 1 or 2;
  • R a and R b are each independently F, Cl, Br, I, OH, CN or NH 2 .
  • R 11 is H, CN or CH 3 , wherein the CH 3 is optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
  • R 11 is H, CN or CF 3 , and other variables are as defined in the present invention.
  • R 1 is H, CN, CF 3 , Other variables are as defined herein.
  • R 2 is H or which stated Optionally substituted with 1, 2 or 3 R b , other variables are as defined herein.
  • R 2 is H, -CH 2 CH 3 or Other variables are as defined herein.
  • R 31 , R 32 and R 34 are each independently CH 3 or -CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 33 is H or CH 3 , and other variables are as defined in the present invention.
  • R 4 is H, CH 3 , CH 2 CH 3 or CH 2 CH 2 CH 3 , and other variables are as defined in the present invention.
  • L 1 , R 1 , R 2 , R 31 , R 32 , R 34 and R 4 are as defined in the present invention.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating intestinal pan-JAK-related diseases.
  • the above-mentioned intestinal pan-JAK-related disease is inflammatory bowel disease.
  • the compound of the present invention exhibits good inhibitory properties in the in vitro activity test of the four subtypes of kinases JAK1, JAK2, JAK3 and TYK2.
  • 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.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting 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
  • the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2).
  • the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of both formula (B-1) and formula (B-2) It exists as a mixture of isomers.
  • the following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2). It exists in the form of a mixture.
  • 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.
  • "Optional" or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with 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 of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • 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.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • 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 n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • 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, in 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 solvent used in the present invention is commercially available.
  • the following abbreviations are used in the present invention: aq stands for water; THF stands for tetrahydrofuran; n-Bu 4 NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; DIEA stands for N,N-diisopropyl CbzCl represents benzyl chloroformate; Xantphos represents 4,5-bisdiphenylphosphine-9,9-dimethylxanthene.
  • Step 1 Dissolve compound 1-1 (12g, 57.69mmol) in acetonitrile (120mL) at 25°C, add tert-butyloxycarbonyl carbonate (16.37g, 75.00mmol, 17.23mL) and potassium phosphate (23.27 g, 109.61 mmol), stirred at 85°C for 2 hours. Further t-butyloxycarbonyl carbonate (2.52 g, 11.54 mmol, 2.65 mL) was added, and stirred at 85° C. for 16 hours. LC-MS showed that the starting material was consumed and the main peak was the product peak. The reaction solution was filtered, and the filter cake was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 1-2. MS ESI calcd: C 10 H 11 Cl 2 N 3 O 4 [M+H] + 308, found 308.
  • Step 2 Dissolve compound 1-2 ((10.3g, 33.43mmol)) in i-PrOH (120mL), add 1-3 (7.94g, 35.10mmol) and DIEA (12.74g, 98.56mmol, 17.17mL) , and the mixture was stirred at 50 °C for 16 hours. TLC showed starting material was consumed. The reaction solution was poured into 300 mL of water, filtered, and concentrated under reduced pressure to obtain compound 1-4.
  • Step 4 Dissolve compound 1-5 (15g, 32.05mmol) in 75mL of trimethyl orthoformate, add 4-methylbenzenesulfonic acid (600mg, 3.48mmol), and stir at 90°C for 2h.
  • LC-MS showed that the starting material was consumed and the main peak was the product peak.
  • the reaction solution was diluted with 200 mL of water and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 1-6.
  • MS ESI calcd. for C23H32ClN5O4 [M+H] + 478 , found 478 .
  • Step 5 Compound 1-6 (16g, 33.47mmol) was dissolved in methanolic hydrochloric acid solution (4M, 48mL), and stirred at 40°C for 2 hours. LCMS showed that the reaction of the raw materials was basically complete, and the main peak was the product peak. The reaction solution was directly concentrated to obtain the crude hydrochloride of compound 1-7. MS ESI calcd. for C13H16ClN5 [M+H] + 278 , found 278 .
  • Step 6 The crude hydrochloride (15g, 47.74mmol) of 1-7 was dissolved in methanol (150mL), DIEA (37.10g, 287.06mmol, 50.00mL) was added, the mixture was stirred at 25°C for 10 minutes, and then the compound was added 1-8 (6.19g, 116.65mmol, 7.74mL), stirred at 25°C for 16 hours.
  • LC-MS showed that the starting material was consumed and the main peak was the product peak.
  • the reaction solution was concentrated to remove methanol, then diluted with 100 mL of water, adjusted to pH 8 by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 7 Dissolve copper bromide (2.55g, 11.42mmol, 534.58 ⁇ L) in acetonitrile (20mL), slowly add tert-butyl nitrite (1.42g, 13.82mmol, 1.64mL), and stir at 25°C for 15 minutes. Cool down to 0°C, then add 1-9 (3g, 9.07mmol), stir at 0°C for 0.5 hours, and stir at 50°C for 32 hours. TLC showed starting material was consumed.
  • reaction solution was quenched with 100 mL of saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL ⁇ 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
  • MS ESI calcd: C 16 H 17 BrClN 5 [M+1] + 394, found 394.
  • Step 8 Dissolve compound 1-10 (100mg, 253.36 ⁇ mol) in dioxane (1mL), add 1-11 (30mg, 322.1 ⁇ mol), cesium carbonate (250mg, 767.3 ⁇ mol), Xantphos (20mg, 34.6 ⁇ mol) and tris(dibenzylideneacetone)dipalladium (40.00mg, 43.68 ⁇ mol), stirred at 100°C for 16 hours.
  • LC-MS showed that the starting material was completely consumed, and the main peak was the product peak.
  • Step 9 Dissolve compound 1-12 (100 mg, 245.7 ⁇ mol) and compound 1-13 (60 mg, 304.2 ⁇ mol) in dioxane (2 mL), add cesium carbonate (200 mg, 613.8 ⁇ mol) and methanesulfonic acid ( 2-Dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl ) Palladium (II) (25 mg, 27.6 ⁇ mol), replaced with nitrogen three times, then heated up to 100° C., and stirred for 16 hours under nitrogen protection.
  • cesium carbonate 200 mg, 613.8 ⁇ mol
  • methanesulfonic acid 2-Dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-bipheny
  • Step 10 Dissolve compound 1-14 (140 mg, 246.6 ⁇ mol) in dichloromethane (2 mL), add trifluoroacetic acid (2.16 g, 18.9 mmol, 1.4 mL), and stir at 25° C. for 30 minutes.
  • LC-MS showed that the starting material was consumed and the main peak was the product peak.
  • the reaction solution was directly concentrated to obtain the crude product, which was prepared and separated by high performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% TFA)-acetonitrile]; acetonitrile%: 1%-30% , 10 minutes) to obtain compound 1-15.
  • Step 1 Dissolve copper chloride (1.77g, 13.15mmol) in acetonitrile (30mL), slowly add tert-butyl nitrite (1.35g, 13.12mmol, 1.56mL), and stir at 25°C for 15 minutes. Cool down to 0°C, then add 1-9 (2.9g, 8.77mmol), stir at 0°C for 0.5 hour, and stir at 50°C for 32 hours.
  • LC-MS showed a small amount of starting material remaining, but the main peak was the product peak.
  • Step 2 Dissolve 2-1 (400mg, 1.14mmol) in n-butanol (4mL), add sodium methylthiolate (80mg, 1.14mmol, 72.73 ⁇ L), and stir at 60°C for 16 hours.
  • LC-MS showed that the starting material was consumed and the main peak was the product peak.
  • Step 3 Dissolve compound 2-2 (250mg, 690.81 ⁇ mol) in methanol (5mL), add diacetoxyiodobenzene (900mg, 2.79mmol), and ammonium carbamate (320mg, 4.10mmol), and the reaction solution is 25°C Stirring was uncovered for 2 hours.
  • LC-MS showed that the starting material was completely consumed, and the main peak was the product peak.
  • the reaction solution was diluted with 20 mL of water, and then extracted with dichloromethane (15 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
  • Step 4 Dissolve compound 2-3 (120mg, 305.4 ⁇ mol) and compound 1-13 (72mg, 365.1 ⁇ mol) in dioxane (2mL), add cesium carbonate (360mg, 1.1mmol) and methanesulfonic acid ( 2-Dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl ) Palladium (II) (36 mg, 39.7 ⁇ mol), replaced with nitrogen three times, then heated to 100° C., and stirred for 16 hours under the protection of nitrogen.
  • cesium carbonate 360mg, 1.1mmol
  • methanesulfonic acid 2-Dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-
  • Step 1 Dissolve compound 3-1 (1 g, 9.69 mmol, 917.4 ⁇ L) in aqueous sodium hydroxide solution (10 mL), add CbzCl (2.40 g, 14.1 mmol, 2 mL) at zero temperature, and stir at 25° C. for 16 hours. After the reaction was completed, the pH was adjusted to 7 with 1M HCl, and then extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain compound 3-2.
  • Step 4 Dissolve compound 3-4 (1.3g, 4.19mmol) in methanol (20mL), add wet palladium carbon (130mg, 10%) successively under the protection of nitrogen, replace with hydrogen three times, and the reaction solution is kept under the protection of hydrogen for 25 °C and stirred for 12 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to obtain compound 3-5.
  • Step 5 Dissolve compound 1-10 (100mg, 253.4 ⁇ mol) in dioxane (2mL), add 3-5 (60mg, 340.5 ⁇ mol), cesium carbonate (200mg, 613.8 ⁇ mol), Xantphos (20mg, 34.6 ⁇ mol) and Pd 2 (dba) 3 (20mg, 21.8 ⁇ mol), stirred at 100°C for 16 hours.
  • LC-MS showed that the starting material was completely consumed, and the main peak was the product peak.
  • MS ESI calcd: C 22 H 28 ClN 7 O 2 S [M+H] + 490, found 490.
  • Step 6 Dissolve compound 3-6 (200mg, 408.2 ⁇ mol) and compound 1-13 (100mg, 507.0 ⁇ mol) in dioxane (2mL), add cesium carbonate (400mg, 1.2mmol) and methanesulfonic acid ( 2-Dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl ) Palladium (II) (50 mg, 55.2 ⁇ mol), replaced with nitrogen three times, then heated to 100° C., and stirred for 16 hours under nitrogen protection.
  • cesium carbonate 400mg, 1.2mmol
  • methanesulfonic acid 2-Dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-y
  • Step 7 Dissolve compound 3-7 (150 mg, 272.4 ⁇ mol) in a mixed solution of methanol (1 mL) and tetrahydrofuran (1 mL), add potassium carbonate (200 mg, 1.5 mmol), and stir at 25° C. for 16 hours. After the reaction was completed, the reaction solution was diluted with 20 mL of water, and then extracted with dichloromethane (20 mL ⁇ 3). The organic phases were combined, 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: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% TFA)-ACN]; B(ACN)%: 5%-35%, 10 minutes) to obtain 3-8.
  • JAK1 Invitrogen, Cat. No. PV4288
  • JAK2 Invitrogen, Cat. No. PV4288
  • JAK3 Invitrogen, Cat. No. PV4080
  • TYK2 Invitrogen, Cat. No. PR8440C
  • ATP Sigma, Cat. No. A7699-1G
  • DMSO Sigma, Cat. No. D2650
  • DTT Sigma, Cat. No. 43815
  • 384-well plate_assay plate Perkin Elmer, Cat. No. 6007299
  • LANCE Ultra ULight TM -JAK-1 peptide Perkin Elmer, Cat. No. TRF0121
  • LANCE Eu-W1024 anti-phosphotyrosine Acid PT66
  • TM Assay Buffer Perkin Elmer, Cat. No. CR97-100).
  • JAK1,2,3 and TYK2 used in this experiment method for activity detection.
  • the enzyme, ULight-labeled peptide substrate, ATP, and detection compound are mixed and the reaction is incubated.
  • EDTA was added to terminate the reaction, and at the same time, Eu-labeled antibody was added.
  • kinase assays the binding of europium-labeled anti-phosphorylated substrate antibodies to phosphorylated ULight-labeled substrates brings donor and acceptor molecules into mutual proximity. After irradiation with 320nm wavelength light, the kinase reacts, and the energy of the europium donor will be transferred to the ULight acceptor dye to generate light with a wavelength of 665nm. The intensity of light emission is proportional to the phosphorylation level of the ULight substrate.
  • the final test concentration of the compound is from 1 ⁇ M to 0.017nM, 3-fold serial dilution, 11 concentrations.
  • the final test concentration of the reference compound Tofacitinib ranged from 1 ⁇ M to 0.017nM, 3-fold serial dilution, 11 concentrations.
  • the content of DMSO in the assay reaction was 1%.
  • the buffer includes: 50mM HEPES (pH 7.5), 0.01% Brij-35, 10mM MgCl 2 , 1mM EDTA, 1mM DTT.
  • 4nM TYK2 and 50nM substrate were mixed with pre-diluted compounds at different concentrations for 15 minutes. Add 15 ⁇ M ATP to start the reaction and incubate at room temperature for 90 minutes. After the reaction was completed, antibody detection was added, and after incubation at room temperature for 60 minutes, Evnvision detection was performed to collect data.
  • XLfit5 software mode205 was used for data analysis and plotting to obtain the IC 50 data in the following table.
  • the compound of the present invention exhibits good inhibitory activity in the in vitro activity test of the two kinase subtypes JAK1 and JAK2.

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Abstract

一种桥环类化合物及其在制备治疗相关疾病的药物中的应用。具体公开了式(Ⅰ)所示化合物及其药学上可接受的盐。

Description

桥环类化合物及其应用
本申请主张如下优先权
CN2021108979689，申请日：2021.08.05。
技术领域
本发明涉及一种桥环类化合物及其在制备治疗相关疾病的药物中的应用。具体涉及式(Ⅰ)所示化合物及其药学上可接受的盐。
背景技术
炎症性肠病(IBD)是一种病因未明的肠道炎症疾病，包括克罗恩病(CD)和溃疡性结肠炎(UC)，其特征是直肠和大肠的粘膜层的发炎和溃疡。常见症状包含腹泻、血便和腹痛。临床过程为间断的、恶化和缓解的交替周期而进行，且患有溃疡性结肠炎的患者罹患结直肠癌的风险增加(丹尼斯等人N Engl J Med,2011,365,1713-1725)。胃肠道的过度炎症反应是由炎性细胞因子(如TNFα、IFN-γ、IL-1、IL-6、IL-12、IL-21和IL-23)介导的，且对先天性和适应性免疫系统的细胞发挥作用，包括T和B淋巴细胞、上皮细胞、巨噬细胞和树突状细胞(Neurath,M.F.Nat.Rev.Immunol.2014,14,329)。Janus激酶(JAK)家族：JAK1、JAK2、JAK3和Tyk2，是非受体酪氨酸激酶，在许多上述的细胞因子的传导反应中起关键作用。当细胞因子与受体连接后，相关的JAK同源或异二聚体被磷酸化和激活，从而使随后的募集、磷酸化，以及信号转导和转录激活因子(STAT)家族转录因子的激活。磷酸化STATs(pSTATs)转运到细胞核并诱导与IBD发病相关的几种趋化因子、细胞因子和蛋白酶的基因转录。
IBD患者的遗传学研究发现，与JAK/STAT途径相关的几种蛋白质(如IL-23R、IL-12B、JAK2、Tyk2和STAT3)的多态性是IBD形成的危险因素。它为治疗IBD引起的过度炎症反应提供了一个有吸引力的靶点(Boland,B.S.等人，Gastroenterology clinics of North America 2014,43,603)。目前有几种JAK抑制剂，如托伐替尼(Tofacitinib)和非戈替尼(Filgotinib)正在IBD的临床开发中。托伐替尼在美国被批准用于治疗类风湿关节炎(RA)和UC。托伐替尼也在CD的临床开发中，由于中、重度CD患者在临床二期的4周临床试验中未能取得显著的疗效，该适应症的进一步试验被迫中止，尽管有基于生物标记物分析的靶点参与的确凿证据，但目前尚不清楚托伐替尼的疗效是否与临床研究设计，UC和CD之间的机制差异，或阻止药物充分暴露于肠道组织的剂量限制性全身不良事件(AE)有关。托伐替尼治疗IBD 2期和3期临床试验常见的系统性不良事件(AE)包括血红蛋白下降、中性粒细胞绝对计数(ANC)下降、总胆固醇(低密度和高密度脂)升高和感染(Sandborn,W.J.等人，N.Engl.J.Med.2012,367,616)。此类AE与类风湿关节炎患者服用托伐替尼后观察到的情况一致，并与EPO、TPO的JAK2依赖性抑制一致。根据托伐替尼上市后安全性试验的结果，使用托伐替尼10mg，每日两次给药，会增加血栓和死亡的风险，FDA对托伐替尼提出了黑框警告。
有几种可能的方法可以克服JAK抑制引起的系统性AE。其中一种方法是开发口服的JAK1选择性抑制剂，如非戈替尼和乌帕替尼(Upadacitinib)，目前正在CD和UC的第3阶段临床试验中使用这种方法。尽管JAK1选择性分子具有理论上的安全优势，最近批准的每日两次剂量为15毫克的乌帕替尼治疗类风湿关节炎也有来自FDA关于血栓形成风险的黑框警告(Upadacitinib使用说明书)。另一种方法是以最大限度地增加JAK抑制剂的肠道组织暴露，同时避免可能导致全身暴露。由于JAK/STAT通路对免疫系统的调节作用，全身性暴露于JAK抑制剂可能具有不利的全身免疫抑制作用。因而需要提供新的JAK抑制剂，其在病灶部位处具有其作用，同时无显著全身作用。具体来说，对治疗胃肠发炎性疾病，如UC和CD具有优势。
发明内容
本发明提供了式(Ⅰ)化合物或其药学上可接受的盐，
Figure PCTCN2022109073-appb-000001
其中，
L 1为-(CH 2) m-、-C(＝O)-或-CH 2-C(＝O)-；
R 1为R 11、
Figure PCTCN2022109073-appb-000002
D 1为O或CH 2；
T 1为N或CH；
R 11为H、CN或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
R 2为H或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
R 3为
Figure PCTCN2022109073-appb-000003
R 4为H或C 1-3烷基；
E 1和E 2分别独立地为O或NH；
E 3为CH 2或O；
R 31、R 32和R 34分别独立地为C 1-3烷基；
R 33为H或C 1-3烷基；
q为1或2；
m为0、1或2；
n为0、1或2；
r为0、1或2；
R a和R b分别独立地为F、Cl、Br、I、OH、CN或NH 2。
本发明的一些方案中，上述R 11为H、CN或CH 3，其中所述CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 11为H、CN或CF 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 1为H、CN、CF 3、
Figure PCTCN2022109073-appb-000004
其他变量如本发明所定义。
本发明的一些方案中，上述R 2为H或
Figure PCTCN2022109073-appb-000005
其中所述
Figure PCTCN2022109073-appb-000006
任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 2为H、-CH 2CH 3或
Figure PCTCN2022109073-appb-000007
其他变量如本发明所定义。
本发明的一些方案中，上述R 31、R 32和R 34分别独立地为CH 3或-CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 33为H或CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 3为
Figure PCTCN2022109073-appb-000008
Figure PCTCN2022109073-appb-000009
其他变量如本发明所定义。
本发明的一些方案中，上述R 3为
Figure PCTCN2022109073-appb-000010
Figure PCTCN2022109073-appb-000011
其他变量如本发明所定义。
本发明的一些方案中，上述R 4为H、CH 3、CH 2CH 3或CH 2CH 2CH 3，其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明的一些方案中，上述的化合物或其药学上可接受的盐，其化合物为
Figure PCTCN2022109073-appb-000012
其中，
L 1、R 1、R 2、R 31、R 32、R 34和R 4如本发明所定义。
本发明还提供了下式化合物或其药学上可接受的盐，
Figure PCTCN2022109073-appb-000013
Figure PCTCN2022109073-appb-000014
本发明提供了上述化合物或其药学上可接受的盐在制备治疗与肠道的pan-JAK相关疾病的药物中的应用。
在本发明的一些技术方案中，上述与肠道的pan-JAK相关疾病为炎症性肠病。
技术效果
本发明的化合物在激酶4个亚型JAK1、JAK2、JAK3和TYK2的体外活性测试中展现了良好的抑制性。
定义和说明
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。
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。
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。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在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。
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。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022109073-appb-000015
和楔形虚线键
Figure PCTCN2022109073-appb-000016
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022109073-appb-000017
和直形虚线键
Figure PCTCN2022109073-appb-000018
表示立体中心的相对构型，用波浪线
Figure PCTCN2022109073-appb-000019
表示楔形实线键
Figure PCTCN2022109073-appb-000020
或楔形虚线键
Figure PCTCN2022109073-appb-000021
或用波浪线
Figure PCTCN2022109073-appb-000022
表示直形实线键
Figure PCTCN2022109073-appb-000023
和直形虚线键
Figure PCTCN2022109073-appb-000024
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2022109073-appb-000025
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2022109073-appb-000026
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
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。“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。
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，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。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。
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。
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。
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。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022109073-appb-000027
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022109073-appb-000028
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022109073-appb-000029
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
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
Figure PCTCN2022109073-appb-000030
直形虚线键
Figure PCTCN2022109073-appb-000031
或波浪线
Figure PCTCN2022109073-appb-000032
表示。例如-OCH 3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；
Figure PCTCN2022109073-appb-000033
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；
Figure PCTCN2022109073-appb-000034
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；
Figure PCTCN2022109073-appb-000035
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
Figure PCTCN2022109073-appb-000036
Figure PCTCN2022109073-appb-000037
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022109073-appb-000038
仍包括
Figure PCTCN2022109073-appb-000039
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“C 1-3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C 1-3烷基包括C 1-2和C 2-3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)。C 1-3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。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12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。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
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。
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(SXRD)，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：
Figure PCTCN2022109073-appb-000040
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。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；THF代表四氢呋喃；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；DIEA代表N,N-二异丙基乙胺；CbzCl代表氯甲酸苄酯；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022109073-appb-000041
软件命名，市售化合物采用供应商目录名称。
具体实施方式
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。
实施例1
Figure PCTCN2022109073-appb-000042
步骤1:在25℃下将化合物1-1(12g,57.69mmol)溶于乙腈(120mL)中，加入叔丁氧羰基碳酸叔丁酯(16.37g,75.00mmol,17.23mL)和磷酸钾(23.27g,109.61mmol)，在85℃下搅拌2小时。再补加叔丁氧羰基碳酸叔丁酯(2.52g,11.54mmol,2.65mL)，在85℃下搅拌16小时。LC-MS显示原料被消耗完，主峰为产物峰。对反应液进行过滤，滤饼减压浓缩，得到粗品。粗品经过柱层析纯化得到化合物1-2。MS ESI计算值:C 10H 11Cl 2N 3O 4[M+H] +308，实测值308。
步骤2:将化合物1-2((10.3g,33.43mmol))溶于i-PrOH(120mL)中，加入1-3(7.94g,35.10mmol)和DIEA(12.74g,98.56mmol,17.17mL)，混合物在50℃下搅拌16小时。TLC显示原料被消耗完。反应液倒入300mL水中，过滤，减压浓缩，得到化合物1-4。 1H NMR(400MHz,CHLOROFORM-d)δ＝1.47-1.51(m,9H)1.53(s,9H)1.83(br d,J＝7.38Hz,2H)1.95-2.15(m,4H)4.30(br s,3H)4.56-5.58(m,2H)7.57-7.93(m,1H)8.39-8.84(m,1H)10.26-10.92(m,1H)。
步骤3:将化合物1-4(15g,30.12mmol)溶于混合溶液(THF:MeOH:H 2O＝3:2:1)150mL中，缓慢加入Fe粉(16.82g,301.22mmol)和NH 4Cl(4.83g,90.37mmol)的混合溶液(THF:MeOH:H 2O＝3:2:1)150mL，在70℃下搅拌1小时。LC-MS显示原料被消耗完，主峰为产物峰。反应液过滤，滤液用100mL水稀释，然后乙酸乙酯萃取(100mL×2)，有机相合并后用无水硫酸钠干燥，过滤并减压浓缩得到化合物1-5。MS ESI计算值C 22H 34ClN 5O 4[M+H] +468，实测值468。
步骤4:将化合物1-5(15g,32.05mmol)溶于75mL原甲酸三甲酯中，加入4-甲基苯磺酸(600mg,3.48mmol)，90℃下搅拌2h。LC-MS显示原料被消耗完，主峰为产物峰。反应液用200mL水稀释，并用乙酸乙酯萃取(50mL×2)，有机相合并后用无水硫酸钠干燥，过滤并减压浓缩，得到化合物1-6。MS ESI计算值C 23H 32ClN 5O 4[M+H] +478，实测值478。
步骤5:将化合物1-6(16g,33.47mmol)溶于盐酸甲醇溶液(4M,48mL)，在40℃下搅拌2小时。LCMS显示原料基本反应完全，主峰为产物峰。反应液直接浓缩得到化合物1-7的盐酸盐粗品。MS ESI计算值C 13H 16ClN 5[M+H] +278，实测值278。
步骤6:将1-7的盐酸盐粗品(15g,47.74mmol)溶于甲醇(150mL)中，加入DIEA(37.10g,287.06mmol,50.00mL)，混合物在25℃搅拌10分钟，然后加入化合物1-8(6.19g,116.65mmol,7.74mL)，在25℃下搅拌16小时。LC-MS显示原料被消耗完，主峰为产物峰。反应液浓缩除去甲醇，然后加入100mL水稀释，加入饱和碳酸氢钠溶液将pH调到8，再用乙酸乙酯萃取(100mL×3)。合并有机相，用饱和食盐水洗涤(60mL×3)，无水硫酸钠干燥，过滤并减压浓缩，得到化合物1-9。 1H NMR(400MHz,DMSO-d6)δ＝1.68-1.82(m,4H),1.89-1.99(m,2H),2.15-2.30(m,2H),2.62-2.72(m,2H),2.75-2.84(m,2H),3.41(br s,2H),4.47-4.77(m,1H),6.19-6.48(m,1H),6.58-6.92(m,2H),7.94-8.37(m,1H).MS ESI计算值C 21H 27ClN 6O 2[M+H] +331,实测值331。
步骤7:将溴化铜(2.55g,11.42mmol,534.58μL)溶于乙腈(20mL)中，缓慢加入亚硝酸叔丁酯(1.42g,13.82mmol,1.64mL)，25℃下搅拌15分钟。降温到0℃，再加入1-9(3g,9.07mmol)，0℃搅拌0.5小时，50℃搅拌32小时。TLC显示原料被消耗完。反应液用100mL饱和碳酸氢钠溶液淬灭，并用乙酸乙酯萃取(100mL×2)，合并的有机相用无水硫酸钠干燥，过滤并减压浓缩，得到粗品。粗品经过柱层析(SiO 2,石油醚：乙酸乙酯＝1：1～0：1)纯化得到化合物1-10。MS ESI计算值:C 16H 17BrClN 5[M+1] +394,实测值394。
步骤8:将化合物1-10(100mg,253.36μmol)溶于二氧六环(1mL)中，加入1-11(30mg,322.1μmol)，碳 酸铯(250mg,767.3μmol)，Xantphos(20mg,34.6μmol)和三(二亚苄基丙酮)二钯(40.00mg,43.68μmol)，100℃下搅拌16小时。LC-MS显示原料被消耗完全，主峰为产物峰。反应液减压浓缩得到粗品，粗品经过柱层析(SiO 2,石油醚：乙酸乙酯＝1：1～0：1,然后二氯甲烷:甲醇＝10:1)纯化得到化合物1-12。MS ESI计算值:C 18H 23ClN 6OS[M+H] +407,实测值407。
步骤9:将化合物1-12(100mg,245.7μmol)和化合物1-13(60mg,304.2μmol)溶于二氧六环(2mL)中，加入碳酸铯(200mg,613.8μmol)和甲磺酸(2-二环己基膦基-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-氨基-1,1-联苯-2-基)钯(II)(25mg,27.6μmol)，氮气置换三次后升温至100℃，氮气保护下搅拌16小时。LC-MS显示原料反应完全，主峰为产物峰。反应液直接浓缩得到粗品。粗品经过柱层析(SiO 2,石油醚：乙酸乙酯＝1：1，然后二氯甲烷:甲醇＝10:1)纯化得到产物1-14。MS ESI计算值：C 27H 37N 9O 3S[M+H] +568,实测值568。
步骤10:将化合物1-14(140mg,246.6μmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(2.16g,18.9mmol,1.4mL)，25℃下搅拌30分钟。LC-MS显示原料被消耗完，主峰为产物峰。反应液直接浓缩得到粗品，粗品经过高效液相色谱法制备分离(柱子:Phenomenex Synergi C18 150*25mm*10μm；流动相:[水(0.1％TFA)-乙腈]；乙腈％:1％-30％,10分钟)得到化合物1-15。 1H NMR(400MHz,CD 3OD)δ＝2.33-2.63(m,9H),2.67-2.85(m,2H),3.08-3.23(m,2H),3.42-3.51(m,6H),3.54-3.69(m,2H),4.30-4.45(m,2H),5.31-5.61(m,1H),5.97-6.37(m,1H),6.58-7.02(m,1H),9.08-9.40(m,1H)。MS ESI计算值:C 22H 29N 9OS[M+H] +468,实测值468。
以化合物1-10为共同中间体，运用同化合物1-15相同的合成及分离方法(即把化合物1-11替换为下列目标分子中相应的片段)得到下列化合物，其表征数据如下表：
Figure PCTCN2022109073-appb-000043
Figure PCTCN2022109073-appb-000044
实施例2
Figure PCTCN2022109073-appb-000045
步骤1:将氯化铜(1.77g,13.15mmol)溶于乙腈(30mL)中，缓慢加入亚硝酸叔丁酯(1.35g,13.12mmol,1.56mL)，25℃下搅拌15分钟。降温到0℃，再加入1-9(2.9g,8.77mmol),0℃搅拌0.5小时，50℃搅拌32小时。LC-MS显示原料有少量剩余，但是主峰为产物峰。反应液用30mL饱和碳酸氢钠溶液淬灭，并用乙酸乙酯萃取(20mL×4)，合并的有机相用无水硫酸钠干燥，过滤并减压浓缩，得到粗品。粗品经过柱层析(SiO 2,石油醚：乙酸乙酯＝1：1～0：1,然后二氯甲烷:甲醇＝10:1)纯化得到化合物2-1。MS ESI计 算值:C 16H 17Cl 2N 5[M+H] +350,实测值350。
步骤2:将2-1(400mg,1.14mmol)溶于正丁醇(4mL)中，加入甲硫醇钠(80mg,1.14mmol,72.73μL)，在60℃下搅拌16小时。LC-MS显示原料被消耗完，主峰为产物峰。反应液加入20mL水稀释，再用二氯甲烷：甲醇＝10:1的混合溶液萃取(20mL×3)，有机相合并用无水硫酸钠干燥，过滤并减压浓缩，得到粗品。粗品经过柱层析(SiO 2,石油醚：乙酸乙酯＝1：1～0：1)纯化得到化合物2-2。MS ESI计算值C 17H 20ClN 5S[M+H] +362,实测值362。
步骤3:将化合物2-2(250mg,690.81μmol)溶于甲醇(5mL)，加入二乙酰氧基碘苯(900mg,2.79mmol)，和氨基甲酸铵(320mg,4.10mmol)，反应液25℃敞口搅拌2小时。LC-MS显示原料被消耗完全，主峰为产物峰。反应液加入20mL水稀释，再用二氯甲烷萃取(15mL×3)，有机相合并用无水硫酸钠干燥，过滤并减压浓缩，得到粗品。粗品经SiO 2制备板层析(乙酸乙酯:甲醇＝10:1)纯化得到化合物2-3。MS ESI计算值C 17H 21ClN 6OS[M+H] +393，实测值393。
步骤4:将化合物2-3(120mg,305.4μmol)和化合物1-13(72mg,365.1μmol)溶于二氧六环(2mL)中，加入碳酸铯(360mg,1.1mmol)和甲磺酸(2-二环己基膦基-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-氨基-1,1-联苯-2-基)钯(II)(36mg,39.7μmol)，氮气置换三次后升温至100℃，氮气保护下搅拌16小时。LC-MS显示原料反应完全，主峰为产物峰。反应液直接浓缩得到粗品。粗品经过两次高效液相色谱法制备分离(柱:Phenomenex Synergi C18 150*25mm*10μm；流动相:[水(0.1％TFA)-ACN]；B(ACN)％:3％-33％,10分钟)，柱:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[H 2O(0.05％氨水v/v)-ACN]；B(ACN)％:12％-42％,10分钟)得到化合物2-4。 1H NMR(400MHz,CD 3OD)δ＝1.71-2.31(m,16H),2.54-2.61(m,2H),2.68-2.74(m,2H),4.84-4.91(m,1H),6.16-6.44(m,1H),7.23-7.36(m,1H),8.07-8.17(m,1H).MS ESI计算值：C 21H 27N 9OS[M+H] +454,实测值454。
实施例3
Figure PCTCN2022109073-appb-000046
步骤1:将化合物3-1(1g,9.69mmol,917.4μL)溶于氢氧化钠水溶液(10mL)中，零度下加入CbzCl(2.40g,14.1mmol,2mL)，25℃下搅拌16小时。反应完毕后，用1M HCl调节pH至7，再用乙酸乙酯(50mL×3)萃取。合并有机相，硫酸钠干燥，过滤，浓缩得到化合物3-2。 1H NMR(400MHz,CDCl 3)δ＝2.42-2.58(m,4H),3.64-3.73(m,4H),5.03-5.08(m,2H),7.24-7.26(m,1H),7.28-7.33(m,4H).
步骤2:将化合物3-2(2g,8.43mmol)溶于甲醇(40mL)中，依次加入二乙酰氧基碘苯(10.86g,33.71mmol)和氨基甲酸铵(3.95g,50.57mmol),混合液在敞口下于25℃搅拌2小时。反应完毕后，反应液浓缩得到粗品，粗品经柱层析(SiO 2,石油醚：乙酸乙酯＝1：1,然后二氯甲烷:甲醇＝20:1)分离纯化得到化合物3-3。 1H NMR(400MHz,DMSO-d 6)δ＝2.96-3.10(m,4H),3.52-3.72(m,2H),3.77-3.86(m,1H),3.88-3.97(m,2H),4.82-5.31(m,2H),7.01-7.58(m,5H).
步骤3:将化合物3-3(1.3g,4.8mmol)溶于二氯甲烷(13mL)中，加入三乙胺(1.45g,14.4mmol,2mL)，再在0℃下缓慢加入乙酰氯(550mg,7.01mmol,0.5mL)，反应液在氮气保护下于25℃搅拌1小时。反应完毕后，反应液直接浓缩得到粗品，粗品经柱层析分离(SiO 2,石油醚/乙酸乙酯＝5/1～0/1)纯化得到化合物3-4。 1H NMR(400MHz,DMSO-d 6)δ1.94-2.02(m,3H),3.45-3.54(m,2H),3.56-3.72(m,4H),3.98-4.08(m,2H),5.00-5.22(m,2H),7.18-7.53(m,5H).
步骤4:将化合物3-4(1.3g,4.19mmol)溶于甲醇(20mL)中，在氮气保护下依次加入湿钯碳(130mg,10％),氢气置换三次，反应液在氢气保护下25℃搅拌12小时。反应完毕后，过滤，滤液浓缩得到化合物3-5。
步骤5:将化合物1-10(100mg,253.4μmol)溶于二氧六环(2mL)中，加入3-5(60mg,340.5μmol)，碳酸铯(200mg,613.8μmol)，Xantphos(20mg,34.6μmol)和Pd 2(dba) 3(20mg,21.8μmol)，100℃下搅拌16小时。LC-MS显示原料被消耗完全，主峰为产物峰。反应液减压浓缩得到粗品，粗品经过柱层析(SiO 2,石油醚/乙酸乙酯＝1/0～1/1然后二氯甲烷:甲醇＝10:1)纯化得到化合物3-6。MS ESI计算值:C 22H 28ClN 7O 2S [M+H] +490,实测值490。
步骤6:将化合物3-6(200mg,408.2μmol)和化合物1-13(100mg,507.0μmol)溶于二氧六环(2mL)中，加入碳酸铯(400mg,1.2mmol)和甲磺酸(2-二环己基膦基-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-氨基-1,1-联苯-2-基)钯(II)(50mg,55.2μmol)，氮气置换三次后升温至100℃，氮气保护下搅拌16小时。LC-MS显示原料反应完全，主峰为产物峰。反应液直接浓缩得到粗品。粗品经过柱层析(SiO 2,石油醚：乙酸乙酯＝1:1～0：1,然后二氯甲烷:甲醇＝10:1)纯化得到产物3-7。MS ESI计算值：C 26H 34N 10O 2S[M+H] +551,实测值551。
步骤7:将化合物3-7(150mg,272.4μmol)溶于甲醇(1mL)和四氢呋喃(1mL)的混合溶液中，加入碳酸钾(200mg,1.5mmol),25℃下搅拌16小时。反应完毕后，反应液加入20mL水稀释，再用二氯甲烷萃取(20mL×3)，有机相合并用，无水硫酸钠干燥，过滤并减压浓缩，得到粗品。粗品经过高效液相色谱制备分离(柱:Phenomenex Synergi C18 150*25mm*10μm；流动相:[水(0.1％TFA)-ACN]；B(ACN)％:5％-35％,10分钟)得到3-8。 1H NMR(400MHz,CD 3OD)δ＝2.37-2.58(m,9H),2.61-2.75(m,2H),3.18(t,J＝7.19Hz,2H),3.54-3.82(m,6H),4.05-4.24(m,2H),4.28-4.45(m,2H),4.96(br s,2H),5.21-5.48(m,1H),6.10-6.23(m,1H),6.30-6.42(m,1H),7.96-8.35(m,1H)。MS ESI计算值C 24H 32N 10OS[M+H] +509，实测值509。
生物测试
实验例1：
试剂和耗材
JAK1(Invitrogen，货号PV4288)，JAK2(Invitrogen，货号PV4288)，JAK3(Invitrogen，货号PV4080)，TYK2(Invitrogen，货号PR8440C)，ATP(Sigma，货号A7699-1G)，DMSO(Sigma，目录号D2650)，DTT(Sigma，目录号43815)，384孔板_测试板(Perkin Elmer，目录号6007299)，LANCE Ultra ULight TM-JAK-1肽(Perkin Elmer，货号TRF0121)，LANCE Eu-W1024抗磷酸酪氨酸(PT66)(Perkin Elmer，货号AD0069)，LANCE TM检测缓冲液(Perkin Elmer，货号CR97-100)。
实验方法
本次试验中JAK1,2,3和TYK2使用
Figure PCTCN2022109073-appb-000047
方法进行活性检测。在检测板中，将酶、ULight标记的多肽底物、ATP以及检测化合物混合，孵育反应。反应后，加入EDTA终止反应，并同时加入Eu标记的抗体。在
Figure PCTCN2022109073-appb-000048
激酶检测中，铕标记的抗磷酸化基质抗体与磷酸化的ULight标记的基质结合可使供体和受体分子相互趋近。经过320nm波长光的照射后，激酶发生反应，铕供体的能量将转移到ULight受体染料中，并生成波长665nm的光。光的发射强度与ULight基质的磷酸化水平成比例。
化合物最终测试浓度：受试化合物最终测试浓度从1μM到0.017nM，3倍梯度稀释，11个浓度。参考化合物Tofacitinib的最终测试浓度从1μM到0.017nM，3倍梯度稀释，11个浓度。DMSO在检测反应中的含量为1％。
激酶检测：缓冲液的配制，缓冲液包括:50mM HEPES(pH 7.5),0.01％Brij-35,10mM MgCl 2,1mM EDTA,1mM DTT。
JAK1酶反应：
在缓冲液中，将2nM JAK1和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加38μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。
JAK2酶反应：
在缓冲液中，将0.03nM JAK2和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加12μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。
JAK3酶反应：
在缓冲液中，将0.08nM JAK3和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加4μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。
TYK2酶反应：
在缓冲液中，将4nM TYK2和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加15μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。
数据分析：
根据％抑制vs.log[化合物浓度]，使用XLfit5软件mode205进行数据分析及拟图得到如下表格IC 50数据。
表1：受试化合物JAK激酶抑制活性总结
Figure PCTCN2022109073-appb-000049
空白表示未检测
结论：本发明的化合物在激酶2个亚型JAK1、JAK2的体外活性测试中展现了良好的抑制活性。

Claims (15)

  1. 式(Ⅰ)化合物或其药学上可接受的盐，
    Figure PCTCN2022109073-appb-100001
    其中，
    L 1为-(CH 2) m-、-C(＝O)-或-CH 2-C(＝O)-；
    R 1为R 11、
    Figure PCTCN2022109073-appb-100002
    D 1为O或CH 2；
    T 1为N或CH；
    R 11为H、CN或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
    R 2为H或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
    R 3为
    Figure PCTCN2022109073-appb-100003
    R 4为H或C 1-3烷基；
    E 1和E 2分别独立地为O或NH；
    E 3为CH 2或O；
    R 31、R 32和R 34分别独立地为C 1-3烷基；
    R 33为H或C 1-3烷基；
    q为1或2；
    m为0、1或2；
    n为0、1或2；
    r为0、1或2；
    R a和R b分别独立地为F、Cl、Br、I、OH、CN或NH 2。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 11为H、CN或CH 3，其中所述CH 3任选被 1、2或3个R a取代。
  3. 根据权利要求2所述的化合物或其药学上可接受的盐，其中R 11为H、CN或CF 3。
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 1为H、CN、CF 3、
    Figure PCTCN2022109073-appb-100004
  5. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 2为H或
    Figure PCTCN2022109073-appb-100005
    其中所述
    Figure PCTCN2022109073-appb-100006
    任选被1、2或3个R b取代。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其中R 2为H、-CH 2CH 3或
    Figure PCTCN2022109073-appb-100007
  7. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 31、R 32和R 34分别独立地为CH 3或-CH 2CH 3。
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 33为H或CH 3。
  9. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 3为
    Figure PCTCN2022109073-appb-100008
    Figure PCTCN2022109073-appb-100009
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中R 3为
    Figure PCTCN2022109073-appb-100010
    Figure PCTCN2022109073-appb-100011
  11. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 4为H、CH 3、CH 2CH 3或CH 2CH 2CH 3。
  12. 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物为
    Figure PCTCN2022109073-appb-100012
    其中，
    L 1、R 1、R 2、R 31、R 32、R 34和R 4如权利要求1所定义。
  13. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2022109073-appb-100013
    Figure PCTCN2022109073-appb-100014
  14. 根据权利要求1～13任意一项所述化合物或其药学上可接受的盐在制备治疗与肠道的Pan-JAK相关的疾病的药物中的应用。
  15. 根据权利要求14所述的应用，其中与肠道Pan-JAK相关的疾病是指炎症性肠病。
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