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WO2022012693A1 - 一类肠道裂解型共药及其制备和用途 - Google Patents

一类肠道裂解型共药及其制备和用途 Download PDF

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WO2022012693A1
WO2022012693A1 PCT/CN2021/107208 CN2021107208W WO2022012693A1 WO 2022012693 A1 WO2022012693 A1 WO 2022012693A1 CN 2021107208 W CN2021107208 W CN 2021107208W WO 2022012693 A1 WO2022012693 A1 WO 2022012693A1
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drug
mmol
methyl
compound
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PCT/CN2021/107208
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English (en)
French (fr)
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寿建勇
敖翔
江磊
刘胜洋
毛旭东
乔智
谢小平
张建华
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轶诺(浙江)药业有限公司
上海轶诺药业有限公司
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Priority to CA3186375A priority Critical patent/CA3186375A1/en
Priority to EP21842552.8A priority patent/EP4186900A1/en
Priority to JP2023503246A priority patent/JP2023535692A/ja
Priority to US18/016,532 priority patent/US20230271982A1/en
Priority to CN202180060562.3A priority patent/CN116249533A/zh
Priority to AU2021309147A priority patent/AU2021309147B2/en
Publication of WO2022012693A1 publication Critical patent/WO2022012693A1/zh

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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present invention relates to a class of gut-splitting co-drug compounds.
  • the present invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds for the treatment of gastrointestinal autoimmune diseases, inflammatory diseases and cancers; and methods and intermediates for the preparation of such compounds.
  • JAK family (JAK1, JAK2, JAK3, TYK2) inhibitors such as tofacitinib have been approved for the treatment of patients with moderately to severely active rheumatoid arthritis (RA) and moderate to severe ulcerative colitis (ulcerative colitis, UC) in some patients.
  • RA rheumatoid arthritis
  • UC ulcerative colitis
  • JAK family inhibitors a number of adverse events mediated by systemic drug exposure have been reported, including serious infections, opportunistic infections, and laboratory abnormalities such as lymphopenia, neutropenia, liver Elevated enzymes, elevated lipids, and elevated serum creatinine. All currently marketed JAK inhibitors carry a boxed warning about safety risks, including the risk of serious infections, malignancies, and blood clots.
  • JAK family inhibitor drugs for the treatment of localized inflammatory diseases will require limiting their systemic exposure.
  • the distribution of JAK family inhibitors in the gastrointestinal tract is increased, while the systemic exposure of the drug is minimized.
  • Berberine also known as berberine, is an isoquinoline alkaloid extracted from plants such as Coptis chinensis. Berberine is a very safe drug that has been used in traditional Chinese medicine for over a thousand years. Its bioavailability is very low. Clinically, it is mainly used to treat gastrointestinal diseases such as diarrhea and intestinal infection. In recent years, studies have also found that berberine also has certain therapeutic prospects in cardiovascular diseases and glucose and lipid metabolism regulation. Berberine (Berberrubine) is the main metabolite of berberine in the body. Animal model studies have found that berberine has similar therapeutic effects to berberine in ulcerative colitis. However, up to now, there is no effective way to improve the therapeutic effect of berberine or its analogs in the art.
  • Chronic enteritis mainly includes two types of ulcerative colitis and Crohn's disease. These chronic intestinal inflammatory diseases have a long course of disease, often recurring, and long-term inflammation is prone to cancer. The incidence of chronic enteritis has been on the rise in recent years. It is currently believed that the pathogenesis of chronic enteritis may be related to genetics, environment, immunity and microorganisms, but the exact mechanism is not clear. Clinical treatment is mainly based on aminosalicylic acid drugs, adrenal glucocorticoid drugs and immunosuppressive drugs, but there are certain adverse reactions, such as gastrointestinal discomfort and allergic reactions.
  • JAK inhibitors combined with berberine analogs can synergize to achieve a more superior effect on the treatment of gastrointestinal inflammatory diseases.
  • the present invention enables the release and enrichment of two drug molecules in the gastrointestinal tract, and the systemic exposure of the compound is limited.
  • the synergistic effect of the two drug molecules achieves better therapeutic effect and safety.
  • the present invention provides a berberine analog (preferably berberine) and a second therapeutic agent JAK family inhibitor (preferably tofacitinib, upatinib, SHR0302) through a cleavable A co-drug composed of a covalently linked co-drug, the co-drug is designed to be able to release the JAK family inhibitor and the first therapeutic agent in a targeted manner in the gastrointestinal tract, thereby increasing the JAK family inhibitor and the first therapeutic agent in the stomach. levels at sites of intestinal inflammation with minimal systemic exposure.
  • a berberine analog preferably berberine
  • a second therapeutic agent JAK family inhibitor preferably tofacitinib, upatinib, SHR0302
  • a first aspect of the present invention provides a co-drug compound shown in the following formula I, which is formed by the coupling of a first drug molecule, a second drug molecule and a linker precursor:
  • D 1 is the first drug group;
  • the first drug group is a structural fragment in the first drug molecule that can be linked with the linker (that is, after the first drug molecule is coupled or condensed with the precursor of the linker) , the fragment formed after shedding the active functional group, the fragment does not include the linker part);
  • D 2 is the second drug group;
  • the second drug group is a structural fragment that can be connected with the linker in the second drug molecule;
  • the first drug molecule and the second drug molecule are drugs with synergistic effect Molecules (that is, after the second drug molecule undergoes a coupling or condensation reaction with the precursor of the linker, the fragment formed after the active functional group is removed, and the fragment does not include the linker part);
  • connection can be the loss of a hydrogen atom to form a covalent connection, or a covalent connection with the linker in other ways, such as a covalent connection formed by the condensation reaction of active groups such as hydroxyl, carboxyl, and amine groups;
  • linker has a structure selected from the following group (a), (b) or (c), in each formula, J 1 is connected to the first drug group, and J 2 is connected to the second drug group;
  • Described Glu has a structure selected from the following group:
  • the A ring is selected from the following group: C6-C10 aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclyl;
  • R 4 is selected from the group consisting of: H, C 1-6 alkyl group, C 1 ⁇ 6 alkoxy, -C 1 ⁇ 4 alkylene -, a cycloalkyl group of C 3 ⁇ 12, C 3 ⁇ 12 cycloalkyl-C 1-4 alkylene-;
  • the B ring and the C ring are each independently selected from the following group: C6-C10 aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclyl;
  • Y, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 are optionally substituted with one or more R, and said R is selected from the group consisting of H, - OH, C1-C4 alkyl, halogen, cyano, nitro, -OR 4 , C 1-6 haloalkyl, sulfonic acid, C0-C4 alkyl-S(O) 2 -C1-C4 alkyl, methyl Acyl, carboxyl, -COOR 4 ; provided that each of Y, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 together form a chemically stable structure;
  • n, p, q, r, s and t are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16;
  • z is selected from the group: 0, 1, 2, 3, 4, 5, 6; preferably, z is selected from the group: 1, 2 or 3.
  • the linking comprises: losing structural fragments in the drug molecule to form a linking site, or linking through a coordination bond.
  • the Y can be replaced by one or more R, provided that each Y together forms a chemically stable structure;
  • Y, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 are optionally substituted with one or more R, and said R is selected from the group consisting of H, - OH, C1-C4 alkyl, halogen, cyano, nitro, -OR 4 , C 1-6 haloalkyl, sulfonic acid, C0-C4 alkyl-S(O) 2 -C1-C4 alkyl, methyl Acyl, carboxyl, -COOR 4 ; provided that each of Y, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 together form a chemically stable structure;
  • n, p, q, r, s, and t are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  • z is selected from the group: 0, 1, 2, 3, 4, 5, 6; preferably, z is selected from the group: 1, 2 or 3.
  • the J 1 and J 2 are each independently selected from the following group: methylene,
  • the J 1 is selected from the following group: methylene,
  • said J 2 is selected from the group: a methylene group
  • the first drug molecule is berberine, berberine and analogs thereof.
  • the second drug molecule is a JAK family inhibitor and its analogs.
  • the linker has the following structure:
  • the first drug molecule is the drug molecule of the following formula II, formula III or formula IV:
  • Ro, Rp, Rq, Rr, Rs and Rt are each independently selected from the group consisting of H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; Ro, Rp, Rq, Rr, Rs and Rt on the atom together form a 5-7 membered heterocyclic ring with the atoms to which they are connected; wherein, the substitution means that the H atom on the group is replaced by one or more selected from the following group. Substituent substitution: halogen, C1-C4 alkyl, phenyl.
  • the JAK family inhibitor and its analogs are selected from the group consisting of: Tofacitnib, Ruxolitinib, Oclacitinib, Barrex Baricitinib, Peficitinib, Abrocitinib, Filgotinib, Upadacitinib, Delgotinib, Itatinib ( Itacitinib), Fedratinib, Decernotinib, SHR-0302, AZD-4205, ASN-002, BMS-986165, PF-06700841, PF-06651600, R-348, INCB-52793 , ATI-501, ATI-502, NS-018, KL-130008, or deuterated derivatives of the above molecules.
  • the described first drug group is selected from the following group:
  • the first drug group is a group formed by the loss of a hydrogen atom of a drug molecule selected from the following group:
  • the first drug group has the structure shown in the following formula:
  • the second drug group is selected from the following group:
  • the second drug group is selected from the following group:
  • the first drug group is and the second drug group is
  • the A-(L 7 ) p -J 2 - has the structure shown in the following formula:
  • the -A(Glu)-(L 7 ) p -J 2 - has a structure selected from the group consisting of:
  • the -(L 1 ) m - and -(L 2 ) n - each independently have a structure selected from the following group:
  • Ra, Rb and Rc are each independently a group formed by the loss of one hydrogen atom from an amino acid selected from the group consisting of: Glycine, Alanine, Valine, Leucine, Isoleucine, Phenylalanine, Tryptophan, Tyrosine, Aspartate, Histidine, Asparagine ), Glutamate, Lysine, Glutamine, Methionine, Arginine, Serine, Threonine, Cysteine (Cysteine), Proline (Proline).
  • amino acid selected from the group consisting of: Glycine, Alanine, Valine, Leucine, Isoleucine, Phenylalanine, Tryptophan, Tyrosine, Aspartate, Histidine, Asparagine ), Glutamate, Lysine, Glutamine, Methionine, Arginine, Serine, Threonine, Cysteine (Cysteine), Proline (Proline).
  • the linker is selected from the following groups (A), (B) or (C):
  • (A) group has the structure of -L a -L-, wherein said L a has a structure selected from the following group:
  • the compound is selected from the following group:
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound described in the first aspect of the present invention or a stereoisomer or racemate or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
  • the pharmaceutical composition is an enteric-coated preparation.
  • the pharmaceutical composition is used to treat diseases selected from the group consisting of gastrointestinal inflammatory diseases (such as ulcerative colitis, Crohn's disease, and immune checkpoint inhibitor therapy).
  • gastrointestinal inflammatory diseases such as ulcerative colitis, Crohn's disease, and immune checkpoint inhibitor therapy.
  • colitis collagenous colitis, lymphocytic colitis, pouchitis, acute/chronic gastritis, acute/chronic appendicitis), gastroenteritis caused by radiotherapy or chemotherapy, autoimmune diseases of the gastrointestinal tract (such as grafts) Anti-host disease, sprue, autoimmune enteropathy), peptic ulcer, irritable bowel syndrome, gastric cancer, esophageal cancer, colon cancer.
  • the third aspect of the present invention provides the use of the precursor compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described in the second aspect of the present invention, for prevention and treatment Treatment of gastrointestinal dysfunction.
  • the functional disease of the gastrointestinal tract is an inflammatory disease of the gastrointestinal tract.
  • the gastrointestinal inflammatory disease is selected from the group consisting of ulcerative colitis, Crohn's disease, and colitis associated with immune checkpoint inhibitor therapy.
  • Figure 1 shows the time-dependent curve of the concentration of the compound of Example 8 in different tissues after oral administration of the compound of Example 8 to mice;
  • Figure 2 shows the time-dependent curve of the concentration of berberine in different tissues after oral administration of the compound of Example 8 to mice;
  • Figure 3 shows the time-dependent curve of the concentration of tofacitinib in different tissues after oral administration of the compound of Example 8 to mice;
  • Figure 4 shows the AUC 0-24h of berberine in different tissue contents after oral administration of the compounds of Examples 1 and 8 to mice;
  • Figure 5 shows the AUC 0-24h of tofacitinib in different tissue contents after oral administration of the compounds of Examples 1 and 8 to mice;
  • Figure 6 is a graph showing the change in disease index after administration of the compound of Example 8 to mice in the oxazolone enema model.
  • JAK family inhibitors and berberine analogs are prepared in the form of co-drugs for administration, and the treatment of gastrointestinal diseases can achieve better results than single drugs at the same dose. and through the design of co-drug molecules, the drug can be released in a targeted manner. Based on the above findings, the inventors have completed the present invention.
  • the terms "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • alkyl as a group or part of another group refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3 - Methylhexyl, octyl, nonyl and decyl, etc.
  • C1-C6 alkyl refers to an alkyl group containing from 1 to 6 carbon
  • 6-10 membered aromatic ring means an aromatic ring having 6-10 ring atoms, which are carbon atoms.
  • the aromatic ring may be monocyclic or bicyclic.
  • benzene ring, naphthalene ring and the like are monocyclic or bicyclic.
  • the term "5-10 membered heteroaromatic ring” means a heteroaromatic ring having 5-10 ring atoms, at least one of which (may be is 1, 2 or 3) is a heteroatom selected from nitrogen, oxygen and sulfur.
  • the heteroaromatic ring can be monocyclic or bicyclic.
  • heterocyclyl as a group or part of another group means a group consisting of 3 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group.
  • the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon, or sulfur atoms of a can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • co-drug in this document, “co-drug”, “co-drug”, “co-drug” or “interactive drug” are used interchangeably and all refer to a drug molecule that can be metabolized in the body to form two different pharmacological acting drug molecules.
  • a typical co-drug is a compound of formula I.
  • the co-drug can be metabolized in the body to form a variety of different therapeutic agents.
  • a preferred first therapeutic agent is a JAK family inhibitor
  • the second therapeutic agent is berberine or the like thing.
  • first therapeutic agent and “first drug molecule” are used interchangeably, and both refer to the first drug molecule used in the co-drug of the present invention. After the first drug molecule loses any active functional group on the group, a first drug group can be formed and connected to the linking site of the co-drug molecule.
  • a preferred class of first drug molecules are JAK family inhibitors, which can be used clinically for the treatment of intestinal diseases, such as intestinal inflammatory diseases.
  • Said JAK family inhibitor can be a JAK inhibitor known in the art, or a compound that has not been verified to have JAK inhibitory activity.
  • Exemplary JAK inhibitors form the first drug group selected from the group consisting of:
  • second therapeutic agent and “second drug molecule” can be used interchangeably, and both refer to the second drug molecule used in the co-drug of the present invention. After the second drug molecule loses any hydrogen atom on the group, a second drug group can be formed and connected to the linking site of the co-drug molecule.
  • berberine and its analogs can be used as the second therapeutic agent of the co-drug, and the preferred second drug molecule is shown in the following formula II, III or IV:
  • the compound of the present invention is a compound represented by formula I or a stereoisomer or racemate or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may contain one or more chiral carbon atoms and thus may give rise to enantiomeric, diastereomeric and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexamethylene Acid, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-tol
  • “Pharmaceutically acceptable base addition salts” refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohe
  • the present invention relates to glucuronide co-drugs of tofacitinib or pharmaceutically acceptable salts thereof; pharmaceutical compositions containing such compounds; use of such compounds for the treatment of gastrointestinal inflammatory diseases methods; and methods and intermediates for the preparation of such compounds.
  • the compounds described herein may contain one or more chiral centers.
  • the depiction or designation of a particular stereoisomer means that the indicated stereocenter has the indicated stereochemistry, with the understanding that, unless otherwise indicated, minor amounts of other stereoisomers may also be present, which With the limitation that the utility of the depicted or named compound is not eliminated by the presence of another stereoisomer.
  • the co-drug compound of the present invention has excellent intestinal directional release effect
  • the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are
  • the pharmaceutical composition of the main active ingredient can be used for the prevention and/or treatment of intestinal functional diseases, preferably gastrointestinal inflammatory diseases.
  • the term "pharmaceutical composition” refers to the formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of a compound of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing An adverse biological reaction or interaction in an undesired manner with any component contained in the composition.
  • the term "pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, Sweetening agents, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor includes, but is not limited to, gliomas, sarcomas, melanomas, articular chondromas, cholangiomas, leukemias, gastrointestinal stromal tumors, histiocytic lymphomas, non-small cell lung cancers, small Cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, colon cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer , melanoma, kidney cancer, oral cancer and other diseases.
  • prophylactic includes reducing the likelihood of the occurrence or worsening of a disease or disorder in a patient.
  • treatment and other similar synonyms include the following meanings:
  • an "effective amount” for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition.
  • An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.
  • the terms “administration”, “administration”, “administration” and the like refer to methods capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with administration techniques useful for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drugs obtained by mixing or combining more than one active ingredient Treatment, which includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form.
  • unfixed combination refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation at variable intervals to a patient as separate entities. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
  • the co-drug compound of the present invention itself cannot be effectively absorbed, and it can release two pharmacodynamic components in a directional direction in the intestinal tract, so it can cause the enrichment of the medicinal components in the gastrointestinal tract treatment site, and reduce the systemic drugs. exposed.
  • the compound of the present invention can effectively release JAK inhibitor (eg tofacitinib) and berberine or its analogs in the intestinal tract to synergistically treat gastrointestinal autoimmune inflammatory diseases.
  • JAK inhibitor eg tofacitinib
  • berberine or its analogs in the intestinal tract to synergistically treat gastrointestinal autoimmune inflammatory diseases.
  • reaction solution was stirred at 25°C for 16 hours. Complete conversion of starting material was monitored by LCMS.
  • the reaction solution was cooled to 0°C, 1 liter of saturated sodium bicarbonate solution was added, and the organic phase was collected by liquid separation. The organic phase was washed with saturated sodium bicarbonate solution (800 mL*8), washed with saturated brine (800 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated under reduced pressure to give the title compound (200 g, 92%).
  • the organic phase was washed three times with saturated brine (500 ml each time), and after separation, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • the diluted reaction solution was washed with water (1.5 L*8) and brine (1.5 L*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • Triphosgene (11.2 g, 37.7 mmol) was dissolved in 100 mL of dichloromethane in a three-necked flask, and Intermediate A-6 (36.0 g, 37.7 mmol) was dissolved in 300 mL of dichloromethane at 0°C It was added dropwise to the triphosgene dichloromethane solution under nitrogen protection. After the dropwise addition, the reaction solution was stirred at room temperature for 10 minutes, and then triethylamine (15.7 mL, 113.2 mmol) was added dropwise to the reaction solution at 0°C under nitrogen protection. After the addition, the reaction solution was stirred at 25-30°C for 3 hours. Complete conversion of starting material was monitored by LCMS.
  • reaction solution was cooled to 0°C, saturated sodium bicarbonate solution (300 mL) was added, and the layers were separated. The organic phase was washed with saturated sodium bicarbonate solution (300 mL*2) and saturated brine (200 mL). It was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound (46.0 g of crude product), which was directly used in the next reaction without further purification.
  • the intermediate was dissolved in pyridine (20 mL), added to the intermediate A-8 (27.7 g, 86.0 mmol) dissolved in pyridine (30 mL) under ice bath, and the reaction was warmed to room temperature (15 °C) and stirred for 16 hours .
  • the reaction of the raw materials was detected by LCMS.
  • Example 1 9-((2-(((((10-((2-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro- 2H-pyran-2- yl)oxo)-5-(((2-(4-(((3S,4S)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl )amino)-N-methyl-7H- Pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)carbamoyl)oxo)methyl)benzene (methyl)amino)-10-carbonyldecyl)oxo)carbonyl)(methyl)amino)ethyl)(methyl)carbamoyl)oxo)-10-methoxy-5,6- Dihydro-[1,3]dioxazolo[4,5-
  • Example 1-11 4-Nitrophenyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino yl)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate
  • Tofacitinib (8.9 g, 28.6 mmol) was dissolved in dichloromethane solution (140 mL), sodium hydroxide (3.4 g, 85.6 mmol) and tetrabutylammonium bromide (920 mg, 2.86 mmol) were added mol) in water (48 mL).
  • To a solution of p-nitrophenyl chloroformate (11.5 g, 57.1 mmol) in dichloromethane (48 mL) was added dropwise the above reaction solution. After the dropwise addition was completed, the reaction solution was stirred at room temperature for 4 h. Complete conversion of starting material was monitored by LCMS.
  • Example 1-10 10-Methoxy-9-((methyl(2-(methyl(((10-((5-(((methyl(2-(methylamino)ethyl)amino) Formyl)oxo)methyl)-2-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(carbomethoxy ⁇ methoxycarbonyl>)tetra Hydrogen-2H- Pyran-2-yl)oxo)phenyl)amino)-10-carbonyldecyl)oxo)carbonyl)amino)ethyl)carbamoyl)oxo)-5,6-dihydro -[1,3]Dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 1-12 9-((2-(((10-((5-(((2-(4-(((3S,4S)-1-(2-cyanoacetyl) -4-Methylpiperidine-3- yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbonweedamido ⁇ oxalamido>)ethyl)(methyl) yl)carbamoyl)oxo)methyl)-2-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(carbamoyl ⁇ methoxycarbonyl) >) Tetrahydro-2H-pyran-2-yl)oxo)phenyl)amino)-10-carbonyldecyl)oxo)carbonyl)(methyl)amino)ethyl)(methyl)amino ylformyl)oxo)-10-methoxy-5,
  • Example 1-10 A solution of Example 1-10 (4.4 g, 3.7 mmol) in dichloromethane (100 mL) was cooled to 0 °C, N,N-diisopropylethylamine (1.56 g, 12 mmol) was added, and the Examples 1-11 (1.76 g, 3.69 mmol) were stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The reaction solution was diluted with 300 ml of dichloromethane, washed successively with water and saturated brine, and the washed organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was isolated by normal phase column chromatography (eluting with 7%-9% methanol in dichloromethane) to give the title compound (2.83 g, 53%) as a yellow foamy solid.
  • Example 1 9-((2-(((((10-((2-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro- 2H-pyran-2- yl)oxo)-5-(((2-(4-(((3S,4S)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl )amino)-N-methyl-7H- Pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)carbamoyl)oxo)methyl)phenyl) Amino)-10-carbonyldecyl)oxo)carbonyl)(methyl)amino)ethyl)(methyl)carbamoyl)oxo)-10-methoxy-5,6-di Hydro-[1,3]dioxazolo[4,5-g]
  • Example 4A 9-((5-((E)-(4-((((((2-(4-(((3S,4S)-1-(2-cyanoacetyl)-4-methyl) piperidin-3-yl)(methyl) yl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)amino Formyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazole and [4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 4B 9-((5-((Z)-(4-((((((2-(4-(((3S,4S)-1-(2-cyanoacetyl)-4-methyl) piperidin-3-yl)(methyl) Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)aminomethyl Acyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo [4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 4-1 (E)-9-((2-Hydroxy-5-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2,9-dioxo Hetero-4,7-diaza Heteroundecyl)phenyl)diazenyl)benzoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo[4,5-g ]isoquine Lino[3,2-a]isoquinoline-7-cation
  • Example 4A 9-((5-((E)-(4-((((((2-(4-(((3S,4S)-1-(2-cyanoacetyl)-4-methyl) piperidin-3-yl)(methyl) Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)aminomethyl Acyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo [4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation and
  • Example 4B 9-((5-((Z)-(4-((((((2-(4-(((3S,4S)-1-(2-cyanoacetyl)-4-methyl) piperidin-3-yl)(methyl) Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)aminomethyl Acyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo [4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 4-1 To a solution of Example 4-1 (156 mg, 0.19 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL), followed by stirring at room temperature for 20 minutes. The reaction was complete as monitored by LCMS. The reaction solution was concentrated under reduced pressure, drained by oil pump, dissolved in dichloromethane (2 mL) solution, cooled to 0° C., N,N-diisopropylethylamine (101 mg, 0.78 mmol) was added, and Example 1- 11 (94 mg, 0.19 mmol) was stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS.
  • reaction solution was concentrated under reduced pressure, and the crude product was separated by Prep-HPLC (acetonitrile/water (containing 0.1% trifluoroacetic acid) gradient washing) to give the title compound 4A (6.0 mg, 3.0%) as a yellow solid; 4B (6.0 mg, 3.0%) ) as a yellow solid.
  • Prep-HPLC acetonitrile/water (containing 0.1% trifluoroacetic acid) gradient washing
  • Example 5 9-((2-(5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetyl)- 4-Methylpiperidin-3-yl) (methyl yl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)amino Formyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzoylamino)ethyl)(methyl)carbamoyl)oxo)-10-methoxy yl-5,6-dihydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 5-1 (E)-9-(((2-(2-hydroxy-5-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2, 9-dioxa-4,7-di Azaundecyl)phenyl)diazenyl)benzamido)ethyl)(methyl)carbamoyl)oxo)-10-methoxy-5,6-di Hydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 5-2 ((E)-9-(((2-(2-hydroxy-5-((4-(((methyl(2-(methylamino)ethyl)carbamoyl)oxy Generation) A (yl)phenyl)diazenyl)benzamido)ethyl)(methyl)carbamoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]di Oxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 5-1 To a solution of Example 5-1 (470 mg, 0.53 mmol) in methanol (2 mL) was added a hydrochloric acid ethyl acetate solution (4 mol/L, 2 mL), followed by stirring at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane (10 mL), concentrated under reduced pressure again, repeated twice, and oil pumped to dryness to obtain the title compound (390 mg, 93.5%) as a yellow solid.
  • Example 5 9-((2-(5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetyl)- 4-Methylpiperidin-3-yl) (methyl yl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)amino Formyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzoylamino)ethyl)(methyl)carbamoyl)oxo)-10-methoxy yl-5,6-dihydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 5-2 A solution of Example 5-2 (390 mg, 0.49 mmol) in dichloromethane (5 mL) was cooled to 0 °C, N,N-diisopropylethylamine (254 mg, 1.97 mmol) was added, and the Examples 1-11 (235 mg, 0.49 mmol) were stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The reaction solution was diluted with dichloromethane (50 mL), washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to normal phase column chromatography (0.1% formic acid in dichloromethane and methanol as eluents) to give the title compound (114 mg, 20%) as a yellow solid.
  • Example 6 9-((2-(6-(5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetyl) yl)-4-methylpiperidine-3- yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbonweedamido ⁇ oxalamido>)ethyl)(methyl) yl)carbamoyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzamido)hexanoylamino)ethyl)(methyl)amino Formyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline -7-Positive ion
  • Example 6-1 Methyl (E)-6-(2-hydroxy-5-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2,9-di oxa-4,7- Diazaundecyl)phenyl)diazenyl)benzamido)hexanoate
  • reaction solution was diluted with ethyl acetate (150 mL), washed with water (100 mL) four times, saturated brine (100 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 6-2 (E)-6-(2-hydroxy-5-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2,9-dioxa) -4,7-Diazepine Undecyl)phenyl)diazenyl)benzamido)hexanoic acid
  • Example 6-1 (800 mg, 1.3 mmol) was dissolved in methanol (5 mL) and water (2 mL), and lithium hydroxide monohydrate (247 mg, 6.5 mmol) was added. The reaction solution was stirred at 65°C for 1 hour. After monitoring the reaction by LCMS, it was cooled to room temperature, neutralized with dilute hydrochloric acid to pH 4-5, extracted with 100 mL of ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound ( 784 mg, 100%) as a yellow solid.
  • Example 6-3 (E)-9-(((2-(6-(2-hydroxy-5-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl -2,9-dioxa-4,7- Diazaundecyl)phenyl)diazenyl)benzamido)hexamido)ethyl)(methyl)carbamoyl)oxo)-10- Methoxy-5,6-dihydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 6-2 To a mixture of Example 6-2 (820 mg, 1.37 mmol), Intermediate C (693 mg, 1.64 mmol) and DMF (1 mL), O-(7-nitrobenzotriazole) was added sequentially -N,N,N,N-tetramethylurea hexafluorophosphate (780 mg, 2.05 mmol), diisopropylethylamine (706 mg, 5.47 mmol). After the addition was complete, the mixture was stirred at room temperature for 0.5 hour.
  • reaction solution was diluted with dichloromethane (100 mL), washed with water (50 mL*4) and brine (50 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • Example 6 9-((2-(6-(5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetyl) yl)-4-methylpiperidine-3- yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbonweedamido ⁇ oxalamido>)ethyl)(methyl) yl)carbamoyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzamido)hexanoylamino)ethyl)(methyl)amino Formyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline -7-Positive ion
  • Example 6-3 To a solution of Example 6-3 (525 mg, 0.52 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL), followed by stirring at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The reaction solution was concentrated under reduced pressure, drained by oil pump and dissolved in dichloromethane (2 mL), the solution was cooled to 0° C., N,N-diisopropylethylamine (270 mg, 2.09 mmol) was added, and Example 1 was added. -11 (249 mg, 0.52 mmol) was stirred at room temperature for 0.5 h. The reaction was complete as monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the crude product was separated by Prep-HPLC (acetonitrile/water (containing 0.1% trifluoroacetic acid) gradient wash) to give the title compound (135 mg, 21%) as a yellow solid.
  • Prep-HPLC acetonitrile/water
  • Example 7 9-((2-(14-((4-(((((2-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methyl) piperidin-3-yl)(methyl) Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)aminomethyl Acyl)oxo)methyl)phenyl)amino)-14-carbonyltetradecanoylamino)ethyl)(methyl)carbamoyl)oxo)-10-methoxy- 5,6-Dihydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 7-2 14-((4-(((tert-butyldimethylsilyl)oxo)methyl)phenyl)amino)-14-carbonyltetradecane acid
  • Example 7-1 To a solution of Example 7-1 (4280 mg, 18.06 mmol) and tetrasebacic acid (6989 mg, 27.09 mmol) in dichloromethane (43 mL) was added N,N-diisopropylethylamine (4659 mg, 36.12 mmol), cooled to 0 °C and stirred for 20 min. To the reaction solution was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (10.3 g, 27.09 mmol). The reaction was warmed to room temperature and stirred for 16 hours.
  • reaction solution was diluted with dichloromethane (20 mL) and washed with water (40 mL).
  • the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 7-3 9-(((2-(14-((4-(((tert-butyldimethylsilyl)oxo)methyl)phenyl)amino)-14-carbonyl tetradecanoylamino)ethyl)(methyl)carbamoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo[4,5-g] isoquine Lino[3,2-a]isoquinoline-7-cation
  • Example 7-4 9-(((2-(14-((4-(hydroxymethyl)phenyl)amino)-14-carbonyltetradecanoylamino)ethyl)(methyl)amino ylformyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquino Linen-7-cation
  • Example 7-3 (2100 mg, 2.38 mmol) in tetrahydrofuran (30 mL) was added pyridine hydrogen fluoride (753 mg, 9.53 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was monitored by LCMS, diluted with dichloromethane (30 mL), washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1360 mg, 74.3%) as a white solid.
  • Example 7-5 10-Methoxy-9-((methyl(2-(14-carbonyl-14-((4-(4,7,10,10-tetramethyl-3,8-di carbonyl-2,9- Dioxa-4,7-diazaundecyl)phenyl)amino)tetradecanoylamino)ethyl)carbamoyl)oxo)-5,6-dihydro- [1,3]Dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 7-4 To Example 7-4 (675 mg, 0.88 mmol) in dichloromethane (10 mL) was slowly added triethylamine (267 mg, 2.64 mmol) at 0°C. A solution of 4-nitrobenzyl chloride (265 mg, 1.32 mmol) in dichloromethane (1 mL) was slowly added dropwise, the reaction was stirred at room temperature for 1 hour, the reaction was cooled to 0 °C, and tert-butylmethane was slowly added dropwise. yl (2-(methylamino)ethyl)carbamate (249 mg, 1.32 mmol) in dichloromethane (1.32 mL), and the reaction was stirred at room temperature for 1 hour.
  • reaction solution was washed with water (20 mL*2), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 7 9-((2-(14-((4-(((((2-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methyl) piperidin-3-yl)(methyl) Amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)aminomethyl Acyl)oxo)methyl)phenyl)amino)-14-carbonyltetradecanoylamino)ethyl)(methyl)carbamoyl)oxo)-10-methoxy- 5,6-Dihydro-[1,3]dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 7-5 210 mg, 0.214 mmol
  • dichloromethane (2 mL) a solution of Example 7-5 (210 mg, 0.214 mmol) in dichloromethane (2 mL) was placed in a single-necked flask, trifluoroacetic acid (0.4 mL) was added, and the reaction solution was stirred at room temperature for 15 minutes. After the reaction was monitored by LCMS, the reaction solution was concentrated under reduced pressure, dichloromethane (1 mL), N,N-diisopropylethylamine (0.1 mL, 0.64 mmol) were added, Example 1-11 (102 mg, 0.21 mmol) and reacted at room temperature for 15 minutes.
  • reaction solution was concentrated under reduced pressure, N,N-dimethylformamide (2 mL) was added, and the sample was directly injected, which was separated by Prep-HPLC (acetonitrile/water (containing 0.1% trifluoroacetic acid) gradient washing) to obtain the target compound ( 15.2 mg, 5.8%) as a yellow solid.
  • Prep-HPLC acetonitrile/water (containing 0.1% trifluoroacetic acid) gradient washing
  • Example 8 9-((5-(5-((E)-(4-((((2-(4-(((3S,4S)-1-(2-cyanoacetyl)-4 -Methylpiperidin-3-yl) (methyl yl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)amino Formyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzamido)pentanoyl)oxo)-10-methoxy-5,6-dihydro- [1,3]Dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 8-1 Methyl (E)-5-(2-hydroxy-5-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2,9-di oxa-4,7- Diazaundecyl)phenyl)diazenyl)benzamido)valerate
  • Example 8-2 (E)-5-(2-hydroxy-5-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2,9-dioxa) -4,7-Diazepine Undecyl)phenyl)diazenyl)benzamido)valeric acid
  • Lithium hydroxide monohydrate (1157 mg, 27.5 mmol) was added to a solution of Example 8-1 (3300 mg, 5.51 mmol) in methanol (30 mL) and water (15 mL), and the reaction was heated under reflux at 65°C for 1 hour. . After cooling, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid. Extracted with ethyl acetate (100 mL) three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (3000 mg, 93.1%) as an orange solid.
  • Example 8-3 (E)-9-((5-(2-hydroxy-5-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2,9 -Dioxa-4,7-di azaundecyl)phenyl)diazenyl)benzamido)pentanoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxin azolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 8 9-((5-(5-((E)-(4-((((2-(4-(((3S,4S)-1-(2-cyanoacetyl)-4 -Methylpiperidin-3-yl) (methyl yl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)amino Formyl)oxo)methyl)phenyl)diazenyl)-2-hydroxybenzamido)pentanoyl)oxo)-10-methoxy-5,6-dihydro- [1,3]Dioxazolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 8-3 To Example 8-3 (300 mg, 0.34 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 15 minutes, the solution was concentrated under reduced pressure, N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (95.8 mg, 0.74 mmol) were added, Example 1-11 (193 mg, 0.4 mmol). The reaction was carried out at room temperature for 15 minutes.
  • Example 10 9-((3-(2-((E)-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4 -Methylpiperidine-3- yl)(methyl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbonweedamido ⁇ oxalamido>)ethyl)(methyl) yl)carbamoyl)oxo)methyl)phenyl)diazenyl)phenyl)propionyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxin azolo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 10-1 Under ice-water bath cooling, sodium periodate (23.1 g, 107 mmol) was added to a solution of Example 10-1 (8.8 g, 53 mmol) in tetrahydrofuran (120 mL) and water (30 mL). Stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with water (100 mL), adjusted to weakly acidic pH with hydrochloric acid (2M), and extracted with ethyl acetate (450 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was slurried with ethyl acetate (100 mL) to give the title compound (4.5 g, 46%) as a yellow solid.
  • Example 10-4 (E)-3-(2-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2,9-dioxa-4,7 - Diaza-11 Alkyl)phenyl)diazenyl)phenyl)propionic acid
  • Example 10-3 (3.7 g, 13.0 mmol) and bis(p-nitrobenzene)carbonate (4.752 g, 15.6 mmol) were mixed in dichloromethane (50 mL), and dichloromethane was added dropwise under ice-water cooling. Isopropylethylamine (3.361 g, 26.0 mmol). The reaction solution was stirred at room temperature for 30 minutes, and then tert-butylmethyl(2-(methylamino)ethyl)carbamate (3.184 g, 16.9 mmol) was added dropwise to the reaction solution at 0°C. After completion of the dropwise addition, the reaction solution was reacted at room temperature for 1 hour and then heated to 40°C and stirred for 2 hours.
  • Example 10-5 (E)-10-methoxy-9-((3-(2-((4-(4,7,10,10-tetramethyl-3,8-dicarbonyl-2 ,9-dioxa- 4,7-diazaundecyl)phenyl)diazenyl)phenyl)propionyl)oxo)-5,6-dihydro-[1,3]dioxazolo[4,5 -g]isoquine Lino[3,2-a]isoquinoline-7-cation
  • Example 10-4 (650 mg, 1.3 mmol) and pyridine (412 mg, 5.2 mmol) were mixed in dichloromethane (30 mL) and oxalyl chloride (486 mg, 1 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 30 minutes, and the conversion of the starting material was monitored by LCMS. The reaction solution was concentrated under reduced pressure, pumped dry and dissolved in acetonitrile (5 mL), added dropwise to intermediate A-8 (420 mg, 1.3 mmol) and pyridine (412 mg, 5.2 mmol) in acetonitrile (30 mL) solution.
  • the reaction solution was stirred at room temperature for 20 minutes, and the complete conversion of the starting material was monitored by LCMS.
  • the reaction solution was concentrated under reduced pressure, diluted with dichloromethane (100 mL), washed with water (100 mL) and diluted hydrochloric acid (1N, 100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 10 9-((3-(2-((E)-(4-((((2-(4-(((3R,4R)-1-(2-cyanoacetyl)-4 -Methylpiperidin-3-yl) (methyl yl)amino)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)amino Formyl)oxo)methyl)phenyl)diazenyl)phenyl)propionyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo[ 4,5- g]Isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 10-5 To a solution of Example 10-5 (217 mg, 0.27 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL) and stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The reaction solution was concentrated under reduced pressure, drained by oil pump, dissolved in N,N-dimethylformamide (1.5 mL) solution, cooled to 0°C, and added with N,N-diisopropylethylamine (139 mg, 1.1 mmol) , add Example 1-11 (258 mg, 0.54 mmol) and stir at room temperature for 0.5 hours.
  • reaction solution was quenched by adding 1N hydrochloric acid, directly injected, and separated by Prep-HPLC (acetonitrile/water (containing 0.1% trifluoroacetic acid) gradient washing) to obtain the title compound (63.0 mg, 22.4%) as a yellow solid.
  • Example 11 (E)-9-((5-(5-((4-(((((2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl ) azetidin-3-yl)-1H-pyrazole- 4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)carbamoyl)oxy substituted)methyl)phenyl)diazenyl)-2-hydroxybenzamido)pentanoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazole and [4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 8-3-A (E)-9-((5-(2-hydroxy-5-((4-(((methyl(2-(methylamino)ethyl)carbamoyl)oxy substituted)methyl)benzene yl)diazenyl)benzoylamino)pentanoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazolo[4,5-g]isoquinoline morpholino [3,2-a]isoquinoline-7-cation hydrochloride
  • Example 8-3 To a solution of Example 8-3 (7.7 g, 7.13 mmol) in ethyl acetate (35 mL) was added hydrochloric acid in ethyl acetate (4N, 70 mL) at 0°C, and reacted at 25°C for 1 hour. After the reaction was monitored by LCMS, the reaction solution was filtered, and the filter cake was rinsed with ethyl acetate to obtain the title compound (6.8 g, 110%) as a red solid.
  • Example 1-A 4-Nitrophenyl 4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazole-4 -base)- 7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate
  • Example 11 (E)-9-((5-(5-((4-(((((2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl ) azetidin-3-yl)-1H-pyrazole- 4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carbon weedamido ⁇ oxalamido>)ethyl)(methyl)carbamoyl)oxy substituted)methyl)phenyl)diazenyl)-2-hydroxybenzamido)pentanoyl)oxo)-10-methoxy-5,6-dihydro-[1,3]dioxazole and [4,5-g]isoquinolino[3,2-a]isoquinoline-7-cation
  • Example 8-3-A To a mixture of Example 8-3-A (118 mg, 0.15 mmol), N-methylmorpholine (19 mg, 0.18 mmol) and N,N-dimethylformamide (2 mL) was added Example 1-A (100 mg, 0.18 mmol). Stir at room temperature for 2 hours. Complete conversion of starting material was monitored by LCMS. The reaction was quenched with hydrochloric acid (1N). The reaction solution was directly injected and separated by Prep-HPLC (acetonitrile/water (containing 0.1% trifluoroacetic acid) gradient wash) to obtain the title compound (93 mg, 42%) as a yellow solid.
  • Prep-HPLC acetonitrile/water (containing 0.1% trifluoroacetic acid) gradient wash
  • the following compounds can be obtained by a method similar to that in Example 1, substituting the corresponding starting materials.
  • the reaction solvent of Preparation Example 1-A can be dichloromethane, N,N-dimethylformamide, etc., and the base can be triethylamine, 2,6-lutidine and the like.
  • the reaction solvent of Preparation Example 1 can be N,N-dimethylformamide, N,N-dimethylacetamide and the like.
  • Biological test 1 co-drug release experiment in mouse duodenum or colon content in vitro (humen content ex vivo assay).
  • C57BL/6 male mice (6-8 weeks old) were euthanized with carbon dioxide and dissected. Remove the duodenum and colon segments into a 1.5 ml centrifuge tube while adding PBS solution. Cut the intestinal segment lengthwise, shake to release the intestinal contents, and mix by inversion.
  • the dimethyl sulfoxide solutions of the example compounds were prepared respectively, and 20 microliters of the above dimethyl sulfoxide solutions were respectively placed in 1 ml of duodenal or colonic contents in PBS solution. Repeated inversion and mixing, placed in a water bath at 37 degrees.
  • Table 1 The release of berberine, tofacitinib, SHR0302, and upatinib over time in different intestinal environments for Examples 1, 8, 14, and 16
  • N.D. means not detected
  • CD-1 mice were administered orally (PO, 15 mg/kg) with test compounds, and blood samples and tissue samples from each segment of the gastrointestinal tract were collected at different time points.
  • concentrations of the example co-drug compounds and their released tofacitinib and berberine in mouse plasma were determined by LC-MS/MS. Animals were approximately 6-8 weeks old at the start of the dosing experiments. Blood and tissue sampling times: 0.5, 1, 2, 4, 8 and 24 hours after administration. Establish biological sample analysis methods and sample detection methods.
  • an oxazolone-induced colitis model was established by referring to the method of Heller et al. On the first day, the skin on the back of the mouse neck was shaved (2cm ⁇ 2cm), and 150ul of 3% oxazolone solution (dissolved in a 4:1 mixed solution of acetone and olive oil) was applied for sensitization. Mice were randomized on day 6 after sensitization. Then, the compound of the corresponding example (120 mg/kg) was administered by gavage, and the blank control group and the model group were given solvent, and the gavage volume was 10 ml/kg body weight.
  • the co-drug compound administration group of the embodiment can significantly improve the disease activity index.

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Abstract

本发明涉及一类肠道裂解型共药（Codrug）及其制备和用途，具体地，本发明提供了一种如式I所示的共药化合物。本发明还提供了使用这类化合物治疗胃肠道自身免疫性疾病、炎症性疾病和癌症的方法；以及用于制备这类化合物的方法和中间物。

Description

一类肠道裂解型共药及其制备和用途 技术领域
本发明涉及一类肠道裂解型共药化合物。本发明还涉及包括这类化合物的药物组合物；使用这类化合物治疗胃肠道自身免疫性疾病、炎症性疾病和癌症的方法；以及用于制备这类化合物的方法和中间物。
背景技术
JAK家族(JAK1、JAK2、JAK3、TYK2)抑制剂如托法替尼已被批准用于治疗患有中度到重度活动性类风湿性关节炎(rheumatoid arthritis，RA)和中重度溃疡性结肠炎(ulcerative colitis，UC)的某些患者。在许多JAK家族抑制剂的临床试验中，报道了大量全身性药物暴露介导的不良事件，包含严重感染、机会性感染及实验室异常，例如淋巴细胞減少症、中性粒白细胞减少症、肝酶升高、脂质升高和血清肌酐升高。目前上市的JAK抑制剂均带有安全风险的黑框警告，包含严重感染、恶性肿瘤以及血栓风险。因此，开发新一代更安全的JAK家族抑制剂药物在治疗局部发炎疾病时将需要限制其全身性暴露量。例如治疗UC时，增加JAK家族抑制剂在胃肠道中的分布量，同时最小化药物的全身性暴露量。
小檗碱(Berberine)又名黄连素，是从黄连等植物中提取的一种异喹啉生物碱。小檗碱是一种非常安全的药物，在传统中药的应用中已有一千多年历史。其生物利用度很低。临床上主要用于治疗腹泻、肠道感染等胃肠道疾病。近年来的研究也发现小檗碱在心血管疾病、糖脂代谢调控方面也具有一定的治疗前景。小檗红碱(Berberrubine)是小檗碱在体内的主要代谢产物。动物模型研究发现，小檗红碱对溃疡性结肠炎具有与小檗碱类似的治疗效果。然而截止目前，本领域尚缺乏提高小檗碱或其类似物的治疗效果的有效途径。
慢性肠炎主要包括溃疡性结肠炎和克罗恩病两种类型。这些慢性肠道炎性疾病病程漫长，常反复发作，且长期的炎症易发生癌变。近年来慢性肠炎发病率呈上升趋势。目前认为慢性肠炎的发病可能与遗传、环境、免疫和微生物有关，但其确切机制并不清楚。临床上的治疗以氨基水杨酸类药物、肾上腺糖皮质激素类药物及免疫抑制剂为主，但都存在一定的不良反应，如胃肠道不适、过敏反应等。我们在此前的工作中发现，JAK抑制剂联合小檗碱类似物能协同作用达到更加优越的治疗胃肠道炎症性疾病的效果。本发明通过设计一类肠道裂解型小檗碱类似物和JAK抑制剂共药化合物,使得两个药物分子在胃肠道释放和富集，而化合物在全身系统性的暴露得到限制。两个药物分子协同作用达到更优的治疗效果和安全性。
发明内容
在一个方面，本发明提供一种小檗碱类似物(优选为小檗红碱)和第二治疗剂JAK家族抑制剂(优选为托法替尼、乌帕替尼、SHR0302)通过一个可裂解的共价连接组成的共药，所述的共药被设计成能够在胃肠道定向释放JAK家族抑制剂和第一治疗剂，进而增加JAK家族抑制剂和所述的第一治疗剂在胃肠道炎症部位的含量，且最小化其全身性暴露量。
本发明的第一方面，提供了一种如下式I所示的共药化合物，所述的共药化合物是由 第一药物分子、第二药物分子和linker前体偶联形成的：
D 1-linker-D 2；
I
其中，
D 1为第一药物基团；所述的第一药物基团为第一药物分子中可与linker连接的结构片段(即，第一药物分子通过与linker的前体进行偶联或缩合反应后，脱落活性官能团后形成的片段，该片段不包括linker部分)；
D 2为第二药物基团；所述的第二药物基团为第二药物分子中可与linker连接的结构片段；且所述的第一药物分子与第二药物分子为具有协同作用的药物分子(即，第二药物分子通过与linker的前体进行偶联或缩合反应后，脱落活性官能团后形成的片段，该片段不包括linker部分)；
其中，所述的连接可以是失去一个氢原子从而形成共价连接，或者通过其他方式与linker共价连接，如通过羟基、羧基、胺基等活性基团的缩合反应形成的共价连接；
且linker具有选自下组(a)、(b)或(c)的结构，各式中，J 1与第一药物基团连接，且J2与第二药物基团连接；
(a)
Figure PCTCN2021107208-appb-000001
所述的Glu具有选自下组的结构：
Figure PCTCN2021107208-appb-000002
其中，所述的A环选自下组：C6-C10芳基、5-10元杂芳基、3-12元杂环基；
(b)
Figure PCTCN2021107208-appb-000003
其中，所述的R 4选自下组：H、C 1-6的烷基、C 1～6烷氧基-C 1～4亚烷基-、C 3～12的环烷基，C 3～12环烷基-C 1～4亚烷基-；
(c)
Figure PCTCN2021107208-appb-000004
其中，所述的B环和C环各自独立地选自下组：C6-C10芳基、5-10元杂芳基、3-12元杂环基；
上述式(a)、(b)和(c)中，所述的J 1、J 2各自独立地为-(Y) z-，且所述的Y选自下组：-NH-、-C(O)-、-C(O)O-、-NHC(O)NH-、-CH＝CH-、-NH(CH 2)-、-NHC(O)-、-CH 2-、-OCH 2CH 2O-、-O-、-S-、-P(O) 2O-、-S(O) 2-、-S(O)-、-C(O)NH-、-N＝N-；所述的Y可以被一个或多个R所取代，条件是各个Y共同组成化学上稳定的结构；
各个L 1、L 2、L 3、L 4、L 5、L 6和L 7各自独立地选自下组：C1-C8的亚烷基、C 1～6亚烷基-O-C 1～4亚烷基(-CH 2-O-CH 2-)、C 2～6烯基、C 2～6炔基、C 3～6环烷基、C6-C10亚芳基、5-10个原子的亚杂芳基、3-12个原子组成的亚杂环基，或选自下组的基团：-NH-、-C(O)-、-CH＝CH-、-NH(CH 2)-、-NHC(O)-、-CH 2-、-OCH 2CH 2O-、-O-、-S-、-P(O) 2O-、-S(O) 2-、-S(O)-、-C(O)NH-、-C(O)O-、-NHC(O)NH-、-N＝N-、-C(O)NH(CH 2) (1-4)-NHC(O)-；前提是各个L 1、L 2、L 3、L 4、L 5、L 6和L 7形成稳定的二价基团；
且所述的Y、L 1、L 2、L 3、L 4、L 5、L 6和L 7任选地被一个或多个R取代，且所述的R选自下组：H、-OH、C1-C4烷基、卤素、氰基、硝基、-OR 4、C 1～6卤代烷基、磺酸基、C0-C4烷基-S(O) 2-C1-C4烷基、甲酰基、羧基、-COOR 4；条件是各个Y、L 1、L 2、L 3、L 4、L 5、L 6和L 7共同组成化学上稳定的结构；
m、n、p、q、r、s和t各自独立地选自0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15或16；
z选自下组：0、1、2、3、4、5、6；较佳地，z选自下组：1、2或3。
在另一优选例中，所述的连接包括：药物分子中失去结构片段从而形成连接位点，或通过配位键连接。
在另一优选例中，上述式(a)、(b)和(c)中，所述的J 1、J 2各自独立地为-(Y) z-，且所述的Y选自下组：-NH-、-C(O)-、-C(O)O-、-NHC(O)NH-、-CH＝CH-、-NH(CH 2)-、-NHC(O)-、-CH 2-、-OCH 2CH 2O-、-O-、-S-、-P(O) 2O-、-S(O) 2-、-S(O)-、-C(O)NH-、-N＝N-；所述的Y可以被一个或多个R所取代，条件是各个Y共同组成化学上稳定的结构；
各个L 1、L 2、L 3、L 4、L 5、L 6和L 7各自独立地选自下组：C1-C8的亚烷基、C 1～6亚烷基-O-C 1～4亚烷基(-CH 2-O-CH 2-)、C 2～6烯基、C 2～6炔基、C 3～6环烷基、C6-C10亚芳基、5-10个原子的亚杂芳基、3-12个原子组成的亚杂环基，或选自下组的基团：-NH-、-C(O)-、-CH＝CH-、-NH(CH 2)-、-NHC(O)-、-CH 2-、-OCH 2CH 2O-、-O-、-S-、-P(O) 2O-、-S(O) 2-、-S(O)-、-C(O)NH-、-C(O)O-、-NHC(O)NH-、-N＝N-、-C(O)NH(CH 2) (1-4)-NHC(O)-；前提是各个L 1、L 2、L 3、L 4、L 5、L 6和L 7形成稳定的二价基团；
且所述的Y、L 1、L 2、L 3、L 4、L 5、L 6和L 7任选地被一个或多个R取代，且所述 的R选自下组：H、-OH、C1-C4烷基、卤素、氰基、硝基、-OR 4、C 1～6卤代烷基、磺酸基、C0-C4烷基-S(O) 2-C1-C4烷基、甲酰基、羧基、-COOR 4；条件是各个Y、L 1、L 2、L 3、L 4、L 5、L 6和L 7共同组成化学上稳定的结构；
且m、n、p、q、r、s和t各自独立地选自0、1、2、3、4、5、6、7或8。
z选自下组：0、1、2、3、4、5、6；较佳地，z选自下组：1、2或3。
在另一优选例中，上述式(a)、(b)和(c)中，所述的J 1、J 2各自独立地选自下组：-NH-、-C(O)-、-C(O)O-、-NHC(O)NH-、-CH＝CH-、-NH(CH 2)-、-NHC(O)-、-CH 2-、-OCH 2CH 2O-、-O-、-S-、-P(O) 2O-、-S(O) 2-、-S(O)-、-C(O)NH-、-N＝N-。
在另一优选例中，所述的J 1和J 2各自独立地选自下组：亚甲基、
Figure PCTCN2021107208-appb-000005
Figure PCTCN2021107208-appb-000006
在另一优选例中，所述的J 1选自下组：亚甲基、
Figure PCTCN2021107208-appb-000007
在另一优选例中，所述的J 2选自下组：亚甲基、
Figure PCTCN2021107208-appb-000008
Figure PCTCN2021107208-appb-000009
在另一优选例中，所述的第一药物分子为小檗碱、小檗红碱及其类似物。
在另一优选例中，所述的第二药物分子为JAK家族抑制剂及其类似物。
在另一优选例中，所述的且linker具有如下所示的结构：
Figure PCTCN2021107208-appb-000010
在另一优选例中，所述的第一药物分子为如下式II、式III或式IV的药物分子：
Figure PCTCN2021107208-appb-000011
其中，
Ro、Rp、Rq、Rr、Rs和Rt各自独立地选自下组：H、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基；或位于相邻两个原子上的Ro、Rp、Rq、Rr、Rs和Rt与其连接的原子共同构成5-7元杂环；其中，所述的取代指基团上的H原子被一个或多个选自下组的取代基取代：卤素、C1-C4烷基、苯基。
在另一优选例中，所述的JAK家族抑制剂及其类似物选自下组：托法替尼 (Tofacitnib)、鲁索替尼(Ruxolitinib)、奥拉西替尼(Oclacitinib)、巴利替尼(Baricitinib)、培非替尼(Peficitinib)、阿布罗替尼(Abrocitinib)、非戈替尼(Filgotinib)、乌帕替尼(Upadacitinib)、迪高替尼(Delgocitinib)伊他替尼(Itacitinib)、菲卓替尼(Fedratinib)、得克替尼(Decernotinib)、SHR-0302、AZD-4205、ASN-002、BMS-986165、PF-06700841、PF-06651600、R-348、INCB-52793、ATI-501、ATI-502、NS-018、KL-130008，或上述分子的氘代衍生物。
在另一优选例中，所述的第一药物基团选自下组：
Figure PCTCN2021107208-appb-000012
或所述的第一药物基团为选自下组的药物分子失去一个氢原子形成的基团：
Figure PCTCN2021107208-appb-000013
Figure PCTCN2021107208-appb-000014
在另一优选例中，所述的第一药物基团具有如下式所示的结构：
Figure PCTCN2021107208-appb-000015
在另一优选例中，所述的第二药物基团选自下组：
Figure PCTCN2021107208-appb-000016
Figure PCTCN2021107208-appb-000017
在另一优选例中，所述的第二药物基团选自下组：
Figure PCTCN2021107208-appb-000018
Figure PCTCN2021107208-appb-000019
在另一优选例中，所述的第一药物基团为
Figure PCTCN2021107208-appb-000020
且所述的第二药物基团为
Figure PCTCN2021107208-appb-000021
在另一优选例中，所述的A-(L 7) p-J 2-具有如下式所示的结构：
Figure PCTCN2021107208-appb-000022
在另一优选例中，所述的-A(Glu)-(L 7) p-J 2-具有选自下组的结构：
Figure PCTCN2021107208-appb-000023
在另一优选例中，所述的-(L 1) m-和-(L 2) n-各自独立地具有选自下组的结构：
Figure PCTCN2021107208-appb-000024
Figure PCTCN2021107208-appb-000025
上述各式中，
Ra、Rb和Rc各自独立地为选自下组的氨基酸失去一个氢原子形成的基团：甘氨酸(Glycine)、丙氨酸(Alanine)、缬氨酸(Valine)、亮氨酸(Leucine)、异亮氨酸(Isoleucine)、苯丙氨酸(Phenylalanine)、色氨酸(Tryptophan)、酪氨酸(Tyrosine)、天冬氨酸(Aspartate)、组氨酸(Histidine)、天冬酰胺(Asparagine)、谷氨酸(Glutamate)、赖氨酸(Lysine)、谷氨酰胺(Glutamine)、甲硫氨酸(Methionine)、精氨酸(Arginine)、丝氨酸(Serine)、苏氨酸(Threonine)、半胱氨酸(Cysteine)、脯氨酸(Proline)。
在另一优选例中，所述的linker选自以下(A)、(B)或(C)组：
(A)组具有-L a-L-的结构，其中所述的L a具有选自下组的结构：
Figure PCTCN2021107208-appb-000026
且所述的L具有如下所示的结构，其中，*为L与L a的连接位点：
Figure PCTCN2021107208-appb-000027
(B)组：
Figure PCTCN2021107208-appb-000028
Figure PCTCN2021107208-appb-000029
(C)组：
Figure PCTCN2021107208-appb-000030
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2021107208-appb-000031
Figure PCTCN2021107208-appb-000032
Figure PCTCN2021107208-appb-000033
Figure PCTCN2021107208-appb-000034
Figure PCTCN2021107208-appb-000035
Figure PCTCN2021107208-appb-000036
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2021107208-appb-000037
Figure PCTCN2021107208-appb-000038
Figure PCTCN2021107208-appb-000039
Figure PCTCN2021107208-appb-000040
Figure PCTCN2021107208-appb-000041
本发明的第二方面，提供了一种药物组合物，其包含治疗有效量的本发明第一方面所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，以及药学上可接受的赋形剂。
在另一优选例中，所述的药物组合物为肠溶制剂。
在另一优选例中，所述的药物组合物用于治疗选自下组的疾病：胃肠道炎症性疾病(如溃疡性结肠炎、克罗恩氏病、与免疫检查点抑制剂疗法相关的结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、结肠袋炎、急/慢性胃炎，急/慢性阑尾炎)、放疗或化疗引起的胃肠炎、胃肠道的自身免疫病(如移植物抗宿主疾病、口炎性腹泻、自身免疫性肠病)、消化性溃疡、肠易激综合征、胃癌、食道癌、结肠癌。
本发明的第三方面，提供了如本发明第一方面所述的前体化合物，或其药学上可接受的盐或本发明第二方面所述的药物组合物的用途，其用于预防和治疗胃肠道功能疾病。
在另一优选例中，所述的胃肠道功能疾病为胃肠道炎症性疾病。
在另一优选例中，所述的胃肠道炎症性疾病选自下组：溃疡性结肠炎、克罗恩氏病、与免疫检查点抑制剂疗法相关的结肠炎。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了小鼠口服给药实施例8化合物后，实施例8化合物在不同组织的浓度随时间变化曲线；
图2显示了小鼠口服给药实施例8化合物后，小檗红碱在不同组织的浓度随时间变化曲线；
图3显示了小鼠口服给药实施例8化合物后，托法替尼在不同组织的浓度随时间变化曲线；
图4显示了小鼠口服给药实施例1和8化合物后，小檗红碱在不同组织含量的AUC 0-24h；
图5显示了小鼠口服给药实施例1和8化合物后，托法替尼在不同组织含量的AUC 0-24h；
图6显示了噁唑酮灌肠模型中，小鼠给药实施例8化合物后的疾病指数变化图。
具体实施方式
本发明人经过长期而深入的研究发现，将JAK家族抑制剂与小檗碱类似物制备成共药形式进行施用，对于胃肠道疾病的治疗能够取得相较于单药在同剂量下更优的治疗效果，且通过共药分子的设计，能够使药物定向释放。基于上述发现，发明人完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
在本申请中，作为基团或是其它基团的一部分，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言，术语“C1-C6烷基”指含有1至6个碳原子的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“6-10元芳环”意指具有6-10个环原子的芳环，所述环原子为碳原子。所述芳环可以单环或双环。例如苯环、萘环等类似基团。
在本申请中，作为基团或是其它基团的一部分，术语“5-10元杂芳环”意指具有5-10个环原子的杂芳环，所述环原子至少有1个(可以是1个、2个或3个)是选自氮、氧和硫的杂原子。所述杂芳环可以单环或双环。例如，嘧啶并吡唑环、吡嗪并咪唑环、吡啶并吡唑环、吡啶并咪唑环、吡啶并嘧啶环、吡啶并吡啶环。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由3至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环。
共药(co-drug)
在本文中，“共药”，“co-drug”“共载药”或“互动药物”可以互换使用，均指一种药物分子，其在体内可以被代谢从而形成两种具有不同药理学作用的药物分子。在本文中，一种典型的共药为式I所示的化合物。
所述的共药可以在体内代谢，从而形成多种不同的治疗剂，在本发明中，一种优选的第一治疗剂为JAK家族抑制剂，而第二治疗剂为小檗碱或其类似物。
第一药物分子
在本文中，“第一治疗剂”、“第一药物分子”可以互换使用，均指用于本发明的共药 的第一药物分子。所述的第一药物分子在失去基团上任一活性官能团后，可以形成第一药物基团并与共药分子的连接位点连接。
一类优选的第一药物分子为JAK家族抑制剂，其在临床上可以用于肠道疾病，如肠道炎症性疾病的治疗。所述的JAK家族抑制剂可以是本领域已知的JAK抑制剂，或者是尚未被验证具有JAK抑制活性的化合物。
示例性的JAK抑制剂形成的第一药物基团选自下组：
Figure PCTCN2021107208-appb-000042
Figure PCTCN2021107208-appb-000043
第二药物分子
在本文中，“第二治疗剂”、“第二药物分子”可以互换使用，均指用于本发明的共药的第二药物分子。所述的第二药物分子在失去基团上任一氢原子后，可以形成第二药物基团并与共药分子的连接位点连接。
本发明中，小檗碱及其类似物可以被用作为共药的第二治疗剂，优选的第二药物分子如下式II、III或IV所示：
Figure PCTCN2021107208-appb-000044
本发明化合物
本发明的化合物为式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐。
本发明的化合物可能含有一个或多个手性碳原子，因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald  Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
制备方法
下列反应方案示例性的说明了制备式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐的方法，其中各基团均如在上所述。应理解在下列反应方案中，所述通式中取代基和/或变量的组合只有在这类组合导致稳定的化合物时才是可允许的。还应理解其他的通式可由有机化学领域的技术人员通过本文公开的方法(通过应用适当取代的起始材料并利用本领域技术人员公知的方法根据需要修改合成参数)或已知方法进行制备。
在各种方面和实施例中，本发明涉及托法替尼的葡萄糖苷酸共药或其药学上可接受的盐；含有这类化合物的药物组合物；使用这类化合物治疗胃肠发炎疾病的方法；和用于制备这类化合物的方法和中间物。
本文所描述的化合物可含有一或多个手性中心。在这类情况下，特定立体异构体的描绘或命名意指所指示的立构中心具有指定的立体化学，其中应理解，除非另外指明，否则也可存在少量的其它立体异构体，其限制条件为所描绘或命名的化合物的效用并不由另一立体异构体的存在消除。
另外，如本文所用，除非另外指明，否则“本发明化合“本发明化合物”和“式I化合物”(或类似术语)意图包含药学上可接受的盐。
应用
由于本发明的共药化合物具有优异的肠道定向释放效果，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗肠道功能疾病，优选地为胃肠道炎症性疾病。
在本申请中，术语“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，术语“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，术语“肿瘤”包括但不限于神经胶质瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
在本申请中，术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
在本申请中，术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
在本申请中，术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
在本申请中，术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在 Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
在本申请中，术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
与现有技术相比，本发明的主要优点在于：
1.本发明的共药化合物本身不能被有效吸收，它能够在肠道定向释放两个药效组分，因此可以造成药效成分在胃肠道治疗部位的富集，而减少全身性的药物暴露。
2.本发明化合物能够在肠道有效释放JAK抑制剂(例如托法替尼)和小檗红碱或其类似物协同治疗胃肠道自身免疫性炎症性疾病。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
各实施例中：
分析方法I
LCMS仪器：waters Acquity UPLC-MS，UV检测器：Acquity UPLC
色谱柱：Acquity UPLC HSS T3 1.8uM,柱温40℃
流动相：A：H2O(0.1％TFA)，B：乙腈，梯度洗脱
中间体A:(10-甲氧基-9-((甲基(2-(甲基(((10-羰基-10-((5-(4,7,10,10-四甲基-3,8-二羰 基-2,9-二氧杂-4,7-二氮杂十一烷基)-2-(((2S,3R,4S,5S,6S)-3,4,5-三乙酰氧基-6-(甲酯基< 甲氧羰基>)四氢-2H-吡喃-2-基)氧代)苯基)氨基)癸基)氧代)羰基)氨基)乙基)氨基甲酰)氧 代)-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子)的制备按照如下式所 示的步骤进行：
Figure PCTCN2021107208-appb-000045
中间体A-1:(2S,3R,4S,5S,6S)-2-(4-甲酰基-2-硝基苯氧基)-6-(甲酯基<甲氧羰基>)四 氢-2H-吡喃-3,4,5-三基三乙酸酯
Figure PCTCN2021107208-appb-000046
在避光条件下，将反应物(2R,3R,4S,5S,6S)-2-溴-6-(甲酯基<甲氧羰基>)四氢-2H-吡喃-3,4,5-三基三乙酸酯(300克，755毫摩尔)，反应物4-羟基-3-硝基苯甲醛(214.6克，1284毫摩尔)和氧化银(788克，3400毫摩尔)加入到4升乙腈中并在25-30℃下搅拌5小时。LCMS监测原料完全转化。将反应液过滤，滤液减压浓缩得粗产品。粗产品用乙酸乙酯稀释，过滤，滤液分别用饱和碳酸氢钠溶液和饱和食盐水洗涤，分液，有机相用无水硫酸钠干燥。有机相减压浓缩得到得标题化合物(295克，81％)，为黄色固 体。
MS(ESI):m/z＝506.1[M+Na] +.
中间体A-2:(2S,3R,4S,5S,6S)-2-(4-(羟甲基)-2-硝基苯氧基)-6-(甲酯基<甲氧羰基>) 四氢-2H-吡喃-3,4,5-三基三乙酸酯
Figure PCTCN2021107208-appb-000047
将中间体A-1(46.5克，96毫摩尔)和19克硅胶加入到450毫升二氯甲烷和90毫升异丙醇中。反应降温到0℃，缓慢加入5.5克硼氢化钠。反应液在0℃下搅拌2小时。LCMS监测原料完全转化。将反应液过滤，向滤液中加入饱和氯化铵溶液(200毫升)，分液后，有机相用饱和食盐水(300毫升)洗涤2次，无水硫酸钠干燥，减压浓缩，得到粗品。粗品用甲基叔丁基醚打浆得到得标题化合物(340克，72.9％)，为白色固体。
MS(ESI):m/z＝508.1[M+Na] +.
中间体A-3:(2S,3S,4S,5R,6S)-2-(甲酯基<甲氧羰基>)-6-(2-硝基-4-(4,7,10,10-四甲基- 3,8-二羰基-2,9-二氧杂-4,7-二氮杂十一烷基)苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯
Figure PCTCN2021107208-appb-000048
将中间体A-2(150克，310毫摩尔)，三乙胺(62.4克，620毫摩尔)加入到1.5升二氯甲烷中。4-硝基苯基氯化酸酯(71.6克，350毫摩尔)溶于300毫升二氯甲烷中，在氮气保护和0℃下滴加到反应液中。滴加完成后，反应液在25℃下搅拌6小时。LCMS监测原料转化完全。将叔-丁基甲基(2-(甲基氨基)乙基)氨基甲酸酯(75.8克，400毫摩尔)在0℃下滴加到上一步反应液中。滴加完成后，反应液在25℃下搅拌16小时。LCMS监测原料转化完全。将反应液冷却到0℃，加入1升饱和碳酸氢钠溶液，分液收集有机相。有机相用饱和碳酸氢钠溶液洗涤(800毫升*8)，饱和食盐水洗涤(800毫升)，无水硫酸钠干燥，过滤。有机相减压浓缩，得到目标化合物(200克，92％)。
MS(ESI):m/z＝722.2[M+Na] +.
中间体A-4:(2S,3R,4S,5S,6S)-2-(2-氨基-4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂- 4,7-二氮杂十一烷基)苯氧基)-6-(甲酯基<甲氧羰基>)四氢-2H-吡喃-3,4,5-三基三乙酸酯
Figure PCTCN2021107208-appb-000049
将中间体A-3(200克，285.8毫摩尔)溶在2升甲醇和550毫升水中，缓慢加入铁粉(80克，1429.1毫摩尔)和氯化铵(153克，2858.1毫摩尔)。反应液在70℃和氮气保护下搅拌5小时。LCMS监测原料转化完全。将反应液过滤，滤饼用2升乙酸乙酯洗涤。有机相减压浓缩，得到粗产品。向粗品中加入2升乙酸乙酯和1.5升水，分液。有 机相用饱和食盐水洗涤3次(每次500毫升)，分液后，有机相用无水硫酸钠干燥，减压浓缩得到粗产品。粗品通过柱层析纯化(二氯甲烷：甲醇＝40：1)得到目标化合物(100克，52％)，为黄色油状物。
MS(ESI):m/z＝670.2[M+H] +.
1HNMR(400MHz,DMSO-d 6)δ6.83(d,J＝8.2Hz,1H),6.66(s,1H),6.50(d,J＝8.2Hz,1H),5.52–5.43(m,2H),5.12–5.03(m,2H),4.86(s,2H),4.68(d,J＝10.0Hz,3H),3.64(s,3H),3.31–3.25(m,3H),2.79(dd,J＝38.7,13.2Hz,7H),2.02(d,J＝12.9Hz,9H),1.36(s,9H).
中间体A-5:(2S,3R,4S,5S,6S)-2-(2-(10-羟基癸酰氨基)-4-(4,7,10,10-四甲基-3,8-二羰 基-2,9-二氧杂-4,7-二氮杂十一烷基)苯氧基)-6-(甲酯基<甲氧羰基>)四氢-2H-吡喃-3,4,5- 三基三乙酸酯
Figure PCTCN2021107208-appb-000050
将中间体A-4(100克，150毫摩尔)溶到N,N-二甲基甲酰胺(600毫升)中，向其加入三乙胺(51.8毫升，0.37毫摩尔)和反应物10-羟基癸酸(39.3克，210毫摩尔)，然后缓慢加入O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(79.5克，210毫摩尔)。加完料后，在氮气保护下，反应液在50℃下搅拌16小时。停止反应，将反应物用2升乙酸乙酯稀释。稀释后的反应液用水(1.5升*8)和食盐水(1.5升*2)洗涤，无水硫酸钠干燥，减压浓缩得到粗产品。粗产品柱层析纯化(二氯甲烷：甲醇＝20:1)得到标题化合物(47.0克，37％)。
MS(ESI):m/z＝862.2[M+Na] +.
中间体A-6:(2S,3S,4S,5R,6S)-2-(甲酯基<甲氧羰基>)-6-(2-(10-((甲基(2-(甲基氨基) 乙基)氨基甲酰)氧代)癸酰氨基)-4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7-二氮杂十 一烷基)苯氧基)四氢-2H-吡喃-3,4,5-三基三乙酸酯
Figure PCTCN2021107208-appb-000051
将中间体A-5(46.0克，57.7毫摩尔)和三乙胺(15.2毫升，109.8毫摩尔)溶于400毫升二氯甲烷中，在0℃和氮气保护下将4-硝基苯基氯化酸酯(14.3克，71.2毫摩尔)的二氯甲烷(60毫升)溶液滴加到反应液中。滴加完后，反应液在25-30℃下搅拌16小时。LCMS监测原料转化完成。将三乙胺(22.8毫升，164.4毫摩尔)加入到上一步反应液。然后将N1,N2-二甲基乙烷-1,2-二胺(14.5克，164.4毫摩尔)在0℃和氮气保护下滴加到上一步反应液中。滴加完后，在25-30℃下搅拌4小时。LCMS监测反应完成，反应液 用二氯甲烷(800毫升)稀释。稀释后的有机相用饱和碳酸氢钠溶液(600毫升*3)和食盐水(700毫升)洗涤，无水硫酸钠干燥，减压浓缩得到粗产品。粗产品通过正相柱层析纯化(二氯甲烷：甲醇＝10：1)得标题化合物(36.0克，68％)，为黄色油状物。
MS(ESI):m/z＝954.5[M+H] +.
中间体A-7:(2S,3R,4S,5S,6S)-2-(2-(10-(((2-((氯羰基)(甲基)氨基)乙基)(甲基)氨基甲 酰)氧代)癸酰氨基)-4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7-二氮杂十一烷基)苯氧 基)-6-(甲酯基<甲氧羰基>)四氢-2H-吡喃-3,4,5-三基三乙酸酯
Figure PCTCN2021107208-appb-000052
将三光气(11.2克，37.7毫摩尔)用100毫升二氯甲烷溶于三口烧瓶中，将中间体A-6(36.0克，37.7毫摩尔)溶入到300毫升二氯甲烷中，在0℃和氮气保护下滴加到三光气二氯甲烷溶液中。滴加完后，反应液在室温下搅拌10分钟，然后将三乙胺(15.7毫升，113.2毫摩尔)在0℃和氮气保护下滴加到反应液中。加完后，反应液在25-30℃下搅拌3小时。LCMS监测原料转化完全。反应液冷却到0℃，加入饱和碳酸氢钠溶液(300毫升)，分液。有机相用饱和碳酸氢钠溶液(300毫升*2)和饱和食盐水(200毫升)洗涤。无水硫酸钠干燥，减压浓缩后得到目标化合物(46.0克粗产品)，未作进一步纯化直接用于下一步反应。
MS(ESI):m/z＝1038.3[M+Na] +.
中间体A-8:10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离 子-9-醇酸
Figure PCTCN2021107208-appb-000053
将盐酸小檗碱(35.0克，94.3毫摩尔)置于圆底烧瓶中，油泵抽真空条件下，加热至180℃，4小时后冷却至室温。粗品用乙醇打浆，过滤，干燥得标题化合物(23.0克，73％)，为红色固体。
MS(ESI):m/z＝322.1[M] +.
中间体A：10-甲氧基-9-((甲基(2-(甲基(((10-羰基-10-((5-(4,7,10,10-四甲基-3,8-二羰 基-2,9-二氧杂-4,7-二氮杂十一烷基)-2-(((2S,3R,4S,5S,6S)-3,4,5-三乙酰氧基-6-(甲酯基< 甲氧羰基>)四氢-2H-吡喃-2-基)氧代)苯基)氨基)癸基)氧代)羰基)氨基)乙基)氨基甲酰)氧 代)-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000054
将中间体A-8(9.6克，30.0毫摩尔)用100毫升吡啶溶在三口瓶中，中间体A-7(46.0克，45.0毫摩尔)溶于300毫升吡啶中在0℃和氮气保护下滴加进三口瓶中。反应液在25℃下搅拌16小时。LCMS监测原料转化完成。将反应液减压浓缩，粗品经柱层析纯化(二氯甲烷：甲醇＝10:1)得到黑色固体粗产品。粗产品在用正相柱层析(二氯甲烷：甲醇＝3：2)纯化得到标题化合物(11.0克，22％)。
MS(ESI):m/z＝601.6(M-100+H/2) +.
1HNMR(400MHz,CDCl 3)δ11.24–10.55(m,1H),8.45(s,2H),7.83(dd,J＝35.6,27.7Hz,3H),7.42(d,J＝20.4Hz,1H),7.21–6.74(m,3H),6.27(d,J＝4.1Hz,0H),6.08(s,2H),5.78(s,0H),5.57–5.23(m,6H),5.06(d,J＝11.4Hz,2H),4.23–3.95(m,5H),3.78(d,J＝18.4Hz,3H),3.54–2.73(m,20H),2.34(t,J＝23.9Hz,2H),2.09(dt,J＝9.8,4.0Hz,8H),1.88–0.86(m,27H).
中间体B:5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨 基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲酰) 氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酸
Figure PCTCN2021107208-appb-000055
中间体B-1:2-羟基-5-((4-(羟甲基)苯基)二氮烯基)苯甲酸
Figure PCTCN2021107208-appb-000056
将4-氨基苯甲醇(2.0克，16.2毫摩尔)悬浮液在0℃的水中(30毫升)用3.4毫升浓盐酸处理，然后缓慢添加冰冷的NaNO 2(1.2克，17.0毫摩尔，8毫升)水溶液。继续在0℃下搅拌1小时后，将上述反应液加入2-羟基苯甲酸钠(2.72克，0.35毫摩尔)和碳酸钾(3.2克，22.7毫摩尔)的水溶液(25毫升)中。在整个滴加过程中，通过滴加氢氧化钠水溶液来保持反应液的pH值在13-14。将混合物在室温下搅拌1小时，用盐酸(2N)调节pH为4-5，产品析出，过滤沉淀并用水(50毫升)洗涤，真空干燥得到标题化合物(4.0克，90％)，为红色固体。
MS(ESI):m/z＝272.8[M+H] +.
中间体B:2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二氧-2,9-二氧-4,7-二氮杂环)苯基)二 氮基)苯甲酸
Figure PCTCN2021107208-appb-000057
将中间体B-1(200毫克，0.73毫摩尔)，二异丙基乙胺(114毫克，0.88毫摩尔)溶入 到5毫升二氯甲烷中，加入双(4-硝基苯基)碳酸酯(268毫克，0.88毫摩尔)。反应液在室温下搅拌48小时。将叔-丁基甲基(2-(甲基氨基)乙基)氨基甲酸酯(165毫克，0.88毫摩尔)和二异丙基乙胺(114毫克，0.88毫摩尔)在0℃下滴加到上一步反应液中。滴加完成后反应液在25℃下搅拌2小时。LCMS监测原料转化完全。反应液减压浓缩，反相柱层析得到目标化合物(195毫克，55％)，为红色固体。
MS(ESI):m/z＝508.9[M+Na] +.
1H NMR(400MHz,CDCl 3)δ8.29(d,J＝2.4Hz,1H),8.04(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),7.82(d,J＝8.4Hz,2H),7.50(d,J＝8.0Hz,2H),7.11(d,J＝9.2Hz,1H),5.10(s,2H),3.35-3.32(m,4H),2.88-2.82(m,3H),2.73-2.68(m,3H),1.32(s,9H).
中间体C:9-(((2-(13-羧基十三烷酰氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基-5,6- 二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000058
中间体C-1:9-(((2-((叔-丁氧基羰基)氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基- 5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000059
将叔丁基(2-(甲胺基)乙基)氨基甲酸酯(15.0克，86.0毫摩尔)溶于二氯甲烷(200毫升)中，冰浴下先后缓慢加入三光气(25.6克，86.0毫摩尔)和吡啶(20.0克，258毫摩尔)。室温下(15℃)搅拌1小时。TLC检测原料反应完全。反应液用水洗(200毫升)，水相用二氯甲烷(100毫升*2)萃取。合并有机相，经饱和食盐水洗，有机相无水硫酸钠干燥，过滤，减压浓缩得到中间体。将中间体溶于吡啶(20毫升)，在冰浴下加入到溶于吡啶(30毫升)的中间体A-8(27.7克，86.0毫摩尔)，反应升到室温(15℃)搅拌16小时。LCMS检测原料反应完全。反应液减压浓缩，正相柱层析纯化(二氯甲烷：甲醇＝10：1)得到黄色固体产物(6.5克，14％)。
MS(ESI):m/z＝522.1[M] +.
中间体C:9-(((2-氨基乙基)(甲基)氨基甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并 [4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子盐酸盐
Figure PCTCN2021107208-appb-000060
将中间体C-1(4.5克，8.6毫摩尔)混合于盐酸甲醇溶液(2摩尔/升，100毫升)中，室温下(15℃)搅拌过夜。LCMS检测反应完成。减压浓缩得到标题化合物(3.6克，100％)，为棕色固体。
MS(ESI):m/z＝422.1[M] +.
中间体D：9-((4-羟基苯甲基)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉 并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000061
向中间体A-8(300毫克，0.93毫摩尔)的乙腈(3毫升)溶液中加入4-(氯甲基)苯基乙酸酯(257毫克，1.4毫摩尔)，碳酸钾(257毫克，1.86毫摩尔)。反应加热至80℃，反应16小时。反应液用二氯甲烷(50毫升)稀释，过滤，滤饼用水洗(50毫升)，滤饼用正相柱层析(二氯甲烷：甲醇＝10：1)纯化后得到标题化合物(97毫克，24％)，为深红色固体。
MS(ESI):m/z＝428.1[M] +.
共药化合物的制备
实施例1:9-(((2-((((10-((2-(((2S,3R,4S,5S,6S)-6-羧基-3,4,5-三羟基四氢-2H-吡喃-2- 基)氧代)-5-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H- 吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲酰)氧代)甲基)苯 基)氨基)-10-羰基癸基)氧代)羰基)(甲基)氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基-5,6- 二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000062
实施例1-11：4-硝基苯基4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨 基)-7H-吡咯并[2,3-d]嘧啶-7-羧酸酯
Figure PCTCN2021107208-appb-000063
将托法替尼(8.9克，28.6毫摩尔)溶解于二氯甲烷溶液中(140毫升)，加入氢氧化钠(3.4克，85.6毫摩尔)和四丁基溴化铵(920毫克，2.86毫摩尔)的水溶液(48毫升)。向对硝基苯基氯甲酸酯(11.5克，57.1毫摩尔)的二氯甲烷(48毫升)溶液中，滴加上述反应液中。滴加完成后，反应液在室温下搅拌4h。LCMS监测原料转化完全。加入500毫升二氯甲烷稀释，用饱和氯化铵(200毫升)洗涤，硅藻土滤去不溶物。滤液分出有机相，然后用200毫升饱和食盐水洗涤。有机相无水硫酸钠干燥，过滤，减压浓缩。粗品用二氯甲烷和石油醚打浆，5次得标题化合物(16.3克，85％)，黄色泡沫状固体。
MS(ESI):m/z＝478.1[M+H] +.
实施例1-10：10-甲氧基-9-((甲基(2-(甲基(((10-((5-(((甲基(2-(甲基氨基)乙基)氨基 甲酰)氧代)甲基)-2-(((2S,3R,4S,5S,6S)-3,4,5-三乙酰氧基-6-(甲酯基<甲氧羰基>)四氢-2H- 吡喃-2-基)氧代)苯基)氨基)-10-羰基癸基)氧代)羰基)氨基)乙基)氨基甲酰)氧代)-5,6-二氢 -[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000064
向中间体A(4.8克，3.7毫摩尔)的二氯甲烷(40毫升)溶液中加入三氟乙酸(10毫升)，室温下搅拌1小时。LCMS监测反应完全。反应液减压浓缩，用二氯甲烷溶解(30毫升)，再次减压浓缩，尽量除去三氟乙酸，油泵抽干得标题化合物(4.43克，100％)，为黄色油状物。
MS(ESI):m/z＝601.4[M/2] +.
实施例1-12:9-(((2-((((10-((5-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3- 基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲 基)氨基甲酰)氧代)甲基)-2-(((2S,3R,4S,5S,6S)-3,4,5-三乙酰氧基-6-(甲酯基<甲氧羰基>) 四氢-2H-吡喃-2-基)氧代)苯基)氨基)-10-羰基癸基)氧代)羰基)(甲基)氨基)乙基)(甲基)氨 基甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000065
将实施例1-10(4.4克，3.7毫摩尔)的二氯甲烷(100毫升)溶液冷却至0℃，加入N,N-二异丙基乙胺(1.56克，12毫摩尔)，加入实施例1-11(1.76克，3.69毫摩尔)室温下搅拌1小时。LCMS监测反应完全。反应液用300毫升二氯甲烷稀释，依次用水，饱和食盐水洗涤，洗涤后的有机相用无水硫酸钠干燥，减压浓缩。粗品用正相柱层析(含7％-9％甲醇的二氯甲烷洗脱)分离得标题化合物(2.83克，53％)，为黄色泡沫状固体。
MS(ESI):m/z＝770.7[M/2] +.
实施例1:9-(((2-((((10-((2-(((2S,3R,4S,5S,6S)-6-羧基-3,4,5-三羟基四氢-2H-吡喃-2- 基)氧代)-5-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基)氨基)-N-甲基-7H- 吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲酰)氧代)甲基)苯基) 氨基)-10-羰基癸基)氧代)羰基)(甲基)氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基-5,6-二 氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000066
将实施例1-12(163毫克，0.105毫摩尔)的甲醇(4毫升)溶液冷却至0℃，加入碳酸钾水溶液(1毫摩尔/毫升，1毫升)。0℃下搅拌2小时。LCMS监测反应完全。反应液用醋酸调节pH值为5，然后减压浓缩。粗品经Prep-HPLC分离(乙腈/水梯度冲洗)得到标题化合物(35.7毫克，24％)，为黄色固体。
MS(ESI):m/z＝1399.5[M] +.
1H NMR:(400MHz,CD 3OD)δ10.06-9.59(m,1H),8.71-8.61(m,1H),8.15-7.98(m,4H),7.60-7.50(m,1H),7.26-7.17(m,1H),6.95-6.72(m,3H),6.72-6.66(m,1H),6.05(s,2H),5.05-4.90(m,4H),4.78-4.59(m,2H),4.21-4.08(m,2H),4.04(s,3H),3.96-3.35(m,18H),3.21-2.95(m,13H),2.29-1.84(m,3H),1.84-1.02(m,20H).
以下各个化合物采用与实施例1类似的方法，替换相应原料获得。
Figure PCTCN2021107208-appb-000067
实施例4A:9-((5-((E)-(4-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲 基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基 甲酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并 [4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
实施例4B:9-((5-((Z)-(4-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基) 氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲 酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并 [4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000068
实施例4-1:(E)-9-((2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7-二氮 杂十一烷基)苯基)二氮烯基)苯甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹 啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000069
将中间体B(486毫克，1.0毫摩尔)，中间体A-8(322毫克，1.0毫摩尔)和二环己基碳二亚胺(247毫克，1.2毫摩尔)置于单口瓶中，加入二氯甲烷(10毫升)。室温搅拌1小时，LCMS监测反应结束后，反应液过滤，减压浓缩，粗品用反相柱层析分离得标题化合物(156毫克，19.7％)，为棕色油状物。
MS(ESI):m/z＝790.1[M] +.
实施例4A:9-((5-((E)-(4-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基) 氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲 酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并 [4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子和
实施例4B:9-((5-((Z)-(4-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基) 氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲 酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并 [4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000070
向实施例4-1(156毫克，0.19毫摩尔)的二氯甲烷(2毫升)溶液中加入三氟乙酸(0.4毫升)，室温下搅拌20分钟。LCMS监测反应完全。反应液减压浓缩，油泵抽干后溶解于二氯甲烷(2毫升)溶液冷却至0℃，加入N,N-二异丙基乙胺(101毫克，0.78毫摩尔)，加入实施例1-11(94毫克，0.19毫摩尔)，室温下搅拌1小时。LCMS监测反应完全。反应液减压浓缩，粗品经Prep-HPLC分离(乙腈/水(含0.1％三氟乙酸)梯度冲洗)得到标题化合物4A(6.0毫克，3.0％)，为黄色固体；4B(6.0毫克，3.0％)，为黄色固体。
MS(ESI):m/z＝1028.4[M] +.
实施例5:9-(((2-(5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲 基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基 甲酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧 基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000071
实施例5-1:(E)-9-(((2-(2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7-二 氮杂十一烷基)苯基)二氮烯基)苯甲酰氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基-5,6-二 氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000072
将中间体C(700毫克，1.65毫摩尔)，中间体B(782毫克，1.65毫摩尔)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(477毫克，2.48毫摩尔)置于单口瓶中，加入N,N-二甲基甲酰胺(5毫升)，加入4-二甲氨基吡啶(50毫克，0.41毫摩尔)。室温搅拌1小时，加入二异丙基乙基胺(427毫克，3.31毫摩尔)。反应液室温搅拌5小时。LCMS监测反应完成后，加入1N盐酸淬灭，反应液直接进样，用反相制备分离得标 题化合物(470毫克，32％)，为黄色固体。
MS(ESI):m/z＝890.3[M] +.
实施例5-2:((E)-9-(((2-(2-羟基-5-((4-(((甲基(2-(甲基氨基)乙基)氨基甲酰)氧代)甲 基)苯基)二氮烯基)苯甲酰氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二 噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000073
向实施例5-1(470毫克，0.53毫摩尔)的甲醇(2毫升)溶液中加入盐酸乙酸乙酯溶液(4摩尔/升，2毫升)，室温下搅拌1小时。LCMS监测反应完全。反应液减压浓缩，用二氯甲烷溶解(10毫升)，再次减压浓缩，重复两次，油泵抽干得标题化合物(390毫克，93.5％)，为黄色固体。
MS(ESI):m/z＝790.2[M+H] +.
实施例5:9-(((2-(5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲 基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基 甲酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧 基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000074
将实施例5-2(390毫克，0.49毫摩尔)的二氯甲烷(5毫升)溶液冷却至0℃，加入N,N-二异丙基乙胺(254毫克，1.97毫摩尔)，加入实施例1-11(235毫克，0.49毫摩尔)室温下搅拌1小时。LCMS监测反应完全。反应液用二氯甲烷(50毫升)稀释，依次用水(50毫升)洗涤，饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，减压浓缩。粗品经正相柱层析(0.1％甲酸的二氯甲烷和甲醇为洗脱剂)得标题化合物(114毫克，20％)，为黄色固体。
MS(ESI):m/z＝1128.4[M+H] +.
1H NMR:(400MHz,CD 3OD)δ9.79-9.59(m,1H),8.59-7.87(m,7H),7.65-7.40(m,4H),7.03-6.83(m,3H),6.70-6.44(m,1H),6.08(s,2H),5.32-4.94(m,3H),3.91-3.72(m,6H),3.62-3.43(m,9H),3.35(s,3H),3.22-2.66(m,13H),2.41-2.26(m,1H),1.84-1.52(m,2H),1.36-1.26(m,4H),1.03-0.85(m,3H).
实施例6:9-(((2-(6-(5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3- 基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲 基)氨基甲酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰氨基)己酰氨基)乙基)(甲基)氨基 甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000075
实施例6-1:甲基(E)-6-(2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7- 二氮杂十一烷基)苯基)二氮烯基)苯甲酰氨基)己酸酯
Figure PCTCN2021107208-appb-000076
将中间体B(1900毫克，3.9毫摩尔)，6-氨基己酸甲酯盐酸盐(849毫克，4.6毫摩尔)和二异丙基乙基胺(2017毫克，15.6毫摩尔)溶解于N,N-二甲基甲酰胺(19毫升)中，加入O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(2228毫克，5.86毫摩尔)。在30℃下搅拌3小时。LCMS监测反应完成后，反应液用乙酸乙酯(150毫升)稀释，水(100毫升)洗涤4次，饱和食盐水(100毫升)洗涤1次，无水硫酸钠干燥，过滤，减压浓缩。粗品用正相柱层析(石油醚：乙酸乙酯＝2：1)分离得标题化合物(870毫克，36.3％)，为黄色固体。
MS(ESI):m/z＝636.2[M+Na] +.
实施例6-2:(E)-6-(2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7-二氮杂 十一烷基)苯基)二氮烯基)苯甲酰氨基)己酸
Figure PCTCN2021107208-appb-000077
将实施例6-1(800毫克，1.3毫摩尔)溶于甲醇(5毫升)和水(2毫升)中，加入一水合氢氧化锂(247毫克，6.5毫摩尔)。反应液65℃搅拌1小时。LCMS监测反应完成后，冷却至室温，用稀盐酸中和至pH值4-5，100毫升乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得标题化合物(784毫克，100％)，为黄色固体。
MS(ESI):m/z＝622.2[M+Na] +.
实施例6-3:(E)-9-(((2-(6-(2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7- 二氮杂十一烷基)苯基)二氮烯基)苯甲酰氨基)己酰氨基)乙基)(甲基)氨基甲酰)氧代)-10- 甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000078
向实施例6-2(820毫克，1.37毫摩尔)，中间体C(693毫克，1.64毫摩尔)和DMF(1毫升)的混合物中，依次加入O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(780毫克，2.05毫摩尔)，二异丙基乙胺(706毫克，5.47毫摩尔)。加完料后，室温搅拌0.5小时。LCMS监测反应完全后，将反应液用二氯甲烷(100毫升)稀释，用水(50毫升*4)、食盐水(50毫升*2)洗涤，无水硫酸钠干燥，减压浓缩得到粗产品。粗产品经硅胶柱层析纯化(甲醇：二氯甲烷＝1：12，(含0.1％甲酸))得到标题化合物(525毫克，38％)，黄色固体。
MS(ESI):m/z＝1003.3[M] +.
实施例6:9-(((2-(6-(5-((E)-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3- 基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲 基)氨基甲酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰氨基)己酰氨基)乙基)(甲基)氨基 甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000079
向实施例6-3(525毫克，0.52毫摩尔)的二氯甲烷(2毫升)溶液中加入三氟乙酸(0.4毫升)，室温下搅拌1小时。LCMS监测反应完全。反应液减压浓缩，油泵抽干后溶解于二氯甲烷(2毫升)，溶液冷却至0℃，加入N,N-二异丙基乙胺(270毫克，2.09毫摩尔)，加入实施例1-11(249毫克，0.52毫摩尔)室温下搅拌0.5小时。LCMS监测反应完全。反应液减压浓缩，粗品经Prep-HPLC分离(乙腈/水(含0.1％三氟乙酸)梯度冲洗)得到标题化合物(135毫克，21％)，为黄色固体。
MS(ESI):m/z＝1241.8[M] +.
1H NMR:(400MHz,CD 3OD)δ9.89-9.59(m,1H),8.59-8.47(m,2H),8.37-8.31(m,1H),8.12-7.93(m,2H),7.70-7.61(m,2H),7.51-7.43(m,2H),6.75-6.73(m,1H),6.05(s,2H),5.17-4.90(m,4H),3.98(s,3H),3.79-3.25(m,14H),3.23-3.06(m,9H),2.32-2.27(m,3H),1.72-1.21(m,11H),0.99-0.87(m,4H).
实施例7:9-(((2-(14-((4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基) 氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲 酰)氧代)甲基)苯基)氨基)-14-羰基十四烷酰氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基- 5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000080
实施例7-1:4-(((叔-丁基二甲基甲硅烷基)氧代)甲基)苯胺
Figure PCTCN2021107208-appb-000081
向(4-氨基苯基)甲醇(5.0克，40.6毫摩尔)，咪唑(3.04克，44.66毫摩尔)的二氯甲烷(70毫升)溶液中加入叔丁基二甲基氯硅烷(6.12克，40.6毫摩尔)，室温反应1小时。向反应液中加入乙酸乙酯(200毫升)，有机相用水洗(400毫升)，无水硫酸钠干燥，减压浓缩。残余物用正相柱分离纯化(石油醚：乙酸乙酯＝5：1)，得标题化合物(9.3克，95％)，为淡黄色液体。
MS(ESI):m/z＝238.1[M+H] +.
实施例7-2:14-((4-(((叔-丁基二甲基甲硅烷基)氧代)甲基)苯基)氨基)-14-羰基十四烷 酸
Figure PCTCN2021107208-appb-000082
向实施例7-1(4280毫克，18.06毫摩尔)和四癸二酸(6989毫克，27.09毫摩尔)的二氯甲烷(43毫升)溶液中加入N，N-二异丙基乙胺(4659毫克，36.12毫摩尔)，降温至0℃并搅拌20分钟。向反应液中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(10.3克，27.09毫摩尔)。反应升至室温搅拌16小时。反应液用二氯甲烷(20毫升)稀释并用水洗(40毫升)，有机相无水硫酸钠干燥，减压浓缩。残余物用正相柱层析分离纯化(石油醚：乙酸乙酯＝1：1),得标题化合物(6.7克，79％)，为淡黄色固体。
MS(ESI):m/z＝500.2[M+Na] +.
实施例7-3:9-(((2-(14-((4-(((叔-丁基二甲基甲硅烷基)氧代)甲基)苯基)氨基)-14-羰基 十四烷酰氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹 啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000083
向实施例7-2(1800毫克，3.77毫摩尔)和中间体C(1592毫克，3.77毫摩尔)的二氯甲烷(20毫升)溶液置于单口瓶中，在0℃下加入N，N-二异丙基乙胺(1947毫克，15.09毫摩尔)，搅拌20分钟后，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(2870毫克，7.55毫摩尔)。反应液升至室温搅拌40分钟。反应液用水(40毫升)洗，有机相无水硫酸钠干燥，减压浓缩。残余物用正相柱层析分离纯化(乙酸乙酯：石油醚＝1：1)，得目标化合物(2200毫克，66.2％)，为白色固体。
MS(ESI):m/z＝881.4[M] +.
实施例7-4:9-(((2-(14-((4-(羟甲基)苯基)氨基)-14-羰基十四烷酰氨基)乙基)(甲基)氨 基甲酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000084
向实施例7-3(2100毫克，2.38毫摩尔)的四氢呋喃(30毫升)中加入氟化氢吡啶(753毫克，9.53毫摩尔)。反应室温搅拌16小时，LCMS监测反应结束，用二氯甲烷(30毫升)稀释，水洗，无水硫酸钠干燥，减压浓缩，得到目标化合物(1360毫克，74.3％)，为白色固体。
MS(ESI):m/z＝767.3[M] +.
实施例7-5:10-甲氧基-9-((甲基(2-(14-羰基-14-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9- 二氧杂-4,7-二氮杂十一烷基)苯基)氨基)十四烷酰氨基)乙基)氨基甲酰)氧代)-5,6-二氢- [1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000085
0℃下向实施例7-4(675毫克，0.88毫摩尔)的二氯甲烷(10毫升)中缓慢加入三乙胺(267毫克，2.64毫摩尔)。缓慢滴加4-硝基苯甲基氯化酸酯(265毫克，1.32毫摩尔)的二氯甲烷(1毫升)溶液，反应室温搅拌1小时，反应降温至0℃，缓慢滴加叔-丁基甲基(2-(甲基氨基)乙基)氨基甲酸酯(249毫克，1.32毫摩尔)的二氯甲烷(1.32毫升)溶液，反应室温搅拌1小时。反应液用水洗(20毫升*2)，无水硫酸钠干燥减压浓缩。残余物用硅胶柱分离纯化(乙酸乙酯：石油醚＝1：1)，得目标化合物(240毫克，28％)，为橙黄色油状物。
MS(ESI):m/z＝981.5[M] +.
实施例7:9-(((2-(14-((4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲基) 氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲 酰)氧代)甲基)苯基)氨基)-14-羰基十四烷酰氨基)乙基)(甲基)氨基甲酰)氧代)-10-甲氧基- 5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000086
向实施例7-5(210毫克，0.214毫摩尔)的二氯甲烷(2毫升)溶液置于单口瓶中，加入三氟乙酸(0.4毫升)，反应液室温搅拌15分钟。LCMS监测反应结束后，反应液减压浓缩，加入二氯甲烷(1毫升)，N，N-二异丙基乙胺(0.1毫升，0.64毫摩尔)，实施例1-11(102毫克，0.21毫摩尔)，室温反应15分钟。反应液减压浓缩，加入N,N-二甲基甲酰胺(2毫升)后直接进样，经Prep-HPLC分离(乙腈/水(含0.1％三氟乙酸)梯度冲洗)得到得目标化合物(15.2毫克，5.8％)，为黄色固体。
MS(ESI):m/z＝1219.7[M] +.
1HNMR(400MHz,CD 3OD)δ10.039-9.792(m,1H),8.76-8.73(m,1H),8.53(s,1H),8.15(m,3H),7.64-7.62(m,1H),7.51-7.50(m,1H),7.46-7.44(m,1H),7.29-7.27(m,1H),6.93-6.91(m,1H),6.78-6.66(m,2H),6.082(s,2H),5.00-4.99(m,5H),4.06(s,3H),3.96-3.87(m,4H),3.68(s,3H),3.57-3.55(m,2H),3.48-3.44(m,4H),3.23-3.21(m,3H),3.08(s,2H),2.42-2.40(m,1H),2.33-2.29(t,J＝8.0Hz,3H),2.25-2.17(m,3H),1.71-1.54(m,7H),1.28-1.20(m,21H),1.09-0.99(m,5H).
实施例8:9-((5-(5-((E)-(4-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲 基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基 甲酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰氨基)戊酰基)氧代)-10-甲氧基-5,6-二氢- [1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000087
实施例8-1:甲基(E)-5-(2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7- 二氮杂十一烷基)苯基)二氮烯基)苯甲酰氨基)戊酸酯
Figure PCTCN2021107208-appb-000088
向中间体B(3.0克，6.17毫摩尔)，1-羟基苯并三唑(1.001克，7.41毫摩尔)，二环 己基碳二亚胺(1.783克，8.64毫摩尔)的二氯甲烷(20毫升)溶液在0℃下搅拌20分钟，向其中加入甲基5-氨基戊酸酯盐酸盐(1.212克，7.41毫摩尔)，N，N-二异丙基乙胺(1752毫克，13.6毫摩尔)，反应恢复到室温反应2小时。LCMS监测反应完全，反应液过滤，滤液减压浓缩。残余物用正相柱层析分离纯化(石油醚：乙酸乙酯＝1:1)，得标题化合物(3.34克，91％)，为红色固体。
MS(ESI):m/z＝622.2[M+Na] +.
实施例8-2:(E)-5-(2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7-二氮杂 十一烷基)苯基)二氮烯基)苯甲酰氨基)戊酸
Figure PCTCN2021107208-appb-000089
向实施例8-1(3300毫克，5.51毫摩尔)的甲醇(30毫升)，水(15毫升)溶液中加入一水合氢氧化锂(1157毫克，27.5毫摩尔)，65℃加热回流反应1小时。冷却后，将反应液用稀盐酸调PH到5。用乙酸乙酯(100毫升)萃取3次，有机相无水硫酸钠干燥，减压浓缩得标题化合物(3000毫克，93.1％)，为橙色固体。
MS(ESI):m/z＝608.2[M+Na] +.
实施例8-3:(E)-9-((5-(2-羟基-5-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7-二 氮杂十一烷基)苯基)二氮烯基)苯甲酰氨基)戊酰基)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁 唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000090
向实施例8-2(1500毫克，2.56毫摩尔)的二氯甲烷(20毫升)溶液置于单口瓶中，加入二环己基碳二亚胺(792毫克，3.84毫摩尔)，中间体A-8(908毫克，2.82毫摩尔)。反应液室温搅拌2小时。LCMS监测反应完全，反应液用水(60毫升)洗3次，有机相无水硫酸钠干燥，减压浓缩。残余物用正相柱层析分离纯化(二氯甲烷：甲醇＝10：1)，得标题化合物(367毫克，16.1％)，为橙色油状物。
MS(ESI):m/z＝889.4[M] +.
实施例8:9-((5-(5-((E)-(4-((((2-(4-(((3S,4S)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲 基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基 甲酰)氧代)甲基)苯基)二氮烯基)-2-羟基苯甲酰氨基)戊酰基)氧代)-10-甲氧基-5,6-二氢- [1,3]二噁唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000091
向实施例8-3(300毫克，0.34毫摩尔)的二氯甲烷(2.5毫升)中加入三氟乙酸(0.5毫升)。反应室温搅拌15分钟，溶液减压浓缩，加入N,N-二甲基甲酰胺(2毫升)，N，N-二异丙基乙胺(95.8毫克，0.74毫摩尔)，实施例1-11(193毫克，0.4毫摩尔)。室温反应15分钟。LCMS检测反应完成后，加入1N盐酸淬灭，反应液直接进样，经Prep-HPLC分离(乙腈/水(含0.1％三氟乙酸)梯度冲洗)得到目标化合物(62.0毫克，16％)，为黄色固体。
MS(ESI):m/z＝1127.5[M] +.
1H NMR(400MHz,CD 3OD)δ9.63-9.60(m,1H),8.70-8.62(m,1H),8.39-8.35(m,1H),8.11-8.02(m,3H),7.91-7.89(m,1H),7.68-7.66(m,2H),7.59-7.56(m,2H),7.46-7.40(m,2H),7.01-6.85(m,3H),6.09(s,2H),5.18-5.16(m,2H),4.03-4.02(m,3H),3.92-3.91(m,3H),3.81-3.73(m,3H),3.65-3.59(m,2H),3.56-3.52(m,4H),3.46-3.39(m,2H),3.24-3.18(m,5H),3.17-3.16(m,3H),2.94-2.91(m,4H),2.36-2.28(m,1H),1.99-1.94(m,2H),1.91-1.86(m,2H),1.68-1.60(m,5H),0.94-0.92(m,2H).
以下各个化合物采用与实施例8类似的方法，替换相应原料获得。
Figure PCTCN2021107208-appb-000092
实施例10:9-((3-(2-((E)-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3- 基)(甲基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲 基)氨基甲酰)氧代)甲基)苯基)二氮烯基)苯基)丙酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁 唑并[4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000093
实施例10-1:1-羟基-3,4-二氢喹啉-2(1H)-酮
Figure PCTCN2021107208-appb-000094
将双氧水(35％，22毫升)滴加入1,2,3,4-四氢喹啉(10.0克，75毫摩尔)和二水合钨 酸钠(1.9克，3.7毫摩尔)的甲醇溶液中(200毫升)。滴加完毕后，室温搅拌过夜。将反应液减压浓缩，残余物溶于水中(200毫升)，二氯甲烷萃取(100毫升*2)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品用二氯甲烷/甲醇(1：1，100毫升)打浆，过滤。滤饼干燥得标题化合物(8.8克，72％)，为棕黄色固体。
MS(ESI):m/z＝164.1[M+H] +.
1H NMR(CDCl 3,400MHz)δ9.03(br,1H),7.33(d,J＝8.0Hz,1H),7.28(t,J＝8.0Hz,1H),7.15(d,J＝8.8Hz,1H),7.05(t,J＝7.6Hz,1H),2.93(t,J＝7.6Hz,2H),2.76(t,J＝8.0Hz,2H).
实施例10-2:3-(2-亚硝基苯基)丙酸
Figure PCTCN2021107208-appb-000095
冰水浴冷下，将高碘酸钠(23.1克，107毫摩尔)加入实施例10-1(8.8克，53毫摩尔)的四氢呋喃(120毫升)和水(30毫升)的溶液中。室温搅拌1小时。反应液减压浓缩除去有机溶剂，残余物用水(100毫升)稀释，盐酸(2M)调节pH值为弱酸性，乙酸乙酯萃取(450毫升)。有机相合并后经无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品用乙酸乙酯(100毫升)打浆得到标题化合物(4.5克，46％)，为黄色固体。
MS(ESI):m/z＝171.2[M+H] +.
实施例10-3:(E)-3-(2-((4-(羟甲基)苯基)二氮烯基)苯基)丙酸
Figure PCTCN2021107208-appb-000096
将实施例10-2(4.5克，25.1毫摩尔)和四氨基苄醇(3.1克，25.1毫摩尔)溶于二氯甲烷(150毫升)中，加入醋酸(15毫升)，氮气保护下室温搅拌48小时。LCMS监测原料反应完全。将反应液用二氯甲烷(100毫升)稀释，依次水洗(100毫升*2)，饱和食盐水(100毫升)洗，有机相无水硫酸钠干燥，减压浓缩，残余物用正相柱层析纯化(二氯甲烷：甲醇＝94：6)，用乙酸乙酯(30毫升)打浆得到得标题化合物(4.0克，56％)，为红色固体。
MS(ESI):m/z＝285.1[M+H] +.
实施例10-4:(E)-3-(2-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂-4,7-二氮杂十一 烷基)苯基)二氮烯基)苯基)丙酸
Figure PCTCN2021107208-appb-000097
将实施例10-3(3.7克，13.0毫摩尔)和二(对硝基苯)碳酸酯(4.752克，15.6毫摩尔)混合于二氯甲烷中(50毫升)，冰水浴冷却下滴加二异丙基乙基胺(3.361克，26.0毫摩尔)。反应液室温搅拌30分钟，然后将叔-丁基甲基(2-(甲基氨基)乙基)氨基甲酸酯(3.184克，16.9毫摩尔)在0℃下滴加到反应液中。滴加完成后反应液在室温下反应1小时然后升温至40℃搅拌2小时。LCMS监测原料转化完全。将反应液用二氯甲烷(200毫升)稀释，水洗(100毫升)，有机相经无水硫酸钠干燥，减压浓缩。残余物用正相柱层析纯化(二氯甲烷：甲醇＝10：1)得到目标化合物(1.1克，17％)，为黄色化固体。
MS(ESI):m/z＝521.1[M+Na] +.
实施例10-5:(E)-10-甲氧基-9-((3-(2-((4-(4,7,10,10-四甲基-3,8-二羰基-2,9-二氧杂- 4,7-二氮杂十一烷基)苯基)二氮烯基)苯基)丙酰)氧代)-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹 啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000098
将实施例10-4(650毫克，1.3毫摩尔)和吡啶(412毫克，5.2毫摩尔)混合于二氯甲烷中(30毫升)，室温下滴加草酰氯(486毫克，1毫摩尔)。反应液室温搅拌30分钟，LCMS监测原料已转化。将反应液减压浓缩，油泵抽干然后将其溶解于乙腈中(5毫升)，滴加到中间体A-8(420毫克，1.3毫摩尔)和吡啶(412毫克，5.2毫摩尔)的乙腈(30毫升)溶液中。反应液室温搅拌20分钟，LCMS监测原料已转化完全。将反应液减压浓缩后用二氯甲烷(100毫升)稀释，用水(100毫升)，稀盐酸(1N，100毫升)洗涤，有机相无水硫酸钠干燥，减压浓缩。残余物用正相柱层析纯化(二氯甲烷：甲醇＝92：8，含0.1％三氟乙酸)得到目标化合物(217毫克，21％)，为黄色化油状物。
MS(ESI):m/z＝803.2[M+H] +.
实施例10:9-((3-(2-((E)-(4-((((2-(4-(((3R,4R)-1-(2-氰基乙酰基)-4-甲基哌啶-3-基)(甲 基)氨基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基 甲酰)氧代)甲基)苯基)二氮烯基)苯基)丙酰)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5- g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000099
向实施例10-5(217毫克，0.27毫摩尔)的二氯甲烷(2毫升)溶液中加入三氟乙酸(0.4毫升)，室温下搅拌1小时。LCMS监测反应完全。反应液减压浓缩，油泵抽干后溶解于N,N-二甲基甲酰胺(1.5毫升)溶液冷却至0℃，加入N,N-二异丙基乙胺(139毫克，1.1毫摩尔)，加入实施例1-11(258毫克，0.54毫摩尔)室温下搅拌0.5小时。反应液加入1N盐酸淬灭后，直接进样，经Prep-HPLC分离(乙腈/水(含0.1％三氟乙酸)梯度冲洗)得到标题化合物(63.0毫克，22.4％)，为黄色固体。
MS(ESI):m/z＝1140.4[M] +.
1H NMR(400MHz,CD 3OD)δ9.60-9.47(m,1H),8.72-8.67(m,1H),8.19-8.07(m,3H),7.87-7.74(m,2H),7.63-7.39(m,6H),6.99-6.51(m,4H),6.09(s,2H),5.21-5.05(m,1H),4.97-4.86(m,3H),4.00-3.71(m,8H),3.66-3.37(m,8H),3.24-3.16(m,9H),3.05-2.81(m,6H),2.40-2.26(m,1H),1.90-1.77(m,1H).
实施例11:(E)-9-((5-(5-((4-((((2-(4-(1-(3-(氰基甲基)-1-(乙基磺酰)吖丁啶-3-基)-1H-吡唑- 4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲酰)氧 代)甲基)苯基)二氮烯基)-2-羟基苯甲酰氨基)戊酰基)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并 [4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000100
实施例8-3-A:(E)-9-((5-(2-羟基-5-((4-(((甲基(2-(甲基氨基)乙基)氨基甲酰)氧代)甲基)苯 基)二氮烯基)苯甲酰氨基)戊酰基)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并[4,5-g]异喹啉并 [3,2-a]异喹啉-7-正离子盐酸盐
Figure PCTCN2021107208-appb-000101
0℃下，向实施例8-3(7.7克，7.13毫摩尔)的乙酸乙酯(35毫升)溶液中加入盐酸乙酸乙酯溶液(4N，70毫升)，25℃下反应1小时。LCMS监测反应结束后，反应液过滤，滤饼用乙酸乙酯淋洗得到标题化合物(6.8克，110％)，红色固体。
MS(ESI):m/z＝789.3[M] +.
实施例1-A:4-硝基苯基4-(1-(3-(氰基甲基)-1-(乙基磺酰)吖丁啶-3-基)-1H-吡唑-4-基)- 7H-吡咯并[2,3-d]嘧啶-7-羧酸酯
Figure PCTCN2021107208-appb-000102
室温下向巴瑞克替尼(100毫克，0.27毫摩尔)，三乙基胺(109毫克，1.08毫摩尔)和二氯甲烷(5毫升)的混合物中加入对硝基苯基氯甲酸酯(108毫克，0.54毫摩尔)。反应液室温搅拌1.5小时。LCMS监测原料转化完全。将反应液用二氯甲烷(50毫升)稀释，分别用水(50毫升)，食盐水(50毫升)洗涤，有机相用无水硫酸钠干燥，减压浓缩得粗产品。粗产品用二氯甲烷(5毫升)打浆，过滤，滤饼干燥得标题化合物(100毫克，85％)，为黄色固体。
MS(ESI):m/z＝537.0[M+H] +.
实施例11:(E)-9-((5-(5-((4-((((2-(4-(1-(3-(氰基甲基)-1-(乙基磺酰)吖丁啶-3-基)-1H-吡唑- 4-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-7-碳杂草酰氨基<乙二酰氨基>)乙基)(甲基)氨基甲酰)氧 代)甲基)苯基)二氮烯基)-2-羟基苯甲酰氨基)戊酰基)氧代)-10-甲氧基-5,6-二氢-[1,3]二噁唑并 [4,5-g]异喹啉并[3,2-a]异喹啉-7-正离子
Figure PCTCN2021107208-appb-000103
向实施例8-3-A(118毫克，0.15毫摩尔)，N-甲基吗啡啉(19毫克，0.18毫摩尔)和N,N-二甲基甲酰胺(2毫升)的混合物中，加入实施例1-A(100毫克，0.18毫摩尔)。室温搅拌2小时。LCMS监测原料转化完全。反应液用盐酸(1N)淬灭。反应液直接进样，经Prep-HPLC分离(乙腈/水(含0.1％三氟乙酸)梯度冲洗)得到标题化合物(93毫克，42％)，为黄色固体。
MS(ESI):m/z＝1186.4[M] +.
1H NMR(400MHz,CD 3CN)δ9.37(s,1H),8.98-8.55(m,4H),8.18-8.02(m,4H),7.66-7.33(m,6H),7.04-6.88(m,3H),6.12(s,2H),5.29-5.09(m,1H),4.77-4.55(m,5H),4.28-4.22(m,3H),4.02(s,3H),3.77-3.46(m,9H),3.12-2.91(m,14H),1.34-1.31(m,5H).
以下化合物采用与实施例1类似的方法，替换相应原料可以得到相应的化合物。制备实施例1-A的反应溶剂可以是二氯甲烷，N,N-二甲基甲酰胺等，碱可以是三乙基胺，2,6-二甲基吡啶等。制备实施例1的反应溶剂可以是N,N-二甲基甲酰胺，N,N-二甲基乙酰胺等。
Figure PCTCN2021107208-appb-000104
Figure PCTCN2021107208-appb-000105
Figure PCTCN2021107208-appb-000106
生物测试1：共药化合物(co-drug)在小鼠十二指肠或结肠内容物中离体释放实验(humen content ex vivo assay).
C57BL/6雄性小鼠(6-8周龄)，二氧化碳安乐死后解剖。取出十二指肠和结肠段置于1.5毫升离心管，同时加入PBS溶液。纵向切开肠段，晃动释放肠内容物，颠倒混匀。分别配置实施例化合物的二甲基亚砜溶液，各取20微升上述二甲基亚砜溶液置于1毫升十二指肠或结肠内容物的PBS溶液中。反复颠倒混匀，置于37度的水浴中。在0小时，1小时，4小时，16小时，20小时的节点分别取上述溶液，加入乙腈，溶液进行涡旋，离心10分钟。取上层清液，加入内标化合物(中间体D)10微升。液相色谱质谱联用仪检测并标准曲线定量实施例化合物、小檗红碱和托法替尼的量(ng)，结果如表1中所示。结果显示，本发明的共药化合物在给药后能够在肠道内进行释放。
表1 实施例1，8，14，16在不同肠道环境下小檗红碱，托法替尼，SHR0302，乌帕替尼随时间的释放
Figure PCTCN2021107208-appb-000107
N.D.表示未检测
生物测试2：共药化合物在小鼠体内药代动力学实验
口服(PO,15mg/kg)给予CD-1小鼠测试化合物，于不同时间点采集血样和胃肠道各段组织样品。LC-MS/MS测定小鼠血浆中实施例共药化合物以及其释放出来的托法替尼和小檗红碱的浓度。给药实验开始时动物年龄约6-8周。采血和组织样品时间：给药后0.5，1，2，4，8和24小时。建立生物样品分析方法及样品检测方法。
结果如图1-5中所示。结果表明，实施例共药化合物能在小鼠肠道内释放托法替尼和小檗红碱，且共药化合物、托法替尼和小檗红碱均主要限制在肠道组织，血浆中只有极低的药物暴露。
生物测试3：共药化合物在恶唑酮诱导的小鼠结肠炎模型上的药效实验
C57BL/6小鼠，参考Heller等方法建立恶唑酮诱导结肠炎模型。第1天将小鼠颈背部皮肤剃毛(2cm×2cm)，并涂抹3％恶唑酮溶液(溶解于丙酮加橄榄油4：1混合溶液中)150ul以致敏。致敏后第6天将小鼠随机分组。随后开始灌胃给予相应实施例化合物(120mg/kg)，空白对照组和模型组给予溶剂，灌胃体积10ml/kg体重。随后第二天1.2％恶唑酮溶液50ul灌肠，空白对照组注入纯水。后续灌胃给药持续4天，每天记录疾病活动指数(Disease Activity Index，DAI)，结果如图6所示，实施例共药化合物给药组和模型组比较，能显著改善疾病活动指数。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种如下式I所示的共药化合物，所述的共药化合物是由第一药物分子、第二药物分子和linker前体偶联形成的：
    D 1-linker-D 2；
    I
    其中，
    D 1为第一药物基团；所述的第一药物基团为第一药物分子中可与linker连接的结构片段；
    D 2为第二药物基团；所述的第二药物基团为第二药物分子中可与linker连接的结构片段；且所述的第一药物分子与第二药物分子为具有协同作用的药物分子；
    且linker具有选自下组(a)、(b)或(c)的结构，各式中，J 1与第一药物基团连接，且J2与第二药物基团连接；
    Figure PCTCN2021107208-appb-100001
    所述的Glu具有选自下组的结构：
    Figure PCTCN2021107208-appb-100002
    其中，所述的A环选自下组：C6-C10芳基、5-10元杂芳基、3-12元杂环基；
    Figure PCTCN2021107208-appb-100003
    其中，所述的R 4选自下组：H、C 1-6的烷基、C 1～6烷氧基-C 1～4亚烷基-、C 3～12的环 烷基，C 3～12环烷基-C 1～4亚烷基-；
    Figure PCTCN2021107208-appb-100004
    其中，所述的B环和C环各自独立地选自下组：C6-C10芳基、5-10元杂芳基、3-12元杂环基；
    上述式(a)、(b)和(c)中，所述的J 1、J 2各自独立地为-(Y) z-，且所述的Y选自下组：-NH-、-C(O)-、-CH＝CH-、-NH(CH 2)-、-NHC(O)-、-CH 2-、-OCH 2CH 2O-、-O-、-S-、-P(O) 2O-、-S(O) 2-、-S(O)-、-C(O)NH-、-N＝N-；所述的Y可以被一个或多个R所取代，条件是各个Y共同组成化学上稳定的结构；
    各个L 1、L 2、L 3、L 4、L 5、L 6和L 7各自独立地选自下组：C1-C8的亚烷基、C 1～6亚烷基-O-C 1～4亚烷基(-CH 2-O-CH 2-)、C 2～6烯基、C 2～6炔基、C 3～6环烷基、C6-C10亚芳基、5-10个原子的亚杂芳基、3-12个原子组成的亚杂环基，或选自下组的基团：-NH-、-C(O)-、-CH＝CH-、-NH(CH 2)-、-NHC(O)-、-CH 2-、-OCH 2CH 2O-、-O-、-S-、-P(O) 2O-、-S(O) 2-、-S(O)-、-C(O)NH-、-N＝N-、-C(O)NH(CH 2) (1-4)-NHC(O)-；前提是各个L 1、L 2、L 3、L 4、L 5、L 6和L 7形成稳定的二价基团；
    且所述的Y、L 1、L 2、L 3、L 4、L 5、L 6和L 7任选地被一个或多个R取代，且所述的R选自下组：H、-OH、C1-C4烷基、卤素、氰基、硝基、-OR 4、C 1～6卤代烷基、磺酸基、甲酰基、羧基、-COOR 4；条件是各个Y、L 1、L 2、L 3、L 4、L 5、L 6和L 7共同组成化学上稳定的结构；
    m、n、p、q、r、s和t各自独立地选自0、1、2、3、4、5、6、7或8；
    z选自下组：0、1、2、3、4、5、6；较佳地，z选自下组：1、2或3。
  2. 如权利要求1所述的共药化合物，其特征在于，所述的第一药物分子为小檗碱衍生物，且为如下式II、式III或式IV的药物分子：
    Figure PCTCN2021107208-appb-100005
    其中，
    Ro、Rp、Rq、Rr、Rs和Rt各自独立地选自下组：H、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基；或位于相邻两个原子上的Ro、Rp、Rq、Rr、Rs和Rt与其连接的原子共同构成5-7元杂环；其中，所述的取代指基团上的H原子被一个或多个选自下组的取代基取代：卤素、C1-C4烷基、苯基。
  3. 如权利要求1所述的共药化合物，其特征在于，所述的第二药物分子为JAK家族抑制剂及其类似物。
  4. 如权利要求3所述的共药化合物，其特征在于，所述的JAK家族抑制剂及其类似 物选自下组：托法替尼(Tofacitnib)、鲁索替尼(Ruxolitinib)、奥拉西替尼(Oclacitinib)、巴利替尼(Baricitinib)、培非替尼(Peficitinib)、阿布罗替尼(Abrocitinib)、非戈替尼(Filgotinib)、乌帕替尼(Upadacitinib)、迪高替尼(Delgocitinib)伊他替尼(Itacitinib)、菲卓替尼(Fedratinib)、得克替尼(Decernotinib)、SHR-0302、AZD-4205、ASN-002、BMS-986165、PF-06700841、PF-06651600、R-348、INCB-52793、ATI-501、ATI-502、NS-018、KL-130008，或上述分子的氘代衍生物。
  5. 如权利要求1所述的共药化合物，其特征在于，所述的第一药物基团选自下组：
    Figure PCTCN2021107208-appb-100006
    或所述的第一药物基团为选自下组的药物分子失去一个氢原子形成的基团：
    Figure PCTCN2021107208-appb-100007
    Figure PCTCN2021107208-appb-100008
  6. 如权利要求1所述的共药化合物，其特征在于，所述的第一药物基团具有如下式所示的结构：
    Figure PCTCN2021107208-appb-100009
  7. 如权利要求1所述的共药化合物，其特征在于，所述的第二药物基团选自下组：
    Figure PCTCN2021107208-appb-100010
    Figure PCTCN2021107208-appb-100011
  8. 如权利要求1所述的共药化合物，其特征在于，所述的第二药物基团选自下组：
    Figure PCTCN2021107208-appb-100012
  9. 如权利要求1所述的共药化合物，其特征在于，所述的linker选自以下(A)、(B)或(C)组：
    (A)组具有-L a-L-的结构，其中所述的L a具有选自下组的结构：
    Figure PCTCN2021107208-appb-100013
    且所述的L具有如下所示的结构，其中，*为L与L a的连接位点：
    Figure PCTCN2021107208-appb-100014
    (B)组：
    Figure PCTCN2021107208-appb-100015
    (C)组：
    Figure PCTCN2021107208-appb-100016
    Figure PCTCN2021107208-appb-100017
  10. 如权利要求1所述的式I化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2021107208-appb-100018
    Figure PCTCN2021107208-appb-100019
    Figure PCTCN2021107208-appb-100020
    Figure PCTCN2021107208-appb-100021
  11. 一种药物组合物，其包含治疗有效量的权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，以及药学上可接受的赋形剂。
  12. 如权利要求11所述的药物组合物，其特征在于，所述的药物组合物为肠溶制剂。
  13. 如权利要求11所述的药物组合物，其特征在于，所述的药物组合物用于治疗选自下组的疾病：胃肠道炎症性疾病(如溃疡性结肠炎、克罗恩氏病、与免疫检查点抑制剂疗法相关的结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、结肠袋炎、急/慢性胃炎，急/慢性阑尾炎)、放疗或化疗引起的胃肠炎、胃肠道的自身免疫病(如移植物抗宿主疾病、口炎性腹泻、自身免疫性肠病)、消化性溃疡、肠易激综合征、胃癌、食道癌、结肠癌。
  14. 如权利要求1所述的前体化合物，或其药学上可接受的盐或权利要求11所述的药物组合物的用途，其特征在于，用于预防和治疗胃肠道功能疾病。
  15. 如权利要求14所述的用途，其特征在于，所述的胃肠道功能疾病为胃肠道炎症性疾病；较佳地，所述的胃肠道炎症性疾病选自下组：溃疡性结肠炎、克罗恩氏病、与免疫检查点抑制剂疗法相关的结肠炎。
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