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WO2018133875A1 - Jak酶抑制剂及其制备方法和用途 - Google Patents

Jak酶抑制剂及其制备方法和用途 Download PDF

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Publication number
WO2018133875A1
WO2018133875A1 PCT/CN2018/073776 CN2018073776W WO2018133875A1 WO 2018133875 A1 WO2018133875 A1 WO 2018133875A1 CN 2018073776 W CN2018073776 W CN 2018073776W WO 2018133875 A1 WO2018133875 A1 WO 2018133875A1
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Prior art keywords
compound
group
formula
substituted
unsubstituted
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PCT/CN2018/073776
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English (en)
French (fr)
Inventor
王喆
范国钦
杨赛
曾志宏
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上海长森药业有限公司
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Priority to CA3055233A priority Critical patent/CA3055233C/en
Priority to JP2019539793A priority patent/JP7112755B2/ja
Priority to AU2018209579A priority patent/AU2018209579B2/en
Priority to EP18741513.8A priority patent/EP3572415B1/en
Priority to KR1020197024793A priority patent/KR102485731B1/ko
Priority to US16/480,174 priority patent/US11524961B2/en
Publication of WO2018133875A1 publication Critical patent/WO2018133875A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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

Definitions

  • the present invention belongs to the field of pharmaceutical synthesis, and in particular, to a JAK enzyme inhibitor, a preparation method thereof and use thereof.
  • Protein kinases also known as Protein Phosphokinase, are a class of enzymes that catalyze the phosphorylation of proteins and are key factors in regulating cell signaling, including cell proliferation and cell differentiation.
  • JAK1 also known as Janus kinase-1
  • JAK2 also known as Janus kinase-2
  • JAK3 also known as JAKL or L-JAK, leukocyte Janus kinase; and Janus
  • TYK2 also known as protein-tyrosine kinase 2
  • Blocking signal transduction at the level of JAK kinase provides promise for the development of therapeutic approaches for inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and cancer. Inhibition of JAK kinase also contributes to the treatment of skin immune diseases such as psoriasis and skin sensitization.
  • Pfizer's Toficitinib has been marketed for the treatment of rheumatoid arthritis; and Incyte's rosotinib is used to treat myelofibrosis and acute graft-versus-host disease.
  • JAK enzyme inhibitors also have some obvious side effects.
  • some JAK inhibitors are prone to the following side effects: infection, including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycetes Infection (mycobacterial infection), fungal infection, decreased immunity (such as decreased NK cells), and anemia.
  • infection including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycetes Infection (mycobacterial infection), fungal infection, decreased immunity (such as decreased NK cells), and anemia.
  • Black Box is even caused by some serious side effects, such as acute tuberculosis, invasive fungal infections, bacterial infections, and some lymphomas or other tumors.
  • Studies have shown that currently available JAK inhibitors tend to have inhibitory activity against both JAK1 and JAK3, and most of these side effects are associated with inhibition of JAK3 activity.
  • JAKs family of kinases are responsible for the regulation of numerous signaling pathways. Since JAK1 and JAK3 are part of the common gamma-chain cytokine receptor complex, this has led to significant difficulties in developing inhibitors with high selectivity for JAK1.
  • a first aspect of the invention provides a compound of formula I, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • X is N or O
  • Y is N or O
  • Z is selected from the group consisting of substituted or unsubstituted C 1 -C 8 alkyl
  • W is N or C
  • R 1 , R 2 , R 3 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2- C6 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl (preferably phenyl), substituted or unsubstituted having 1- 3 5-10 membered heteroaryl (preferably 5- or 6-membered), substituted or unsubstituted benzo 5-10 membered heteroaryl selected from the group consisting of the following heteroatoms of N, O, S (more Good land is ⁇ );
  • R 4 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted, having 1-3 selected from the group N, a 3-10 membered heterocycloalkyl of a hetero atom of S, O, CH 2 OR 5 , wherein R 5 is selected from the group consisting of C 1 -C 6 alkylcarbonyl, trialkylsilyl;
  • substitution means substitution by one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of: halogen (preferably F), CN, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • halogen preferably F
  • CN C 1 -C 6 alkyl
  • halogenated C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • the XR 2 and YR 3 are the same or different.
  • X is nitrogen and YR 3 is oxygen.
  • R 1 , R 2 and R 3 are independently selected from the group consisting of a substituted or unsubstituted C1-C5 alkyl group, a substituted or unsubstituted C3-C5 ring. Alkyl, substituted or unsubstituted 3-5 membered heterocyclic group.
  • the 3-5 membered heterocyclic group has 1-2 hetero atoms selected from N, O, and S.
  • the 3-5 membered heterocyclic group is aromatic or non-aromatic, and saturated or unsaturated (e.g., a 4-5 membered heteroaryl ring group).
  • R 1 , R 2 and R 3 are independently selected from the group consisting of:
  • (a2) a substituted or unsubstituted group: a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group;
  • (a3) a substituted or unsubstituted group: oxyheteropropyl, oxetanyl, oxolyl, aziridine, azetidinyl, or azacyclopentyl;
  • At least one of R 1 , R 2 and R 3 (such as 1 or 2) is a group selected from the group (a1), (a2) and (a3).
  • At least one of R 1 , R 2 and R 3 (such as 1 or 2) is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, cyclobutene base.
  • R 1 and R 2 are each independently selected from the group consisting of C1-C5 alkyl (especially methyl, ethyl and propyl), C1-C5 haloalkyl (such as partially halogenated or fully Halogenated alkyl group, including but not limited to: -CF 3 , -C 2 H 4 F, -C 2 H 2 F 3 , -C 2 F 5 ), cyclopropyl, cyclobutyl, oxa Cyclopropyl, oxetanyl.
  • C1-C5 alkyl especially methyl, ethyl and propyl
  • C1-C5 haloalkyl such as partially halogenated or fully Halogenated alkyl group, including but not limited to: -CF 3 , -C 2 H 4 F, -C 2 H 2 F 3 , -C 2 F 5
  • cyclopropyl cyclobutyl
  • oxa Cyclopropyl ox
  • the chiral carbon atom when the compound of Formula I contains one or more chiral carbon atoms, the chiral carbon atom can be R, S, or a combination thereof.
  • the S atom adjacent to XR 2 and YR 3 may be chiral or achiral, and when the S atom is chiral, its configuration may be R. , S or a combination thereof.
  • the compound of formula I is a compound of formula II or formula III:
  • R 1 , R 2 , R 3 , R 4 , W, X, Y, Z are as defined above.
  • W is N
  • X is nitrogen
  • YR 3 is oxygen
  • the compound of formula I is a compound of formula IV:
  • R 1 , R 2 , R 3 , R 4 , W, X, Y, and Z are as defined above.
  • the compound of formula I is a racemate comprising an optically active compound of formula V and compound VI:
  • R 1 , R 2 , R 4 and Z are as defined above.
  • the compound of formula I is a compound of formula VII:
  • n is a positive integer of 2-10; and R 4 and Z are as defined above.
  • the compound of formula I is selected from the group consisting of
  • a second aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof Method, including the steps:
  • the catalyst in the step (i), is a base.
  • the catalyst in the step (i), is selected from the group consisting of tetraalkylammonium fluoride, tetraalkylammonium hydroxide, ruthenium, osmium, hydroxide, alkoxide, silicic acid. Salt, alkali metal phosphate, oxide, tertiary amine, alkali metal carbonate, alkali metal hydrogencarbonate, alkali metal hydrogen phosphate, phosphine or alkali metal salt of a carboxylic acid, or a combination thereof.
  • reaction is carried out in an organic solvent.
  • the organic solvent is selected from the group consisting of acetonitrile, dimethylacetamide, or a combination thereof.
  • the method is carried out at room temperature.
  • the method takes between 2 and 6 hours.
  • the compound of formula Ic has high yield and high purity.
  • the compound Id is prepared from a compound selected from the group consisting of PPh 3 Cl 2 , phosphorus pentachloride, thionyl chloride, N-chlorosuccinimide, or a combination thereof.
  • step (ii) is carried out in the presence of a base.
  • the compound of formula I is a compound of formula VIII, and the method comprises the steps of:
  • the compound VIII-1 and VIII-2 are reacted in the presence of a base, wherein the base is an organic base or an inorganic base.
  • the step (iv) is carried out in an organic solvent selected from the group consisting of acetonitrile or N,N-dimethylacetamide.
  • the step (v) is carried out under acidic conditions of an aqueous hydrochloric acid solution, an isopropanol hydrochloride solution, or a dioxane hydrochloride solution.
  • the step (vi) is carried out in a chlorinating agent selected from the group consisting of PPh 3 Cl 2 , phosphorus pentachloride, thionyl chloride, and N-chlorobutyl Diimide, or a combination thereof.
  • a chlorinating agent selected from the group consisting of PPh 3 Cl 2 , phosphorus pentachloride, thionyl chloride, and N-chlorobutyl Diimide, or a combination thereof.
  • the step (vii) is carried out in the presence of a base selected from the group consisting of tetraalkylammonium fluoride, tetraalkylammonium hydroxide, ruthenium, osmium, hydroxide, alcohol Salts, silicates, alkali metal phosphates, oxides, tertiary amines, alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydrogen phosphates, phosphines or alkali metal salts of carboxylic acids, or combinations thereof.
  • a base selected from the group consisting of tetraalkylammonium fluoride, tetraalkylammonium hydroxide, ruthenium, osmium, hydroxide, alcohol Salts, silicates, alkali metal phosphates, oxides, tertiary amines, alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydrogen phosphates, phos
  • the step (vii) is carried out in the presence of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, tetraalkylammonium fluoride, or a combination thereof.
  • an acid selected from the group consisting of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, tetraalkylammonium fluoride, or a combination thereof.
  • the compound of formula I is a compound of formula IX, the method comprising the steps of:
  • R 1 , R 4 are as defined in the first aspect of the invention.
  • the step (ix) is carried out in a chlorinating agent selected from the group consisting of PPh 3 Cl 2 , phosphorus pentachloride, thionyl chloride, and N-chlorobutyl Diimide, or a combination thereof.
  • a chlorinating agent selected from the group consisting of PPh 3 Cl 2 , phosphorus pentachloride, thionyl chloride, and N-chlorobutyl Diimide, or a combination thereof.
  • the step (x) is carried out in the presence of a base selected from the group consisting of tetraalkylammonium fluoride, tetraalkylammonium hydroxide, ruthenium, osmium, hydroxide, alcohol Salts, silicates, alkali metal phosphates, oxides, tertiary amines, alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydrogen phosphates, phosphines or alkali metal salts of carboxylic acids, or combinations thereof.
  • a base selected from the group consisting of tetraalkylammonium fluoride, tetraalkylammonium hydroxide, ruthenium, osmium, hydroxide, alcohol Salts, silicates, alkali metal phosphates, oxides, tertiary amines, alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydrogen phosphates, phos
  • R 1 , R 2 , R 4 , Z are as described in the first aspect of the invention.
  • a fourth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, a hydrate or solvate; (2) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises other JAK kinase inhibitors.
  • the additional JAK kinase inhibitor may be selected from the group consisting of tofacitinib, rosotinib, or a combination thereof.
  • the fifth aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a fourth Use of the pharmaceutical composition of the aspect for the preparation of a JAK kinase inhibitor.
  • the present inventors have for the first time unexpectedly discovered a novel JAK inhibitor with novel structure, excellent bioactivity and extremely excellent selectivity.
  • the selectivity of the compound of the present invention represented by the ratio of JAK3/JAK1 or the selectivity represented by the ratio of JAK3/JAK2 is increased by about 100-fold on average. Therefore, the side effects associated with the inhibition of JAK3 in the compounds of the present invention are extremely markedly lowered, and the safety will be remarkably improved.
  • the present invention has been completed on this basis.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • alkyl as used herein includes a straight or branched alkyl group.
  • C 1 -C 8 alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.
  • alkenyl as used herein, includes a straight or branched alkenyl group.
  • C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.
  • alkynyl includes a straight or branched alkynyl group.
  • C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
  • C 3 -C 8 cycloalkyl means a cycloalkyl group having 3-8 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.
  • C 1 -C 8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" means having from 3 to 10 atoms and wherein 1-3 of the atoms are A saturated or partially saturated cyclic group selected from the group consisting of heteroatoms of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from A cyclic aromatic group of the following group of heteroatoms of N, S and O. It may be a single ring or a fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
  • the groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo” means substituted with an atom selected from the group consisting of F, Cl, Br, and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond.
  • a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • proton transfer such as 1H-carbazole and 2H-carbazole.
  • Valence tautomers include interconversion through some bonding electron recombination.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
  • hydrate refers to a complex formed by the coordination of a compound of the invention with water.
  • a compound of the invention refers to a compound of formula (I), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
  • pharmaceutically acceptable salt refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the compound of the present invention has excellent inhibitory activity against JAK kinase, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are main active ingredients.
  • the pharmaceutical composition can be used for preventing and/or treating (stabilizing, alleviating or curing) JAK kinase-related diseases (for example, skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriatic arthritis, juvenile arthritis, Crohn's disease, myasthenia gravis, cancer including prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoproliferative, pancreatic cancer, leukemia, lymphoma or multiple bone marrow Tumor, etc.).
  • JAK kinase-related diseases for example, skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriatic arthritis, juvenile arthritis, Crohn's disease, myasthenia gravis, cancer including prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoproliferative, pancreatic cancer, leukemia,
  • compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • other pharmaceutically acceptable compounds e.g., anti-HBV agents.
  • the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • one or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound e.g, an anti-HBV agent
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compound of the present invention is novel in structure and has an excellent JAK kinase inhibitor effect
  • the compounds of the invention are more selective for the inhibition of JAK1.
  • the nuclear magnetic resonance spectrum was analyzed by a Bruker AV-400 (400 MHz) nuclear magnetic instrument.
  • the mass spectrometry data was analyzed by a liquid-mass spectrometer of Finnigan LCQ Advantage, among other needs, and all reactions were operated under dry argon-protected anhydrous anaerobic conditions.
  • the solid metal organic compound is stored in an argon-protected dry box.
  • Tetrahydrofuran and diethyl ether are obtained by distillation, and sodium metal and benzophenone are added thereto during distillation.
  • Dichloromethane, pentane and hexane were treated with calcium hydride.
  • the special raw materials and intermediates involved in the present invention are provided by Tianjin Changsen Pharmaceutical Co., Ltd., and other chemical reagents from Shanghai Chemical Reagent Company, Aldrich, and Acros. And other reagent suppliers to buy. If the intermediate or product required for the reaction in the synthesis is insufficient for the next step, the synthesis is repeated a plurality of times.
  • the raw materials and reagents according to the present invention can be purchased commercially or custom-made, unless otherwise specified.
  • the compounds of the invention may contain one or more asymmetric centers, such that the series of compounds may be in racemic or single enantiomeric form.
  • the compound prepared by the present invention (Formula IV) is a heterocyclic compound having a purity higher than 95%, and the structural characterization of each final product is determined by MS or/and hydrogen spectrum nuclear magnetic resonance (1H NMR) analysis, respectively.
  • MS or/and hydrogen spectrum nuclear magnetic resonance (1H NMR) analysis respectively.
  • 4-chloropyrrolopyridine (308 g, 2.0 mol, SM-1) was dissolved in 1.5 L of anhydrous DMAc, cooled to 10 ° C in an ice water bath, and NaH (104 g, 2.6 mol, 60%) was added in portions. The temperature was maintained at 10-15 ° C, and the mixture was stirred at this temperature for 1 h after the completion of the dropwise addition.
  • a tetrahydrofuran solution of methyl tert-carboxylate (390 g, 2.6 mol dissolved in 1.5 L of anhydrous tetrahydrofuran, SM-2) was slowly added dropwise, maintaining the temperature below 20 ° C, and the addition was completed after 1 h.
  • reaction solution was allowed to warm to room temperature for 2 h, and TLC showed the reaction was completed.
  • the reaction was quenched by dropwise addition of water under ice water, and extracted with methyl t-butyl ether. The organic phase was concentrated to give a white solid 1a (530 g).
  • the compound 2a was dissolved in 500 mL of tetrahydrofuran, and a 4N hydrochloric acid solution (800 mL) was added dropwise thereto, and the mixture was reacted at room temperature overnight, and HPLC showed that the starting material was completely reacted, and the target compound was 73.1%.
  • triphenylphosphine (2.89 g, 11 mmol) and hexachloroethane (2.60 g, 11 mmol) were added to chloroform (30 ml), and the mixture was heated to 70 ° C for 18 hours, and solid precipitated, and after cooling, 0.36 M was obtained. Ph 3 PCl 2 chloroform suspension.
  • Example 7 for the preparation of the compound 1b, the present example was purified using the starting material SM-6 to give the compound 1c.
  • Example 8 of the preparation of the compound 2b this example was purified from the starting material 1c to give the compound 2c.
  • Example 9 for the preparation of the compound 3b, the present example was purified from the starting material 2c to give the compound 3c.
  • Example 10 for the preparation of the compound LW104-A, this example was purified from the starting material 3c to give the compound LW104-B.
  • Example 7 of the preparation of the compound 1b the present example was purified using the starting material SM-7 to give the compound 1d.
  • Example 8 for the preparation of the compound 2b, this example was purified from the starting material 1d to give the compound 2d.
  • Example 9 for the preparation of the compound 3b, this example was purified from the starting material 2d to give the compound 3d.
  • Example 7 for the preparation of the compound 1b, this example was purified using the starting material SM-8 to give the compound 1e.
  • 1 H NMR 400 MHz, CDCl 3 ): ⁇ 0.22 (s, 6H), 0.88 (s, 9H), 1.30 (s, 3H), 1.32 (s, 3H), 2.99-3.06 (m, 1H), 3.69 ( Br,1H)
  • Example 8 of the preparation of the compound 2b this example was purified from the starting material 1e to give the compound 2e.
  • Example 9 for the preparation of the compound 3b, this example was purified from the starting material 2e to give the compound 3e.
  • Example 7 of the preparation of the compound 1b the present example was purified using the starting material SM-9 to give the compound 1f.
  • 1 H NMR 400 MHz, CDCl 3 ): ⁇ 0.28 (s, 6H), 0.93 (s, 9H), 1.13-1.15 (m, 2H), 1.24-1.25 (m, 2H), 2.41-2.47 (m, 1H) ), 3.94 (br, 1H).
  • Example 8 of the preparation of the compound 2b this example was purified from the starting material 1f to give the compound 2f.
  • Example 9 for the preparation of the compound 3b, this example was purified from the starting material 2f to give the compound 3f.
  • Example 27 which was used to prepare the compound 1g, the present example was purified from the starting material SM-12 to give the compound 1i.
  • Example 28 for the preparation of the compound LW104-F this example was purified from the starting material 1i to give the compound LW104-H.
  • Example 28 which was used to prepare the compound LW104-F, this example was purified from the starting material 1j to give the compound LW104-I.
  • Example 28 for the preparation of the compound LW104-F this example was purified from the starting material 1k to give the compound LW104-L.
  • Example 28 which was used to prepare the compound LW104-F, this example was purified from the starting material 1l to give the compound LW104-M.
  • Example 28 for the preparation of the compound LW104-F this example was purified from the starting material 1n to give the compound LW104-O.
  • Test Example Detecting the inhibitory effect of compounds on JAK1-3 enzyme activity
  • JAK1 Invitrogen, Cat. No PV4775
  • JAK2 Invitrogen, Cat. No PV4288
  • JAK3 Invitrogen, Cat. No PV4080
  • ATP Sigma, Cat. No. A7699-1G
  • DMSO Sigma, Cat. No
  • D2650 DTT (Sigma, Cat. No. 43815).
  • Test compounds were finally tested at concentrations ranging from 10 M to 0.17 nM, 3 fold dilutions, and 11 concentrations.
  • the final concentration of the reference compound Tofacitinib was from 1 M to 0.017 nM, a 3-fold gradient dilution, 11 concentrations.
  • Buffer preparation buffer including 50 mM HEPES (pH 7.5), 0.01% Brij-35, 10 mM MgCl2, 1 mM EGTA.
  • the enzyme and substrate were mixed with different concentrations of the compound prepared in advance, and allowed to stand at room temperature for 15 minutes.
  • the reaction was initiated by the addition of ATP and incubated for 90 minutes at room temperature (where a positive control was set).
  • the 10 ⁇ L reaction system included 2.5 ⁇ L of the compound, 5 ⁇ L of a mixture of the enzyme and the substrate, and 2.5 ⁇ L of ATP.
  • the antibody was added for detection. After incubation at room temperature for 60 minutes, Evnvision was detected and data was collected. Data analysis and mapping according to XLfit5 software.
  • test results of JAK1-3 enzyme inhibitory activity and cytostatic activity of the compound of the present invention are shown in Table 1.
  • IC50 activity is classified according to the following table
  • the compound of the formula I of the present invention exhibits very excellent activity for inhibiting JAK1 and/or JAK2.
  • the IC50 value of the compound of the present invention is substantially 10 nM or lower, so that for a subject weighing about 70 kg (such as a patient, especially a patient with rheumatoid arthritis or psoriasis), the daily dose is usually 10 mg to 30 mg. It is extremely effective in suppressing JAK1 and/or JAK2.
  • the compound of the formula I of the present invention exhibits a very excellent JAK selectivity, i.e., the IC50 ratio of JAK3/JAK1 and/or the IC50 ratio of JAK3/JAK2 is much superior to the currently marketed drug (e.g., Toficitinib).
  • the side effects associated with the inhibition of JAK3 in the compounds of the present invention will be extremely markedly lowered, and the safety will be remarkably improved, especially in the case of daily doses of 10 mg to 50 mg.
  • the side effects associated with inhibition of JAK3 include, but are not limited to, side effects such as bacterial infection, fungal infection, viral infection, anemia, and the like.

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Abstract

本发明提供了一种新型的JAK酶选择性抑制剂及其制备方法和用途，具体地，本发明公开了一种可作JAK激酶抑制剂的具有化学式I所示结构的化合物或其立体异构体或互变异构体，或其药学上可接受的盐，水合物或溶剂化物。

Description

JAK酶抑制剂及其制备方法和用途 技术领域
本发明属于药物合成领域，具体地说，本发明涉及一种JAK酶抑制剂及其制备方法和用途。
背景技术
蛋白激酶(Protein kinases)又称蛋白质磷酸化酶(Protein Phosphokinase)，是一类催化蛋白质磷酸化反应的酶，是调节细胞信号包括细胞增殖和细胞分化中的关键因素。
目前，有四种已知的哺乳动物JAK家族成员：JAK1(亦称Janus激酶-1)、JAK2(亦称Janus激酶-2)、JAK3(亦称JAKL或L-JAK,白细胞Janus激酶；和Janus激酶-3)和TYK2(亦称蛋白质-酪氨酸激酶2)。
在JAK激酶水平下的阻断信号转导为炎性疾病、自身免疫病、骨髓增殖性疾病和癌症的治疗方法的开发提供了前景。JAK激酶的抑制也有助于皮肤免疫疾病如银屑病和皮肤敏化的治疗。已经上市的有辉瑞的托伐替尼(Toficitinib)，用于治疗类风湿性关节炎；以及Incyte的鲁索替尼，用于治疗骨髓纤维化以及急性移植物抗宿主病。
然而，目前已有的一些JAK酶抑制剂也存在一些明显的毒副作用，例如一些JAK抑制剂容易引起以下副作用：感染，包括肺炎、病毒感染(如带状疱疹感染)、细菌感染、放线菌感染(分枝杆菌感染)、真菌感染、免疫力下降(如NK细胞减少)以及贫血。在美国，甚至因为部分严重的副作用而得到黑框警示(Black box)，这些严重的副作用包括，例如急性肺结核、侵入性真菌感染、细菌感染、以及部分淋巴瘤或其它肿瘤。研究表明，目前已有的JAK抑制剂往往对JAK1和JAK3均有抑制活性，大多数的这些副作用的产生与JAK3的活性受抑制有关。
然而，研究表明，JAKs家族激酶负责调节众多信号通路。由于JAK1和JAK3是常见的γ-链细胞因子受体复合物的组成部分，这导致开发对JAK1具有高选择性的抑制剂存在很大的难度。
综上所述，目前本领域迫切需要研发出Janus激酶或相关激酶的抑制剂，尤其是对JAK1具有高选择性的抑制剂。
发明内容
本发明的目的在于提供一种新型的JAK酶抑制剂及其制备方法和用途。
本发明第一方面提供了一种如式I所示的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物：
Figure PCTCN2018073776-appb-000001
其中：
X是N或O；
Y是N或O；
Z选自下组：取代的或未取代的C 1-C 8烷基；
W是N或者C；
R 1、R 2、R 3各自独立地选自下组：氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 6-C 10芳基(较佳地为苯基)、取代或未取代的具有1-3个选自下组N、O、S的杂原子的5-10元杂芳基(较佳地为五元或六元)、取代或未取代的苯并5-10元杂芳基(较佳地为吲哚基)；
R 4选自下组：取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的具有1-3个选自下组N、S、O的杂原子的3-10元杂环烷基、CH 2OR 5，其中R 5选自下组：C 1-C 6烷基羰基、三烷基硅基；
所述R 1、R 2、R 3、R 4、Z中，所述取代是指被选自下组的一个或多个(如2个、3个、4个等)取代基所取代：卤素(较佳地为F)、CN、C 1-C 6烷基、卤代的C 1-C 6烷基、或C 1-C 6烷氧基。
在另一优选例中，所述的XR 2与YR 3是相同或不同的。
在另一优选例中，X为氮，YR 3为氧。
在另一优选例中，所述的R 1、R 2和R 3中一个或多个独立地选自下组：取代或未取代的C1-C5烷基、取代或未取代的C3-C5环烷基、取代或未取代的3-5元杂环基。
在另一优选例中，所述的3-5元杂环基具有1-2个选自N、O、S的杂原子。
在另一优选例中，所述的3-5元杂环基是芳香的或非芳香的，以及饱和的或非饱和的(如4-5元杂芳环基)。
在另一优选例中，所述的R 1、R 2和R 3中一个或多个独立地选自下组：
(a1)取代或未取代的以下基团：甲基、乙基、丙基(包括正丙基、异丙基)、丁基(包括n-，i-,或t-丁基)、戊基；
(a2)取代或未取代的以下基团：环丙基、环丁基、或环戊基；
(a3)取代或未取代的以下基团：氧杂环丙基、氧杂环丁基、氧杂环戊基、氮杂环丙基、氮杂环丁基、或氮杂环戊基；
其中，所述的取代指用下组的一个或多个(如2个、3个、4个等)取代基所取代：F、Cl、Br、-OH、-CN、NH 2、＝O、C 1－C 3烷基或C 1－C 3卤代烷基。
在另一优选例中，R 1、R 2和R 3中至少一个(如1个或2个)为选自组(a1)、(a2)和(a3)的基团。
在另一优选例中，R 1、R 2和R 3中至少一个(如1个或2个)为选自下组：C1-C4烷基、C1-C4卤代烷基、环丙基、环丁基。
在另一优选例中，R 1和R 2各自独立地选自下组：C1-C5烷基(尤其是甲基、乙基和丙基)、C1-C5卤代烷基(如部分卤代或全卤代的烷基，包括(但并不限于)：-CF 3、-C 2H 4F、-C 2H 2F 3、-C 2F 5)、环丙基、环丁基、氧杂环丙基、氧杂环丁基。
在另一优选例中，当式I化合物包含一个或多个手性碳原子时，该手性碳原子可以是R、S或其组合。
在另一优选例中，在式I化合物中，与XR 2与YR 3相邻的S原子可以是手性的或非手性的，当该S原子为手性时，其构型可以是R、S或其组合。
在另一优选例中，当XR 2与YR 3不相同时，所述式I化合物为式II或式III所示的化合物：
Figure PCTCN2018073776-appb-000002
所述式II或式III中，R 1、R 2、R 3、R 4、W、X、Y、Z的定义如上所述。
在另一优选例中，W为N，X为氮，YR 3为氧，所述式I化合物为式IV所示的化合物:
Figure PCTCN2018073776-appb-000003
式IV中，R 1、R 2、R 3、R 4、W、X、Y、Z的定义如上所述。
在另一优选例中，式I化合物为外消旋体，其中包括光学活性的化合物式V以及化合物式VI：
Figure PCTCN2018073776-appb-000004
所述式V或式VI中，R 1、R 2、R 4、Z的定义如上所述。
在另一优选例中，式I化合物为式VII的化合物：
Figure PCTCN2018073776-appb-000005
其中，n为2-10的正整数；R 4、Z的定义如上所述。
在另一优选例中，所述式I化合物选自下组：
Figure PCTCN2018073776-appb-000006
Figure PCTCN2018073776-appb-000007
Figure PCTCN2018073776-appb-000008
Figure PCTCN2018073776-appb-000009
Figure PCTCN2018073776-appb-000010
Figure PCTCN2018073776-appb-000011
本发明第二方面提供了一种制备如本发明第一方面所述的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物的方法，包括步骤：
Figure PCTCN2018073776-appb-000012
(i)催化剂存在下，化合物Ia与式Ib反应，制得化合物Ic；
(ii)化合物Ic与Id反应，制得化合物I其中，所述R 1、R 2、R 4、X、Y、Z的定义如本发明第一方面所述。
在另一优选例中，所述步骤(i)中，所述催化剂为碱。
在另一优选例中，所述步骤(i)中，所述催化剂选自下组：四烷基氟化铵、氢氧化四烷基铵、胍、脒、氢氧化物、醇盐、硅酸盐、碱金属磷酸盐、氧化物、叔胺、碱金属碳酸盐、碱金属碳酸氢盐、碱金属磷酸氢盐、膦或羧酸的碱金属盐、或其组合。
在另一优选例中，所述反应在有机溶剂中进行。
在另一优选例中，所述有机溶剂选自下组：乙腈、二甲基乙酰胺、或其组合。
在另一优选例中，所述方法在室温下进行。
在另一优选例中，所述方法的时间为2-6小时。
在另一优选例中，所述式Ic化合物具有高收率和高纯度。
在另一优选例中，化合物Id由选自下组的化合物制得：PPh 3Cl 2、五氯化磷、氯化亚砜、N-氯代丁二酰亚胺、或其组合。
在另一优选例中，所述步骤(ii)在碱存在下进行。
在另一优选例中，当R 2、R 4为氢时，所述式I化合物为式VIII化合物，所述方法包括步骤：
Figure PCTCN2018073776-appb-000013
其中，所述Z、R 1定义如本发明第一方面所述。
在另一优选例中，所述步骤(iv)中，所述化合物VIII-1与VIII-2在碱存在下进行反应，其中，所述碱为有机碱或无机碱。
在另一优选例中，所述步骤(iv)在选自乙腈或者N，N-二甲基乙酰胺的有机溶剂中进行。
在另一优选例中，所述步骤(v)在酸性条件下进行，所述酸性条件为盐酸水溶液、盐酸异丙醇溶液、或者盐酸二氧六环溶液。
在另一优选例中，所述步骤(vi)在氯代试剂中进行，所述氯代试剂选自下组：PPh 3Cl 2、五氯化磷、氯化亚砜、N-氯代丁二酰亚胺、或其组合。
在另一优选例中，所述步骤(vii)在碱存在下进行，所述碱选自下组：四烷基氟化铵、氢氧化四烷基铵、胍、脒、氢氧化物、醇盐、硅酸盐、碱金属磷酸盐、氧化物、叔胺、碱金属碳酸盐、碱金属碳酸氢盐、碱金属磷酸氢盐、膦或羧酸的碱金属盐、或其组合。
在另一优选例中，所述步骤(vii)在酸存在下进行，所述酸选自下组：盐酸、硫酸、对甲苯磺酸、四烷基氟化铵、或其组合。
在另一优选例中，当R 2为C 1-C 6烷基或者C 6-C 10芳基时，所述式I化合物为式IX化合物，所述方法包括步骤：
Figure PCTCN2018073776-appb-000014
其中，所述Z、R 1、R 4定义如本发明第一方面所述。
在另一优选例中，所述步骤(ix)在氯代试剂中进行，所述氯代试剂选自下组：PPh 3Cl 2、五氯化磷、氯化亚砜、N-氯代丁二酰亚胺、或其组合。
在另一优选例中，所述步骤(x)在碱存在下进行，所述碱选自下组：四烷基氟化铵、氢氧化四烷基铵、胍、脒、氢氧化物、醇盐、硅酸盐、碱金属磷酸盐、氧化物、叔胺、碱金属碳酸盐、碱金属碳酸氢盐、碱金属磷酸氢盐、膦或羧酸的碱金属盐、或其组合。
本发明第三方面，提供结构如下所示的化合物：
Figure PCTCN2018073776-appb-000015
Figure PCTCN2018073776-appb-000016
其中，所述R 1、R 2、R 4、Z如本发明第一方面所述。
本发明第四方面，提供一种药物组合物，其包含(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
在另一优选例中，所述药物组合物还包含其它JAK激酶抑制剂。
在另一优选例中，所述其它JAK激酶抑制剂可选自下组：托法替尼，鲁索替尼、或其组合。
本发明第五方面，提供如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物或如本发明第四方面所述的药物组合物的用途，其用于制备JAK激酶抑制剂。
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。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地发现一种新的JAK抑制剂，结构新颖，并且具有很好的生物活性及极其优异的选择性。具体地，本发明化合物，以JAK3/JAK1之比为代表的选择性或以JAK3/JAK2之比为代表的选择性平均提高约100倍。因此，本发明化合物与JAK3受抑制相关的副作用极其显著下降，而安全性将显著提高。在此基础上完成了本发明。
术语说明
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，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变 动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
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”。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用，术语“C 3-C 8环烷基”指具有3-8个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C 1-C 8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用，术语“C 6-C 10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基 等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
活性成分
如本文所用，“本发明化合物”指式(I)所示的化合物，并且还包括及式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用，“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
式I化合物
本发明所制备得到的新型JAK抑制剂，即式I化合物如下表A所示：
表A 本发明式I化合物列表
Figure PCTCN2018073776-appb-000017
Figure PCTCN2018073776-appb-000018
Figure PCTCN2018073776-appb-000019
Figure PCTCN2018073776-appb-000020
Figure PCTCN2018073776-appb-000021
Figure PCTCN2018073776-appb-000022
Figure PCTCN2018073776-appb-000023
Figure PCTCN2018073776-appb-000024
药物组合物和施用方法
由于本发明化合物具有优异的JAK激酶的抑制活性，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(稳定、减轻或治愈)JAK激酶相关疾病(例如，皮肤病，类风湿性关节炎，多发性硬化，I型糖尿病，牛皮癣关节炎，少年关节炎，克罗恩氏病，重症肌无力，癌症包括前列腺癌，肾癌，肝癌，乳腺癌，肺癌，甲状腺癌，卡波 济氏肉瘤，巨大淋巴增生症，胰腺癌，白血病，淋巴癌或多发性骨髓瘤等)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2018073776-appb-000025
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如抗-HBV剂)联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如抗-HBV剂)。该其他药学上可接受的化合物(例如抗-HBV剂)中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗HBV感染或HBV相关疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点在于：
1.本发明的化合物结构新颖且具有优异的JAK激酶抑制剂作用；
2.本发明的化合物对于JAK1的选择抑制性更好。
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，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
通用材料及测试方法：
实施例中涉及到的仪器及原料说明如下:
核磁共振氢谱是Bruker AV-400(400MHz)核磁仪分析得到。
化学位移以四甲基硅烷为内标来记录，以ppm为单位来表示(CDC1 3:δ7.26ppm)。记录的数据信息如下:化学位移及其裂分和偶合常数(s:单重峰；d:双重峰；t：三重峰；q： 四重峰；br：宽峰；m：多重峰)。
质谱数据除其他需要，都采用菲尼根高级LCQ公司(Finnigan LCQAdvantage)的液质联用仪进行分析，所有反应都在干燥氩气保护的无水无氧条件下进行操作。固体金属有机化合物在氩气保护干燥箱中进行储藏。
四氢呋喃和乙醚是经过蒸馏得到，蒸馏时在其中加入金属钠和二苯甲酮。二氯甲烷，戊烷和己烷是用氢化钙来处理。
本发明中涉及的特殊原料和中间体由天津长森药业有限公司等订制加工提供，其他所有化学试剂从上海化学试剂公司、阿尔得里奇公司(Aldrich)、阿克罗公司(Acros)等试剂供应商购买。如合成过程中反应所需的中间体或产物不够下一步试验，则重复多次合成至足够数量为止。
本发明所涉及的原料和试剂除特殊说明外均可市售或订制加工购买得到。
本发明中化合物可含有一个或多个不对称中心，因此该系列化合物可为消旋或者单一对映体形式。本发明所制备的化合物(通式IV)是纯度高于95％的杂环化合物，每个最终产物的结构表征分别由MS或/和氢谱核磁共振(1HNMR)分析确定。以下通过实施例说明本发明各类化合物和中间体的合成。
实施例1:化合物1a的合成
Figure PCTCN2018073776-appb-000026
氩气保护下，4-氯吡咯并吡啶(308g，2.0mol,SM-1)溶解到1.5L无水DMAc中，冰水浴降温至10℃，分批加入NaH(104g，2.6mol，60％)维持温度在10-15℃，滴加完毕后该温度下搅拌1h。缓慢滴加特特戊酸甲酯的四氢呋喃溶液(390g，2.6mol溶于1.5L无水四氢呋喃，SM-2)，维持温度低于20℃，1h后滴加完毕。反应液升至室温反应2h，TLC显示反应完全。冰水浴下滴加水淬灭反应，甲基叔丁基醚萃取。浓缩有机相得到白色固体1a(530g)。
实施例2:化合物2a的合成
Figure PCTCN2018073776-appb-000027
三口瓶中加入化合物1a(309g，1.16mol)，1-(1-乙氧基乙基)-4-吡唑硼酸频哪醇酯(339g，1.28mol，SM-3)，氟化铯(352g，2.32mol)，正丁醇(1.5L)，水(1.5L)。抽换氩气三次后，加入四(三苯基膦)钯(10g，12mmol)。再次抽换氩气后，升温至回流，反应16h，HPLC显示反应完全。降温后分液，乙酸乙酯萃取，浓缩后直接进行下一步(含有正丁醇)。
实施例3:化合物3a的合成
Figure PCTCN2018073776-appb-000028
化合物2a溶于500mL四氢呋喃中，滴加4N盐酸溶液(800mL)，室温反应过夜，HPLC显示原料反应完全，目标化合物纯度73.1％。冰水浴下缓慢滴加10％氢氧化钠溶液至PH＝7-8，有大量固体生成。过滤，滤饼以水冲洗，烘箱干燥，得到固体3a(193g)，纯度92％，两步收率56％。
实施例4:化合物4a的合成
Figure PCTCN2018073776-appb-000029
将化合物3a(189g)以及3-(氰基亚甲基)氮杂环丁烷-1-甲酸叔丁酯(184g，SM-4)加入到乙腈(1L)中，冰水浴冷却，加入DBU后维持该温度反应0.5h，随后室温反应4h，有大量固体析出。加入MTBE500mL，搅拌10min后过滤，滤饼以MTBE洗涤。烘箱45℃干燥过夜，得到固体4a(254g)，收率81％，纯度95％。
实施例5:化合物5a的合成
Figure PCTCN2018073776-appb-000030
将化合物4a(240g)溶于二氯甲烷(1L)中，冰水浴下滴加4M HCl/dioxane溶液(500ml)，反应过夜。0℃下加入5％氨水溶液调pH＝8～10，二氯甲烷萃取，干燥后浓缩。乙腈打浆2h，过滤(过滤较慢)，滤饼以MTBE洗涤，烘干得到白色固体114g，纯度97％。滤液浓缩后以乙腈打浆，过滤烘干后得到白色固体56.6g，纯度95％。两部分收率为88.9％。
实施例6:Ph 3PCl 2氯仿悬浊液的合成
Figure PCTCN2018073776-appb-000031
氮气保护下，将三苯基膦(2.89g，11mmol)和六氯乙烷(2.60g，11mmol)加入氯仿(30ml)中，加热至70℃反应18小时，有固体析出，冷却后得到0.36M Ph 3PCl 2氯仿悬浊液。
实施例7:化合物1b的合成
Figure PCTCN2018073776-appb-000032
氮气保护下，将SM-5(0.939g，9.9mmol)溶于无水THF(15ml)中，室温下加入Et 3N(2.75ml，19.8mmol)，搅拌5min后，滴加TBSCl(1.73g，11.5mmol)的甲苯(5ml)溶液，有固体析出，室温搅拌过夜，过滤，浓缩后柱层析得到白色固体800mg。
实施例8:化合物2b的合成
Figure PCTCN2018073776-appb-000033
氮气保护下将0.36M的Ph 3PCl 2/氯仿悬浊液(8.8ml，3.18mmol)冷却至0℃，加入三乙胺(482mg，4.77mmol)，搅拌15min后，0℃下加入化合物1b(709mg，3.0mmol)，搅拌20min后将化合物5a(200mg，0.53mmol)加入上述反应体系中，加完升至室温搅拌反应过夜，TLC显示有部分原料没有反应完全。加入水淬灭反应，乙酸乙酯萃取。有机相浓缩后柱层析分离，淋洗液(正庚烷/乙酸乙酯＝1：1，随后CH 2Cl 2/MeOH＝30/1)得到白色固体。
实施例9:化合物3b的合成
Figure PCTCN2018073776-appb-000034
将化合物2b(3.9g)溶于甲醇(50ml)，室温下加入氨水(25ml)，有部分原料析出，随着反应的进行固体逐渐溶解，反应18小时后，TLC显示原料消失，EA萃取，干燥浓缩后，柱层析分离(流动相:正庚烷/EA＝1:1)，得到白色固体3b(760mg),收率30％。
实施例10:化合物LW104-A的合成
Figure PCTCN2018073776-appb-000035
化合物(35mg)溶于5mL四氢呋喃中，加入四丁基氟化铵(44mg),室温搅拌0.5h后，TLC显示有部分原料剩余，补加部分TBAF，继续反应0.5h。反应完全后，加入水淬灭反应，乙酸乙酯萃取。有机相以饱和食盐水洗涤，无水硫酸钠干燥。浓缩后柱层析(heptane/EA＝20/1)得到白色固体10mg。 1HNMR(400MHz,d6-DMSO):δ3.03(q,J＝6.4Hz，1H),3.63(s,3H),4.06(dd,J＝8.0,4.8Hz,2H),4.16(s,1H),4.43(d,J＝9.2Hz,2H),7.07(d,J＝2.8Hz,1H),7.61(s,1H),8.45(s,1H),8.70(s,1H),8.91(s,1H),12.13(br,1H).
实施例11:化合物1c的合成
Figure PCTCN2018073776-appb-000036
按照上述制备化合物1b的实施例7，本实施例用原料SM-6，纯化后得到化合物1c。
实施例12:化合物2c的合成
Figure PCTCN2018073776-appb-000037
按照上述制备化合物2b的实施例8，本实施例用原料1c，纯化后得到化合物2c。
实施例13:化合物3c的合成
Figure PCTCN2018073776-appb-000038
按照上述制备化合物3b的实施例9，本实施例用原料2c，纯化后得到化合物3c。 1HNMR(400MHz,d6-DMSO):δ0.01(s,3H),0.03(s,3H),0.83(s,9H),1.23(t,J＝8.0Hz,3H),3.00-3.07(m,1H),3.63(s,2H),4.04(d,J＝9.2Hz,2H),4.41(dd,J＝9.2,6.0Hz,2H),7.06(s,1H),7.61-7.62(m,1H),8.44(s,1H),8.70(s,1H),8.91(s,1H),12.13(br,1H).
实施例14:化合物LW104-B的合成
Figure PCTCN2018073776-appb-000039
按照上述制备化合物LW104-A的实施例10，本实施例用原料3c，纯化后得到化合物LW104-B。 1HNMR(400MHz,d6-DMSO):δ1.23(t,J＝6.4Hz,3H),3.03(q,J＝6.4Hz，1H),3.63(s,2H),4.06(dd,J＝8.0,4.8Hz,2H),4.16(s,1H),4.43(d,J＝9.2Hz,2H),7.07(d,J＝2.8Hz,1H),7.61(s,1H),8.45(s,1H),8.70(s,1H),8.91(s,1H),12.13(br,1H).MS-ESI:[M+Na] +＝393。
实施例15:化合物1d的合成
Figure PCTCN2018073776-appb-000040
按照上述制备化合物1b的实施例7，本实施例用原料SM-7，纯化后得到化合物1d。
实施例16:化合物2d的合成
Figure PCTCN2018073776-appb-000041
按照上述制备化合物2b的实施例8，本实施例用原料1d，纯化后得到化合物2d。
实施例17:化合物3d的合成
Figure PCTCN2018073776-appb-000042
按照上述制备化合物3b的实施例9，本实施例用原料2d，纯化后得到化合物3d。
实施例18:化合物LW104-C的合成
Figure PCTCN2018073776-appb-000043
按照上述制备化合物LW104-A的实施例10，本实施例用原料3d，纯化后得到化合物LW104-C。 1HNMR(400MHz,d6-DMSO):δ3.97(dd,J＝9.6,4.8Hz,2H),4.21(t,J＝9.6Hz,2H),4.74(s,1H),5.28(t,J＝4.8Hz,2H),6.96(d,J＝1.6Hz,1H),7.20-7.23(m,1H),7.36(d,J ＝8.8Hz,1H),7.52-7.53(m,3H),7.57(t,J＝7.2Hz,1H),7.85-7.88(m,2H),8.25(s,1H),8.62(d,J＝8.0Hz,1H),12.09(br,1H).MS-ESI:[M-H] +＝417。
实施例19:化合物1e的合成
Figure PCTCN2018073776-appb-000044
按照上述制备化合物1b的实施例7，本实施例用原料SM-8，纯化后得到化合物1e。 1HNMR(400MHz,CDCl 3):δ0.22(s,6H),0.88(s,9H),1.30(s,3H),1.32(s,3H)，2.99-3.06(m,1H),3.69(br,1H)
实施例20:化合物2e的合成
Figure PCTCN2018073776-appb-000045
按照上述制备化合物2b的实施例8，本实施例用原料1e，纯化后得到化合物2e。
实施例21:化合物3e的合成
Figure PCTCN2018073776-appb-000046
按照上述制备化合物3b的实施例9，本实施例用原料2e，纯化后得到化合物3e。 1HNMR(400MHz,d6-DMSO):δ0.01(s,3H),0.03(s,3H),0.82(s,9H),1.26(m,6H), 3.09-3.16(m,1H),3.62(s,2H),3.98(d,J＝9.2Hz,2H),4.40(dd,J＝8.8,5.6Hz,2H),7.05(d,J＝3.6Hz,1H),7.60-7.62(m,1H),8.43(s,1H),8.70(s,1H),8.90(s,1H),12.12(br,1H)。
实施例22:化合物LW104-D的合成
Figure PCTCN2018073776-appb-000047
按照上述制备化合物LW104-A的实施例10，本实施例用原料3e，纯化后得到化合物LW104-D。 1HNMR(400MHz,d6-DMSO):δ1.23-1.25(m,6H),3.10-3.20(m,1H),3.64(s,2H),4.02(dd,J＝15.6,8.4Hz,2H),4.45(dd,J＝15.6,8.4Hz,2H),7.07(d,J＝2.0Hz,1H),7.60-7.62(m,1H),8.44(s,1H),8.70(s,1H),8.90(s,1H),12.16(br,1H)。MS-ESI:[M+Na] +＝407。
实施例23:化合物1f的合成
Figure PCTCN2018073776-appb-000048
按照上述制备化合物1b的实施例7，本实施例用原料SM-9，纯化后得到化合物1f。 1HNMR(400MHz,CDCl 3):δ0.28(s,6H),0.93(s,9H),1.13-1.15(m,2H),1.24-1.25(m,2H),2.41-2.47(m,1H),3.94(br,1H).
实施例24:化合物2f的合成
Figure PCTCN2018073776-appb-000049
按照上述制备化合物2b的实施例8，本实施例用原料1f，纯化后得到化合物2f。
实施例25:化合物3f的合成
Figure PCTCN2018073776-appb-000050
按照上述制备化合物3b的实施例9，本实施例用原料2f，纯化后得到化合物3f。
实施例26:化合物LW104-E的合成
Figure PCTCN2018073776-appb-000051
按照上述制备化合物LW104-A的实施例10，本实施例用原料3f，纯化后得到化合物LW104-E。 1HNMR(400MHz,d6-DMSO):δ0.86-0.91(m,2H),1.10-1.15(m,2H),2.58-2.61(m,1H),3.59(s,2H),4.02(s,2H),4.09(s,J＝9.6Hz,2H),4.46(dd,J＝9.2,1.6Hz, 2H),7.04(d,J＝2.0Hz,1H),7.58(d,J＝3.2Hz,1H),8.42(s,1H),8.67(s,1H)，8.89(s,1H),12.10(br,1H).MS-ESI:[M+H] +＝383。
实施例27:化合物1g的合成
Figure PCTCN2018073776-appb-000052
氮气保护下将0.36M的Ph 3PCl 2/氯仿悬浊液(9.7ml，3.5mmol)冷却至0℃，加入三乙胺(482mg，4.77mmol)，搅拌15min后，0℃下加入SM-10(500mg，3.0mmol)，搅拌20min后将化合物5a(200mg，0.53mmol)加入上述反应体系中，加完升至室温搅拌反应过夜，TLC显示有部分原料没有反应完全。加入水淬灭反应，乙酸乙酯萃取。有机相浓缩后柱层析分离，淋洗液(正庚烷/乙酸乙酯＝1：1，随后CH 2Cl 2/MeOH＝30/1)得到白色固体1g(150mg)。 1HNMR(400MHz,d6-DMSO):δ1.09(s,9H),2.55(s,3H),3.01(s,3H),3.67(s,2H),4.16(dd,J＝8.8,2.0Hz,2H),4.53(dd,J＝13.6,9.6Hz,2H),6.25(s,2H),7.21(d,J＝4.0Hz,1H),7.76(d,J＝4.4Hz,1H),8.50(s,1H),8.82(s,1H),8.96(s,1H).
实施例28:化合物LW104-F的合成
Figure PCTCN2018073776-appb-000053
将化合物2b(140mg)溶于甲醇(5ml)，室温下加入氨水(3ml)，有部分原料析出，随着反应的进行固体逐渐溶解，反应18小时后，TLC显示原料消失，EA萃取，干燥浓缩后，柱层析分离(二氯甲烷/甲醇＝15/1)，得到白色固体。LW104-F(600mg)。 1HNMR(400MHz,d6-DMSO):δ2.56(s,3H),3.00(s,3H),3.67(s,2H),4.16(d,J＝9.2Hz, 2H),4.53(dd,J＝14.8,9.2Hz,2H),7.08(d,J＝2.8Hz,1H),7.61-7.62(m,1H),8.47(s,1H),8.71(s,1H),8.92(s,1H),12.03(br,1H).MS-ESI:[M+Na] +＝393。
实施例29:化合物1h的合成
Figure PCTCN2018073776-appb-000054
按照上述制备化合物1g的实施例27，本实施例用原料SM-11，纯化后得到化合物1h。
实施例30:化合物LW104-G的合成
Figure PCTCN2018073776-appb-000055
按照上述制备化合物LW104-F的实施例28，本实施例用原料1h，纯化后得到化合物LW104-G。 1HNMR(400MHz,d6-DMSO):δ1.29-1.33(m,3H),3.04(s,3H),3.49(d,J＝12.8Hz,2H),3.58(d,J＝9.2Hz,1H),4.00(d,J＝8.8Hz,1H),4.14(d,J＝8.8Hz,1H),4.38(d,J＝9.2Hz,1H),4.57(q,J＝6.8Hz,1H),7.05(d,J＝2.4Hz,1H),7.16-7.17(m,1H),7.24-7.28(m,2H),7.35-7.36(m,2H),7.60-7.62(m,1H),8.41(s,1H),8.70(s,1H),8.77(s,1H),12.14(br,1H)。MS-ESI:[M-H] +＝459。
实施例31:化合物1i的合成
Figure PCTCN2018073776-appb-000056
按照上述制备化合物1g的实施例27，本实施例用原料SM-12，纯化后得到化合物1i。
实施例32:化合物LW104-H的合成
Figure PCTCN2018073776-appb-000057
按照上述制备化合物LW104-F的实施例28，本实施例用原料1i，纯化后得到化合物LW104-H。 1HNMR(400MHz,d6-DMSO):δ1.29-1.33(m,3H),3.04(s,3H),3.49(d,J＝12.8Hz,2H),3.58(d,J＝9.2Hz,1H),4.00(d,J＝8.8Hz,1H),4.14(d,J＝8.8Hz,1H),4.38(d,J＝9.2Hz,1H),4.57(q,J＝6.8Hz,1H),7.05(d,J＝2.4Hz,1H),7.16-7.17(m,1H),7.24-7.28(m,2H),7.35-7.36(m,2H),7.60-7.62(m,1H),8.41(s,1H),8.70(s,1H),8.77(s,1H),12.14(br,1H).MS-ESI:[M-H] +＝459。
实施例33:化合物1j的合成
Figure PCTCN2018073776-appb-000058
按照上述制备化合物1g的实施例27，本实施例用原料SM-13，纯化后得到化合物1j。
实施例34:化合物LW104-I的合成
Figure PCTCN2018073776-appb-000059
按照上述制备化合物LW104-F的实施例28，本实施例用原料1j，纯化后得到化合物LW104-I。 1HNMR(400MHz,d6-DMSO):δ1.07-1.29(m,6H),1.61-1.70(m,4H),2.98(s,3H),3.18-3.23(m,1H),3.65(s,2H),4.14(t,J＝8.4Hz,2H),4.51(dd,J＝9.2,6.0Hz,2H),7.09(dd,J＝3.2,0.8Hz,1H),7.61(t,J＝2.8Hz,1H),8.47(s,1H),8.70(s,1H),8.91(s,1H),12.14(br,1H).MS-ESI:[M-H] +＝437。
实施例35:化合物LW104-J的合成
化合物LW104-J通过LW104-B通过手性拆分制得的第一个峰；制备方法:色谱柱Chiralpak IA；流速1.0mL/min；流动相：甲醇/乙腈＝90/10；波长24nm；柱温：35℃。 1HNMR(400MHz,d6-DMSO):δ1.23(t,J＝6.4Hz,3H),3.03(q,J＝6.4Hz，1H),3.63(s,2H),4.06(dd,J＝8.0,4.8Hz,2H),4.16(s,1H),4.44(d,J＝9.2Hz,2H),7.08(d,J＝2.8Hz,1H),7.62(s,1H),8.46(s,1H),8.71(s,1H),8.92(s,1H),12.14(br,1H).MS-ESI:[M+Na] +＝393
实施例36:化合物LW104-K的合成
化合物LW104-K通过LW104-B通过手性拆分制得的第二个峰；制备方法:色谱柱Chiralpak IA；流速1.0mL/min；流动相：甲醇/乙腈＝90/10；波长24nm；柱温：35℃。 1HNMR(400MHz,d6-DMSO):δ1.23(t,J＝6.4Hz,3H),3.04(q,J＝6.4Hz，1H),3.63(s,2H),4.06(dd,J＝8.0,4.8Hz,2H),4.16(s,1H),4.45(d,J＝9.2Hz,2H),7.08(d,J＝2.8Hz,1H),7.61(s,1H),8.45(s,1H),8.71(s,1H),8.91(s,1H),12.13(br,1H).MS-ESI:[M+Na] +＝393.
实施例37:化合物1k的合成
Figure PCTCN2018073776-appb-000060
按照上述制备化合物1g的实施例27，本实施例用原料SM-14，纯化后得到化合物1k。 1H NMR(400MHz,DMSO-d 6)δ8.98(s,1H),8.80(s,1H),8.51(s,1H),7.81(d,J＝3.7Hz,1H),7.21(d,J＝3.7Hz,1H),5.65(s,2H),4.62(dd,J＝9.2,3.0Hz,2H),4.22(dd,J＝9.2,2.6Hz,2H),3.69(s,2H),3.54(t,J＝8.0Hz,2H),2.78(tt,J＝7.6,5.1Hz,1H),2.60(s,3H),1.07–1.01(m,1H),0.98–0.88(m,3H),0.84(t,J＝8.0Hz,2H),-0.10(s,9H).
实施例38:化合物LW104-L的合成
Figure PCTCN2018073776-appb-000061
按照上述制备化合物LW104-F的实施例28，本实施例用原料1k，纯化后得到化合物LW104-L。 1H NMR(400MHz,DMSO-d 6)δ12.15(s,1H),8.94(s,1H),8.71(s,1H),8.47(s,1H),7.62(dd,J＝3.5,2.3Hz,1H),7.09(dd,J＝3.6,1.7Hz,1H),4.60(dd,J＝9.2,4.5Hz, 2H),4.19(dd,J＝9.1,2.3Hz,2H),3.67(s,2H),2.77(m,J＝12.7,6.3,5.8Hz,1H),2.59(s,3H),1.06–0.99(m,1H),0.96–0.87(m,3H).MS-ESI:[M+H] +＝397。
实施例39:化合物1l的合成
Figure PCTCN2018073776-appb-000062
按照上述制备化合物1g的实施例27，本实施例用原料SM-15，纯化后得到化合物1l。MS-ESI:[M+H] +＝541。
实施例38:化合物LW104-M的合成
Figure PCTCN2018073776-appb-000063
按照上述制备化合物LW104-F的实施例28，本实施例用原料1l，纯化后得到化合物LW104-M。 1H NMR(400MHz,DMSO-d 6)δ12.14(s,1H),8.93(s,1H),8.71(s,1H),8.47(s,1H),7.62(dd,J＝3.6,2.4Hz,1H),7.09(dd,J＝3.6,1.7Hz,1H),4.59(dd,J＝9.2,3.7Hz,2H),4.18(dd,J＝9.1,4.6Hz,2H),3.66(s,2H),2.99(q,J＝7.1Hz,2H),2.81–2.71(m,1H),1.04(t,J＝7.2Hz,3H),0.92(m,4H).MS-ESI:[M+Na] +＝411。
实施例39:化合物1m的合成
Figure PCTCN2018073776-appb-000064
按照上述制备化合物1g的实施例27，本实施例用原料SM-16，纯化后得到化合物1m。MS-ESI:[M+H] +＝553。
实施例40:化合物LW104-N的合成
Figure PCTCN2018073776-appb-000065
按照上述制备化合物LW104-F的实施例28，本实施例用原料1m，纯化后得到化合物LW104-N。 1H NMR(400MHz,DMSO-d 6)δ12.14(s,1H),8.95(s,1H),8.71(s,1H),8.47(s,1H),7.62(dd,J＝3.6,1.7Hz,1H),7.09(dd,J＝3.4,1.5Hz,1H),4.62(d,J＝8.8Hz,2H),4.23(dd,J＝9.2,4.9Hz,2H),3.66(s,2H),2.74(m,1H),2.53(d,J＝4.3Hz,1H),1.07–0.97(m,1H),0.96–0.84(m,3H),0.48–0.37(m,2H),0.35–0.22(m,2H).MS-ESI:[M+H] +＝423。
实施例41:化合物1n的合成
Figure PCTCN2018073776-appb-000066
按照上述制备化合物1g的实施例27，本实施例用原料SM-17，纯化后得到化合物1n。 1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.80(s,1H),8.51(s,1H),7.79(d,J＝3.7Hz,1H),7.21(d,J＝3.7Hz,1H),5.65(s,2H),4.63(dd,J＝8.9,6.4Hz,2H),4.23(dd,J＝9.0,2.7Hz,2H),3.70(s,2H),3.54(t,J＝8.0Hz,2H),3.16(q,J＝7.2Hz,2H),2.56(tt,J＝7.1,3.8Hz,1H),1.22(t,J＝7.3Hz,3H),0.83(t,J＝8.0Hz,2H),0.51–0.19(m,4H),-0.11(s,9H)。
实施例42:化合物LW104-O的合成
Figure PCTCN2018073776-appb-000067
按照上述制备化合物LW104-F的实施例28，本实施例用原料1n，纯化后得到化合物LW104-O。 1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.94(s,1H),8.71(s,1H),8.48(s,1H),7.83–7.44(m,1H),7.10(dd,J＝3.4,1.5Hz,1H),4.59(dd,J＝9.1,2.7Hz,2H),4.19(dd,J＝9.1,3.1Hz,2H),3.68(s,2H),3.15(q,J＝7.2Hz,2H),2.55(dd,J＝7.1,3.7Hz,1H),1.21(t,J＝7.3Hz,3H),0.57–0.13(m,4H).MS-ESI:[M+H]+＝411。
测试例:检测化合物对JAK1-3酶活性的抑制效应
试剂和耗材
JAK1(Invitrogen,Cat.No PV4775),JAK2(Invitrogen,Cat.No PV4288),JAK3(Invitrogen,Cat.No PV4080),ATP(Sigma,Cat.No.A7699-1G),DMSO(Sigma,Cat.No. D2650),DTT(Sigma,Cat.No.43815)。
384孔板_化合物稀释板(Greiner，Cat.No.781280),384孔板_测试板(Perkin Elmer,Cat.No.6007299),LANCE Ultra ULight TM-JAK-1peptide(Perkin Elmer,Cat.No.TRF0121),LANCE Eu-W1024Anti-phosphotyrosine(PT66)(Perkin Elmer,Cat.No.AD0069),LANCE TMDetection Buffer(Perkin Elmer,Cat.No.CR97-100)
实验方法
化合物最终测试浓度：
受试化合物最终测试浓度从10M到0.17nM，3倍梯度稀释，11个浓度。
参考化合物Tofacitinib(托法替尼)的最终测试浓度从1M到0.017nM，3倍梯度稀释，11个浓度。
激酶检测：
缓冲液的配制，缓冲液包括50mM HEPES(pH 7.5)，0.01％Brij-35，10mM MgCl2，1mM EGTA。
配制缓冲液后，将酶和底物与预先稀释配制的不同浓度化合物混合，室温放置15分钟。加入ATP启动反应，室温孵育90分钟(其中设置阴阳性对照)。10μL的反应体系包括2.5μL的化合物，5μL酶和底物的混合物和2.5μL的ATP。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。根据XLfit5软件进行数据分析及拟图。
本发明化合物的JAK1-3酶抑制活性和细胞抑制活性的测试结果如表1所示。
表1:本发明的化合物抑制JAK的活性测试结果
Figure PCTCN2018073776-appb-000068
其中，IC50活性按下表分级
抑制活性IC 50(nM) JAK1 JAK2
0.1-10 A A
10-100 B B
100-500 C C
500-2000 D D
讨论:
上述实验结果提示：
(1)本发明的式I化合物表现出非常优异的抑制JAK1和/或JAK2的活性。本发明化合物IC50值基本上均在10nM级或更低，这样对于体重约70kg的对象(如病人，尤其是风湿性关节炎或银屑病患者)而言，日服用剂量通常为10mg-30mg就可极其有效抑制JAK1和/或JAK2。
(2)本发明的式I化合物表现出非常优异的JAK选择性，即JAK3/JAK1的IC50之比和/或JAK3/JAK2的IC50之比远远优于目前已上市的药物(例如Toficitinib)。出乎意料的是，对于本发明化合物而言，以JAK3/JAK1的IC50之比为代表的选择性平均提高了约80倍(32/0.4＝80)，优选化合物的选择性提高了≥100倍；以JAK3/JAK2之比为代表的选择性提高了约115倍(24.4/0.21＝115)。因此，本发明化合物与JAK3受抑制相关的副作用将极其显著下降，而安全性将显著提高，尤其是在日服用剂量为10mg-50mg的情况下。所述的与JAK3受抑制相关的副作用包括(但并不限于)：细菌感染、真菌感染、病毒感染、贫血等副作用。
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 (10)

  1. 一种如式I所示的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物：
    Figure PCTCN2018073776-appb-100001
    其中：
    X是N或O；
    Y是N或O；
    Z选自下组：取代的或未取代的C1-C8烷基；
    W是N或者C；
    R 1、R 2、R 3各自独立地选自下组：氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自下组N、O、S的杂原子的5-10元杂芳基、取代或未取代的苯并5-10元杂芳基；
    R 4选自下组：取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的具有1-3个选自下组N、S、O的杂原子的3-10元杂环烷基、CH 2OR 5，其中R 5选自下组：C 1-C 6烷基羰基、三烷基硅基；
    所述R 1、R 2、R 3、R 4、Z中，所述取代是指被选自下组的一个或多个取代基所取代：卤素、CN、C 1-C 6烷基、卤代的C 1-C 6烷基、或C 1-C 6烷氧基。
  2. 如权利要求1所述的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物，其特征在于，当XR 2与YR 3不相同时，所述式I化合物为式II或式III所示的化合物：
    Figure PCTCN2018073776-appb-100002
    所述式II或式III中，R 1、R 2、R 3、R 4、W、X、Y、Z的定义如权利要求1所述。
  3. 如权利要求1所述的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物，其特征在于，W为N，X为氮，YR 3为氧，所述式I化合物为式IV所示的化合物:
    Figure PCTCN2018073776-appb-100003
    式IV中，R 1、R 2、R 3、R 4、W、X、Y、Z的定义如权利要求1所述。
  4. 如权利要求1所述的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物，其特征在于，式I化合物为式VII的化合物：
    Figure PCTCN2018073776-appb-100004
    其中，n为2-10的正整数；R 4、Z的定义如权利要求1所述。
  5. 如权利要求1所述的化合物、或其立体异构体、或其互变异构体，或其药学上 可接受的盐、水合物或溶剂化物，其特征在于，所述式I化合物选自下组：
    Figure PCTCN2018073776-appb-100005
    Figure PCTCN2018073776-appb-100006
    Figure PCTCN2018073776-appb-100007
    Figure PCTCN2018073776-appb-100008
    Figure PCTCN2018073776-appb-100009
    Figure PCTCN2018073776-appb-100010
  6. 一种制备如权利要求1所述的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物的方法，包括步骤：
    Figure PCTCN2018073776-appb-100011
    (i)催化剂存在下，化合物Ia与式Ib反应，制得化合物Ic；
    (ii)化合物Ic与Id反应，制得化合物I，其中，所述R 1、R 2、R 4、X、Y、Z的定义如权利要求1所述。
  7. 如权利要求6所述的方法，其特征在于，当R 2、R 4为氢时，所述式I化合物为式VIII化合物，所述方法包括步骤：
    Figure PCTCN2018073776-appb-100012
    其中，所述Z、R 1定义如权利要求1所述；
    或者，
    当R 2为C 1-C 6烷基或者C 6-C 10芳基时，所述式I化合物为式IX化合物，所述方法包括步骤：
    Figure PCTCN2018073776-appb-100013
    其中，所述Z、R 1、R 4定义如权利要求1所述。
  8. 结构如下所示的化合物：
    Figure PCTCN2018073776-appb-100014
    其中，所述R 1、R 2、R 4、Z如权利要求1所述。
  9. 一种药物组合物，其特征在于，包含(1)如权利要求1所述的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
  10. 如权利要求1所述的化合物、或其立体异构体、或其互变异构体，或其药学上可接受的盐、水合物或溶剂化物或如权利要求9所述的药物组合物的用途，其特征在于，用于制备JAK激酶抑制剂。
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