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WO2022117012A1 - 螺环jak抑制剂、含其的药物组合物及其应用 - Google Patents

螺环jak抑制剂、含其的药物组合物及其应用 Download PDF

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Publication number
WO2022117012A1
WO2022117012A1 PCT/CN2021/134880 CN2021134880W WO2022117012A1 WO 2022117012 A1 WO2022117012 A1 WO 2022117012A1 CN 2021134880 W CN2021134880 W CN 2021134880W WO 2022117012 A1 WO2022117012 A1 WO 2022117012A1
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group
compound
substituted
pharmaceutically acceptable
solvate
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PCT/CN2021/134880
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English (en)
French (fr)
Inventor
吕志俭
李佳
苏明波
高安慧
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百极弘烨（广东）医药科技有限公司
百极弘烨(南通)医药科技有限公司
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Priority to CN202180080571.9A priority Critical patent/CN116783198A/zh
Publication of WO2022117012A1 publication Critical patent/WO2022117012A1/zh

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • 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

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a spirocyclic JAK inhibitor, a pharmaceutical composition containing the same, and applications.
  • PKs Protein kinases
  • PKs are a group of enzymes that constitute one of the largest human enzyme families that regulate a variety of important biological processes including, inter alia, cellular kinases that catalyze protein, lipid, sugar, nucleoside and other cellular metabolism phosphorylation and plays a key role in all aspects of eukaryotic cell physiology.
  • Aberrant kinase activity has been shown to be involved in a number of human diseases, including cancer, autoimmune and inflammatory diseases.
  • Janus kinases are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors, which play an important role in the process of cytokine signaling.
  • the JAK family includes four members, JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAKs typically associate in pairs with cytokine receptors as homodimers or heterodimers. Cytokines bind to their receptors, causing dimerization of the receptor molecules, and receptor-coupled JAKs approach each other and are activated by phosphorylation of interacting tyrosine residues.
  • the JAK family transmits cytokine-mediated signals into cells through the JAK-STAT (signal transducer and activator of transcription) pathway.
  • STAT Signal Transducer and Activator of Transcription
  • JAK kinases show that blocking signal transduction at the level of JAK kinases holds promise for the development of treatments for inflammatory diseases, autoimmune diseases, myeloproliferative diseases and cancer. Inhibition of JAK kinases also aids in the treatment of skin immune diseases such as psoriasis and skin sensitization.
  • skin immune diseases such as psoriasis and skin sensitization.
  • Pfizer's Toficitinib for the treatment of rheumatoid arthritis
  • Incyte's ruxolitinib for the treatment of myelofibrosis and acute graft-versus-host disease.
  • JAK enzyme inhibitors also have some obvious toxic side effects.
  • some JAK inhibitors are prone to cause the following side effects: infection, including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycetes Infections (mycobacterial infections), fungal infections, decreased immunity (eg, decreased NK cells), and anemia.
  • infection including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycetes Infections (mycobacterial infections), fungal infections, decreased immunity (eg, decreased NK cells), and anemia.
  • viral infection such as herpes zoster infection
  • bacterial infection such as herpes zoster infection
  • actinomycetes Infections mycobacterial infections
  • fungal infections eg, decreased NK cells
  • anemia e.g, decreased NK cells
  • JAKs family kinases are responsible for regulating numerous signaling pathways. Since JAK1 and JAK3 are components of a common ⁇ -chain cytokine receptor complex, it is difficult to develop inhibitors that are highly selective for JAK1.
  • JAK1 plays a key role in the regulation of biological responses, and JAK1 is widely expressed and associated with several major cytokine receptor families. It is involved through the IL-2 receptor gamma subunit family (IL-2, IL-4, IL-7R, IL-9R, IL-15R and IL-21R), the IL-4 receptor family (IL-4R, IL-21R) -13R), signaling of members of the gp130 receptor family and class II cytokine receptors, including the IL-10 receptor family and both the Type I and Type II IFN receptor families.
  • IL-2 receptor gamma subunit family IL-2, IL-4, IL-7R, IL-9R, IL-15R and IL-21R
  • IL-4 receptor family IL-4R, IL-21R
  • the present invention provides an inhibitor of JAK or related kinases, especially an inhibitor with high selectivity to JAK1.
  • the first aspect of the present invention provides a compound represented by formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate,
  • R1, R2 and R3 are each independently selected from the group consisting of substituted or unsubstituted H, D, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfone, sulfoxide, amido , sulfonamido, ester, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3 -C10 cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R a ;
  • R 1 and R 2 together with the atoms to which they are attached form a substituted or unsubstituted group of the following groups: 5-6 membered aryl or heteroaryl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl; Wherein, described substitution refers to be replaced by one or more R a ;
  • H atoms in -(CH 2 ) r - and -(CH 2 ) p - may be optionally substituted by one or more Ra ;
  • C is selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3 -C10 cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R a ;
  • r and p are each independently 1, 2, 3, 4;
  • n, k and l are each independently 0, 1, 2, 3, and m+n ⁇ 1, k+l ⁇ 1;
  • the H in the moiety can be optionally substituted with one or more Ra ;
  • each R is independently selected from the group consisting of substituted or unsubstituted groups: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12-membered heteroaryl and C6-C12 aryl; wherein, the substitution described in R a refers to being substituted by one or more groups selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester, formyl, formamido, C1-C
  • R1, R2 and R3 are each independently selected from the group consisting of substituted or unsubstituted H, D, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfone, sulfoxide, amido , sulfonamido, ester, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3 -C10 cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R a ;
  • R 1 and R 2 together with the atoms to which they are attached form a substituted or unsubstituted group of the following groups: 5-6 membered aryl or heteroaryl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl; wherein , the substitution refers to being substituted by one or more R a ;
  • H atoms in -(CH 2 ) r - and -(CH 2 ) p - may be optionally substituted by one or more Ra ;
  • C is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 Cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R a ;
  • r and p are each independently 1, 2, 3, 4;
  • n, k and l are each independently 0, 1, 2, 3, and m+n ⁇ 1, k+l ⁇ 1;
  • the H in the moiety can be optionally substituted with one or more Ra ;
  • each R is independently selected from the group consisting of substituted or unsubstituted groups: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12-membered heteroaryl and C6-C12 aryl; wherein, the substitution described in R a refers to being substituted by one or more groups selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester, formyl, formamido, C1-C
  • each R a is independently selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, Formyl, formamido, C1-C6 alkyl, halogenated C1-C6 alkyl, (CH 2 ) t G, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl, wherein t is 1, 2 or 3; G is selected from: 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate Partially selected from:
  • Ra is defined as above.
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has the structure shown in formula II:
  • R 1 , R 2 , R 3 , Ra , B and C are as defined above.
  • C is selected from the group consisting of substituted or unsubstituted groups: 3 -8-membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, C6-C10 aryl; wherein, the substitution refers to being substituted by one or more R a ;
  • Ra is defined as above.
  • C is selected from the group consisting of substituted or unsubstituted groups: cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, piperidinyl, Linyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, furanyl, thiazolyl, pyrrolyl, indolyl, naphthyl, wherein the substitution refers to substitution by one or more R a ; R a is as defined above.
  • Ra is defined as above.
  • C is selected from: H, methoxy, phenyl, methyl, ethyl, thiazolyl, pyridyl, cyclopropyl, pyrazinyl, cyclohexyl, benzothienyl, benzoyl furanyl, pyrimidinyl, naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from fluorine, chlorine, bromine, nitro, cyano, Hydroxy, ethynyl, methyl, methoxy, methyl formate, trifluoromethyl, phenyl, aminosulfonyl (or sulfonamido).
  • C is selected from: H, methoxy, phenyl, methyl, ethyl, cyclopropyl, cyclohexyl, Naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl group, methoxy group, methyl formate group, trifluoromethyl group, phenyl group, aminosulfonyl group (or sulfonamido group).
  • C is selected from: H, methyl, methoxy, phenyl,
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 is hydrogen
  • the compound has the structure shown in formula II:
  • R 1 , R 2 , R 3 , Ra , B and C are as defined above.
  • each C1-C6 alkyl group is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.
  • each C1-C6 alkoxy group is independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy , tert-butoxy.
  • each C2-C6 alkenyl group is independently selected from vinyl, propenyl, and allyl.
  • each C2-C6 alkynyl group is independently selected from ethynyl and propynyl.
  • each 3- to 10-membered heterocycloalkyl group is independently selected from tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperazinyl, piperidinyl, and morpholinyl.
  • each C3-C10 cycloalkyl group is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • each 5-12-membered heteroaryl group is independently selected from pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, indole base, benzothienyl, benzofuranyl.
  • each C6-C12 aryl group is independently selected from phenyl and naphthyl.
  • R 1 , R 2 , R 3 , R a , B and C are specific groups corresponding to the specific compounds in the examples.
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate the compound is selected from the following group:
  • the compound of formula I is selected from the compounds shown in the examples.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate; and acceptable carrier.
  • the pharmaceutical composition further includes a drug selected from the group consisting of:
  • PD-1 inhibitors eg, nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10 , BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.
  • PD-L1 inhibitors such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.
  • CD20 antibodies such as rituximab, obinutuzumab, Ofatumumab, veltuzumab, tositumumab, 131I-tosit
  • the third aspect of the present invention provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention or its stereoisomer or optical isomer, The pharmaceutically acceptable salts, prodrugs or solvates are mixed to form a pharmaceutical composition.
  • the compounds of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.
  • the pharmaceutical composition is used to treat or prevent diseases related to the activity or expression level of JAK kinase.
  • the pharmaceutical composition is used as a JAK kinase inhibitor, preferably as a JAK1 kinase inhibitor.
  • the fourth aspect of the present invention provides the use of the compound described in the first aspect or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof for preparing treatment or prevention Medicines or pharmaceutical compositions for diseases associated with the activity or expression of JAK kinases.
  • the disease is selected from the group consisting of cancer, myeloproliferative disease, inflammation, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease, human or animal autoimmune disease, Rheumatoid Arthritis, Skin Disorders, Multiple Sclerosis, Rheumatoid Arthritis, Psoriatic Arthritis, Inflammatory Bowel Disease, Myasthenia Gravis, Psoriasis.
  • the cancer is selected from the group consisting of prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoid hyperplasia, pancreatic cancer, leukemia, lymphoma, and multiple myeloma.
  • the disease related to the activity or expression level of the JAK kinase is a JAK1-related disorder.
  • the JAK1-related disorder is preferably selected from the group consisting of type I diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis , Crohn's disease and alopecia areata.
  • the inventors have unexpectedly discovered a new JAK inhibitor for the first time, which has a novel structure, good biological activity and excellent selectivity against JAK1.
  • the selectivity represented by the ratio of JAK2/JAK1 or the ratio represented by the ratio of JAK3/JAK1 or the ratio of TYK2/JAK1 is increased by an average of about 10-fold (most compounds are increased by about 20- 100 times). Therefore, the side effects associated with the inhibition of JAK3 by the compounds of the present invention are significantly reduced, and the safety is significantly improved.
  • the present invention has been completed on this basis.
  • the substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. That is, when the linking group -L1- listed in the present invention does not indicate its linking direction, its linking direction can be linked in the same direction as the reading order from left to right, or it can be linked in the opposite direction to the above-mentioned direction. to connect.
  • An example is as follows, The linking group -L1- is -CD-, if -CD- connects ring A and ring B in the same direction as the reading order from left to right If -CD- is formed by connecting ring A and ring B in the opposite direction to the above
  • the term “about” means that the value may vary by no more than 1% from the recited value.
  • 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 (including)” can be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • alkyl includes straight or branched chain alkyl groups.
  • C 1 -C 6 alkyl means straight or branched chain alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • alkenyl includes straight or branched chain alkenyl groups.
  • C 2 -C 6 alkenyl refers to straight or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -butenyl, or similar groups.
  • alkynyl includes straight or branched chain alkynyl groups.
  • C2 - C6alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • cycloalkyl refers to a cyclic alkyl group (saturated or containing a double bond) containing the specified number of C atoms, eg "C3-C10 cycloalkyl” refers to a cyclic alkyl group having 3-10 (preferably 3, 4, 5, 6, 7 or 8) carbon atoms. It may be a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Bicyclic forms, such as bridged or spiro forms, are also possible. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.
  • C1-C6alkoxy refers to a straight or branched chain alkoxy group having 1-6 carbon atoms; it has the formula C1-C6alkyl-O- or -C1-C5alkane Alkyl-O-C1-C5 alkyl (eg, -CH2 -O- CH2CH3 , -CH2 - O- ( CH2 ) 2CH3 , -CH2CH2 - O - CH2CH3 ) Structure, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.
  • heterocyclyl refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S, and O
  • heterocyclyl and heterocycloalkyl have the same meaning and can be used interchangeably. It may be monocyclic or bicyclic, eg bridged or spirocyclic.
  • the 3-10-membered heterocyclic(alkyl) group is preferably a 3-8-membered heterocyclic(alkyl) group, more preferably a 6-8-membered heterocyclic(alkyl) group.
  • Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
  • aryl refers to an aromatic ring group containing no heteroatoms in the ring
  • C6-C12 aryl refers to an aromatic ring group having 6 to 12 carbon atoms that contains no heteroatoms in the ring
  • the aryl group can be fused to a heteroaryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring connected with the parent structure is an aryl ring.
  • the C6-C12 aryl group is preferably a C6-C10 aryl group.
  • Aryl groups can be optionally substituted or unsubstituted.
  • heteroaryl refers to a cyclic aromatic group having 1-3 atoms that are heteroatoms selected from the following groups of N, S, and O
  • heteroaryl refers to a group having 5-12 atoms A cyclic aromatic group of atoms wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be a single ring or a fused ring form.
  • heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamido, Formyl, formamide, carboxyl and carboxylate, etc.
  • halogen or "halogen atom” refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br.
  • the term "amido" refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, as above defined. R and R' can be the same or different in the dialkylamine moiety.
  • amide groups include, but are not limited to: -CONH2 , -CONHCH3, -CONHCH2CH3 , -CON (CH3)2 , -CONH cyclopropyl , -CONH cyclobutyl, -CONH cyclopentyl, - CONH cyclohexyl, -CONCH 3 cyclopropyl, -CONCH 3 cyclobutyl, -CONCH 3 cyclopentyl, -CONCH 3 cyclohexyl.
  • sulfonamido refers to a group with the structure -SO 2 NRR', wherein R and R' can independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • sulfonamido groups include, but are not limited to : -SO2NH2 , -SO2NHCH3 , -SO2NHCH2CH3 , -SO2N ( CH3 ) 2 , -SO2NHcyclopropyl , -SO 2 NH cyclobutyl, -SO 2 NH cyclopentyl, -SO 2 NH cyclohexyl, -SO 2 NCH 3 cyclopropyl, -SO 2 NCH 3 cyclobutyl, -SO 2 NCH 3 cyclopentyl, -SO 2 NCH 3 cyclohexyl.
  • carboxamido refers to containing The group, carboxamido is also intended to include substituted carboxamido, having the formula wherein each R independently represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, as defined above. Each R may be the same or different.
  • amino means having the structure -N-RR', where R and R' each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above , R and R' can be the same or different.
  • amino groups include, but are not limited to: -NH2 , -NHCH3 , -NHCH2CH3, -N( CH3 ) 2 , -NHcyclopropyl, -NHcyclobutyl, -NHcyclopentyl , -NH Cyclohexyl, -NCH 3 cyclopropyl, -NCH 3 cyclobutyl, -NCH 3 cyclopentyl, -NCH 3 cyclohexyl.
  • sulfoxide means having -S(O)-R, R independently representing hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above.
  • sulfoxide groups include, but are not limited to: -S(O) -CH3 , -S(O)-CH2CH3, -S(O)-CH ( CH3 ) 2 .
  • sulfone means having -S(O) 2 -R, R independently representing hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above.
  • sulfone groups include, but are not limited to: -S(O) 2 - CH3 , -S(O) 2 - CH2CH3 , -S(O) 2 - CH ( CH3 ) 2 .
  • ester group means having the structure -C(O)-OR or RC(O)-O-, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl , Heterocyclyl, as defined above.
  • ester groups include, but are not limited to: -C(O)-O- CH3 , -C(O)-O- CH2CH3 , -C (O)-O - CH2CH2CH3 , -C (O)-O-CH(CH 3 ) 2 , -OC(O)-CH 3 , -OC(O)-CH 2 CH 3 , -OC(O)-CH 2 CH 2 CH 3 , -OC(O )-CH(CH 3 ) 2 .
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the group described in the present invention is "substituted or unsubstituted", the group of the present invention can be substituted by a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12-membered heteroaryl base, C6-C12 aryl.
  • a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12-membered heteroaryl base,
  • the structural formulas described herein are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, those containing asymmetric R, S configuration of the center, (Z), (E) isomer of double bond, etc. Accordingly, individual stereochemical isomers or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.
  • tautomer means that structural isomers having different energies can exceed a low energy barrier, thereby interconverting.
  • proton tautomers ie, protonation
  • Valence tautomers include interconversion by some bonding electron recombination.
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.
  • compounds of the present invention refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds of formula I.
  • the compound of formula I of the present invention has the following structure,
  • R 1 , R 2 , R 3 , B, C, m, n, k and l are as defined above.
  • the compound of formula I has the structure described in formula II,
  • R 1 , R 2 , R 3 , R a , q, B and C are as defined above.
  • C is selected from the group consisting of substituted or unsubstituted groups: 3-8-membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, C6-C10 aryl
  • C is selected from the group consisting of substituted or unsubstituted groups: cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl , phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, furanyl, thiazolyl, pyrrolyl, indolyl, naphthyl, wherein the substitution refers to being substituted by one or more R a ;
  • Ra is defined as above.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (eg, organic amines) such as benzathine, dicyclohexylamine , Hepamine (salt with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with the specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have hydrogen substituents or any permissible organic compound described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds.
  • stable refers to a compound that is stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the above-mentioned purposes.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (eg, 0°C to 150°C, preferably 10°C to 100°C).
  • the reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.
  • the compounds of the present invention can be prepared by the following steps
  • R 1 , R 2 , R 3 , m, n, k and l are as defined above;
  • R is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 Cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl;
  • B' is selected from the group consisting of amino, hydroxyl, carboxyl, sulfonic acid, -CO-NH-R';
  • C' is selected from: amino group, hydroxyl group, carboxyl group, sulfonic acid group, CO-O-R', -CO-NH-R';
  • R' is selected from substituted or unsubstituted following groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl, 5 -12-membered heteroaryl, C6-C12 aryl;
  • substitution refers to substitution with one or more groups selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.
  • the starting materials and reagents used in the synthesis method of the compounds of the present invention can be purchased commercially or synthesized by methods reported in the literature.
  • compositions and methods of administration are provided.
  • the compounds of the present invention have excellent inhibitory activity against JAK kinases, the compounds of the present invention or stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, and containing the compounds of the present invention are the main activities
  • the pharmaceutical composition of ingredients can be used to prevent and/or treat (stabilize, alleviate or cure) JAK kinase-related diseases (eg, skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriatic arthritis, juvenile arthritis) , Crohn's disease, myasthenia gravis, cancer (including prostate, kidney, liver, breast, lung, thyroid, Kaposi's sarcoma, giant lymphoid hyperplasia, pancreatic cancer, leukemia, lymphoma or multiple myeloma, etc.)).
  • JAK kinase-related diseases eg, skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes, psori
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition are capable of admixture with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compounds or pharmaceutical compositions 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 with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, 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 tinctures.
  • liquid dosage forms 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 mixtures of these substances, and the like.
  • 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, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as JAK inhibitors.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, eg, JAK inhibitors).
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (eg, JAK inhibitors) can be used simultaneously, separately or sequentially with the compounds of the invention Prevention and/or treatment of diseases related to the activity or expression of JAK kinases.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the compound of the present invention has a novel structure and excellent JAK kinase inhibitory effect
  • the compounds of the present invention can be used as JAK kinase inhibitors, especially as highly selective inhibitors of JAK1.
  • the compounds of the present invention have better pharmacokinetic properties and efficacy, such as better druggability, low toxicity and side effects, and good bioavailability.
  • the percentages for the yields are all mass percentages.
  • PTLC Thin layer chromatography
  • LCMS chromatography was performed using an Agilent Technologies 1260 Link 6100 quadrupole spectrometer.
  • A formic acid-water
  • B formic acid-acetonitrile
  • eluent gradient 0-5.5 min 0-95% B, 5.5-6 min 95% B, 6-8 min 0% B with SB-Aq 50 mm x 2.1 mm x 3.5 ⁇ m capillary column.
  • MS Mass spectrometry
  • ESI electrospray ion mass spectrometry
  • MS mass range 100-100 amu; positive ion electrospray ionization.
  • Alk is alkyl
  • AR is aryl
  • Boc tert-butoxycarbonyl
  • LiOH Lithium Hydroxide
  • MgSO 4 magnesium sulfate
  • Na 2 SO 4 sodium sulfate
  • PE petroleum ether
  • Ph phenyl
  • 1,4-cyclohexanedione monoethylene glycol ketal (A1-1, 10.0 g, 64.0 mmol) was added to anhydrous THF (100 ml), stirred in an ice bath for 5 min, and sodium hydrogen (3.07 g) was added in batches. , 76.8mmol, 60%dispersion in mineral oil), continue to stir in ice bath for 0.5h, then slowly add triethyl phosphonoacetate (14.78g, 65.9mmol) in THF solution (50ml), after dripping, it naturally rises to room temperature to continue Stir for 2h.
  • 1,4-dioxa-10- azabispiro [ 4.2.48.25 ]tetradec-11-one (A1-4, 2g, 9.47mmol) was added to dry THF (30ml) , stirred for 5 min, slowly added borane THF solution (47.4 ml, 47.4 mmol, 1 M), warmed to 70 °C, and stirred for 16 h.
  • Step 5 10-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-dioxa- 10 -azaspiro[ 4.2.48.25 ]tetradecane (A1-6)
  • Examples 5-75 were obtained, as shown in Table 1 below.
  • 6-oxo-2-azaspiro[3.3]heptane trifluoroacetate (A76-01, 215 mg, 0.95 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (148 mg, 0.96 mmol) was added to N-methylpyrrolidone (4 ml), then potassium carbonate (900 mg, 6.5 mmol) was added, the temperature was raised to 80° C. and stirred for 14 h. After confirming that the reaction was complete by LCMS, it was cooled to room temperature, filtered with suction, and the filter cake was collected and dried under reduced pressure to obtain 6-oxo-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl as an off-white solid. )-2-azaspiro[3.3]heptane (A76-02, 40 mg, crude) was used in the next step without purification.
  • 6-oxo-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptane (A76-02, 40 mg, 0.18 mmol) was added to absolute ethanol (2ml), then add 7mol/L NH 3 in MeOH solution (2ml, 14mmol) and isopropyl titanate (105mg, 0.37mmol), stir at room temperature for 6h, then add sodium borohydride (67mg, 1.8mmol), continue Stir for 16h. After confirming that the reaction was complete by LCMS, ammonia water (2 mL) was added to quench the reaction, stirred at room temperature for 15 min, suction filtered, and the filtrate was collected.
  • JAK kinase activity is measured using a homogeneous time-resolved fluorescence technique. Reactions for this method were in 384 shallow well plates and the total reaction volume was 10 ⁇ L. Mixture of kinase protein, compound, ATP and substrate in reaction buffer of 50 mM Hepes (pH 7.0), NaN 3 0.02%, BSA 0.01%, 0.1 mM Orthocanadate, 5 mM MgCl 2 , 1 mM DTT After 1 hour of reaction, an antibody capable of recognizing phosphorylation of the substrate, a dye XL-615 and a detection buffer (Cisbio) containing EDTA were added to the system.
  • reaction buffer 50 mM Hepes (pH 7.0), NaN 3 0.02%, BSA 0.01%, 0.1 mM Orthocanadate, 5 mM MgCl 2 , 1 mM DTT
  • the reaction signal of the kinase was detected by the multi-well plate detector of PE Company.
  • the parameter settings are excitation light 320nm, emission light 615nm and 665nm.
  • the activity of JAK is indirectly reflected by the signal ratio of 665nm and 615nm.
  • background wells without enzyme and holoenzyme activity wells without compound were set.
  • the concentration of ATP was 2 ⁇ M, and the concentration of JAK1 protein was 0.2 ng/ ⁇ L.
  • the concentration of ATP was 2 ⁇ M, and the concentration of JAK1 protein was 0.01 ng/ ⁇ L.
  • the concentration of ATP was 2 ⁇ M, and the concentration of JAK1 protein was 0.04 ng/ ⁇ L.
  • the concentration of ATP was 2 ⁇ M, and the concentration of JAK1 protein was 0.2 ng/ ⁇ L.
  • test data are divided into the following categories: A: IC 50 ⁇ 10nM; B: IC 50 11-100 nM; C: IC 50 101-1000 nM; D: IC 50 1001-10000 nM; E: IC 50 >10000 nM.
  • the compounds of formula I of the present invention exhibit very excellent JAK inhibitory activity, especially JAK1 activity.
  • the IC50 value of the compounds of the present invention can be as low as 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), a daily dose of 10 mg-30 mg is usually sufficient. Extremely potent inhibition of JAK, especially JAK1.
  • the compound of formula I of the present invention exhibits very excellent JAK selectivity, that is, the ratio of IC50 of JAK3/JAK1, the ratio of IC50 of JAK2/JAK1, and the ratio of IC50 of TYK2/JAK1 are increased by about 10 times (mostly About 20-100 times), far superior to the currently marketed drugs.

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Abstract

本发明涉及一种螺环JAK抑制剂、含其的药物组合物及其应用。具体地，本发明涉及如式I所示的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，也涉及所述化合物的药物组合物以及其作为JAK抑制剂，以及在制备预防和/或治疗与JAK，尤其是JAK1相关疾病的药物中的医药用途。

Description

螺环JAK抑制剂、含其的药物组合物及其应用 技术领域
本发明属于药物化学领域，具体涉及一种螺环JAK抑制剂、含其的药物组合物及应用。
背景技术
蛋白激酶(PK)是调控多种重要生物过程的一组酶，其构成了人最大的酶家族之一，所述生物过程尤其包括细胞激酶催化蛋白质、脂质、糖、核苷和其他细胞代谢物的磷酸化并在真核细胞生理学的所有方面起关键作用。已经表明在许多人类疾病中涉及激酶活性异常，这些疾病包括癌症、自身免疫性疾病和炎性疾病。
Janus激酶(JAK)是转导细胞因子信号从膜受体到STAT转录因子的细胞质酪氨酸激酶，其在细胞因子信号传递过程中起重要作用。JAK家族包括四个成员JAK1、JAK2、JAK3及酪氨酸激酶2(TYK2)。JAK通常与细胞因子受体成对缔合作为均二聚体或杂二聚体。细胞因子与其受体结合，引起受体分子的二聚化，与受体偶联的JAKs相互接近并通过交互的酪氨酸残基磷酸化作用而活化。JAK家族通过JAK-STAT(信号转导与转录活化因子)通路将细胞因子介导的信号传递至细胞中。
信号转导和转录激活子(Signal Transducer and Activator of Transcription,STAT)是一组能与靶基因调控区DNA结合的胞质蛋白。作为JAKs的下游底物，STATs可以在外界信号的刺激下，发生酪氨酸磷酸化从而被激活，随后转入细胞核调节基因的转录。当细胞因子与其受体结合时，JAK家族成员自磷酸化和/或彼此转磷酸化，随后STATs磷酸化，然后迁移至细胞核内以调节转录。
许多异常的免疫应答，如过敏、哮喘、(异体)移植排斥、类风湿性关节炎、肌萎缩性脊髓侧索硬化症和多发性硬化症等自身免疫性疾病，骨髓增生失调，白血病和淋巴瘤等血液系统恶性肿瘤，它们的调节都与JAK/STAT信号通路有关。
研究表明，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。
JAK1在生物反应调节中起关键作用，且JAK1被广泛表达并与几种主要的细胞因子受体家族相关联。它参与通过IL-2受体γ亚单位家族(IL-2、IL-4、IL-7R、IL-9R、IL-15R和IL-21R)、IL-4受体家族(IL-4R、IL-13R)、gp130受体家族和II类细胞因子受体(包括IL-10受体家族以及I型和II型IFN受体家族两者)的成员的信号传导。
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
本发明提供了一种JAK或相关激酶的抑制剂，尤其是对JAK1具有高选择性的抑制剂。
本发明第一方面，提供一种式I所示的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，
Figure PCTCN2021134880-appb-000001
式中，
R 1、R 2和R 3各自独立地选自取代或未取代的下组基团：H、D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；其中，所述的取代是指被一个或多个R a取代；
或者R 1和R 2与它们连接的原子一起构成取代或未取代的下组基团：5-6元芳基或杂芳基、3-10元杂环烷基、C3-C10环烷基；其中，所述的取代是指被一个或多个R a取代；
B独立地选自下组：键、-(CH 2) r-、C(＝O)、N-R b、C(＝O)O-、
Figure PCTCN2021134880-appb-000002
-(CH 2) p-R c、O、S、SO、SO 2；R c选自：C(＝O)O-、
Figure PCTCN2021134880-appb-000003
其中，R b独立地选自下组：H、C1-C6烷基；
其中，-(CH 2) r-和-(CH 2) p-中的H原子可以任选地被一个或多个R a取代；
C选自取代或未取代的下组基团：H、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；其中，所述的取代是指被一个或多个R a取代；
r和p各自独立地为1、2、3、4；
m、n、k和l各自独立地为0、1、2、3，且m+n≥1，k+l≥1；
Figure PCTCN2021134880-appb-000004
部分中的H可以任选地被一个或多个R a取代；
其中，各R a独立地选自取代或未取代的下组基团：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基；其中，R a中所述的取代是指被选自下组的一个或多个基团取代：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基。
在另一优选例中，式I所示的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，
Figure PCTCN2021134880-appb-000005
式中，
R 1、R 2和R 3各自独立地选自取代或未取代的下组基团：H、D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；其中，所述的取代是指被一个或多个R a取代；
或者R 1和R 2与它们连接的原子一起构成取代或未取代的下组基团：5-6元芳基或杂芳基、3-10元杂环基、C3-C10环烷基；其中，所述的取代是指被一个或多个R a取代；
B独立地选自下组：键、-(CH 2) r-、C(＝O)、N-R b、C(＝O)O-、
Figure PCTCN2021134880-appb-000006
-(CH 2) p-R c、O、S、SO、SO 2；R c选自：C(＝O)O-、
Figure PCTCN2021134880-appb-000007
其中，R b独立地选自下组：H、C1-C6烷基；
其中，-(CH 2) r-和-(CH 2) p-中的H原子可以任选地被一个或多个R a取代；
C选自取代或未取代的下组基团：C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；其中，所述的取代是指被一个或多个R a取代；
r和p各自独立地为1、2、3、4；
m、n、k和l各自独立地为0、1、2、3，且m+n≥1，k+l≥1；
Figure PCTCN2021134880-appb-000008
部分中的H可以任选地被一个或多个R a取代；
其中，各R a独立地选自取代或未取代的下组基团：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基；其中，R a中所述的取代是指被选自下组的一个或多个基团取代：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基。
在另一优选例中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、卤代C1-C6烷基、(CH 2) tG、C1-C6烷氧基、卤代C1-C6烷氧基、C2-C6烯基、C2-C6炔基、 3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基，其中，t为1、2或3；G选自：3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，
Figure PCTCN2021134880-appb-000009
部分选自:
Figure PCTCN2021134880-appb-000010
Figure PCTCN2021134880-appb-000011
其中，q为0、1、2、3、4或5；
R a的定义如上所述。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其具有式II所示的结构：
Figure PCTCN2021134880-appb-000012
其中，q为0、1、2、3、4或5；
R 1、R 2、R 3、R a、B和C的定义如上所述。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，B选自下组：C(＝O)O-、
Figure PCTCN2021134880-appb-000013
其中，R b的定义上所述。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，C选自取代或未取代的下组基团：3-8元杂环烷基、C3-C8环烷基、5-10元杂芳基、C6-C10芳基；其中，所述的取代是指被一个或多个R a取代；
R a的定义如上所述。
在另一优选例中，C选自取代或未取代的下组基团：环戊基、环己基、四氢呋喃基、四氢吡咯基、四氢吡喃基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基、嘧啶基、咪唑基、吡唑基、呋喃基、噻唑基、吡咯基、吲哚基、萘基，其中，所述取代是指被一个或多个R a取代；R a的定义如上所述。
在另一优选例中，
Figure PCTCN2021134880-appb-000014
选自:
Figure PCTCN2021134880-appb-000015
Figure PCTCN2021134880-appb-000016
Figure PCTCN2021134880-appb-000017
其中，q为0、1、2、3、4或5；
R a的定义如上所述。
在另一优选例中，B选自：-NH-、
Figure PCTCN2021134880-appb-000018
-NH-C(＝O)-，任选地，上述基团中的各氢被C1-C6烷基取代。
在另一优选例中，C选自：H、甲氧基、苯基、甲基、乙基、噻唑基、吡啶基、环丙基、吡嗪基、环己基、苯并噻吩基、苯并呋喃基、嘧啶基、萘基、环丁基、环戊基、环庚基；其中，任选地，C被选自下述的取代基取代：氟、氯、溴、硝基、氰基、羟基、乙炔基、甲基、甲氧基、甲酸甲酯基、三氟甲基、苯基、氨基磺酰基(或磺酰胺基)。
在另一优选例中，C选自：H、甲氧基、苯基、甲基、乙基、
Figure PCTCN2021134880-appb-000019
环丙基、
Figure PCTCN2021134880-appb-000020
环己基、
Figure PCTCN2021134880-appb-000021
萘基、环丁基、环戊基、环庚基；其中，任选地，C被选自下述的取代基取代：氟、氯、溴、硝基、氰基、羟基、乙炔基、甲基、甲氧基、甲酸甲酯基、三氟甲基、苯基、氨基磺酰基(或磺酰胺基)。
在另一优选例中，C选自：H、甲基、甲氧基、
Figure PCTCN2021134880-appb-000022
Figure PCTCN2021134880-appb-000023
苯基、
Figure PCTCN2021134880-appb-000024
Figure PCTCN2021134880-appb-000025
Figure PCTCN2021134880-appb-000026
在另一优选例中，R 1为氢。
在另一优选例中，R 2为氢。
在另一优选例中，R 3为氢。
在另一优选例中，
Figure PCTCN2021134880-appb-000027
选自
Figure PCTCN2021134880-appb-000028
在另一优选例中，所述化合物具有式II所示的结构：
Figure PCTCN2021134880-appb-000029
其中，q为0、1、2、3、4或5；
R 1、R 2、R 3、R a、B和C的定义如上所述。
在另一优选例中，各C1-C6烷基独立地选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基。
在另一优选例中，各C1-C6烷氧基独立地选自甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基、叔丁氧基。
在另一优选例中，各C2-C6烯基独立地选自乙烯基、丙烯基、烯丙基。
在另一优选例中，各C2-C6炔基独立地选自乙炔基、丙炔基。
在另一优选例中，各3-10元杂环烷基独立地选自四氢呋喃基、四氢吡咯基、四氢噻吩、四氢吡喃基、哌嗪基、哌啶基、吗啉基。
在另一优选例中，各C3-C10环烷基独立地选自环丙基、环丁基、环戊基、环己基、环庚基。
在另一优选例中，各5-12元杂芳基独立地选自吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、吲哚基、苯并噻吩基、苯并呋喃基。
在另一优选例中，各C6-C12芳基独立地选自苯基、萘基。
在另一优选例中，式I中，R 1、R 2、R 3、R a、B和C为实施例中各具体化合物相对应的具体基团。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，所述化合物选自下组：
Figure PCTCN2021134880-appb-000030
Figure PCTCN2021134880-appb-000031
Figure PCTCN2021134880-appb-000032
Figure PCTCN2021134880-appb-000033
在另一优选例中，所述的式I化合物选自实施例中所示化合物。
本发明第二方面，提供一种药物组合物，其包含第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物；和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括选自下组的药物：
PD-1抑制剂(如纳武单抗、派姆单抗、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗、阿维鲁单抗(avelumab)、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、veltuzumab,托西莫单抗、131I-托西莫单抗、替伊莫单抗、90Y-替伊莫单抗、90In-替伊莫单抗、替伊莫单抗(ibritumomab tiuxetan)等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、阿卡替尼、赞布替尼、Vecabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼、沙普替尼、Naquotinib、吡咯替尼、罗乐替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、司曲替尼、Ningetinib、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、伏立诺他、Fimepinostat、Droxinostat、恩替诺特、达西司特、Quisinostat、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)，或其组合。
本发明第三方面，提供一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物进行混合，从而形成药物组合物。
在另一优选例中，本发明化合物可以制备成散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂等。
在另一优选例中，所述药物组合物用于治疗或预防与JAK激酶的活性或表达量相关的疾病。
在另一优选例中，所述药物组合物用作JAK激酶抑制剂，优选用作JAK1激酶抑制剂。
本发明第四方面，提供一种第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物的用途，其用于制备治疗或预防与JAK激酶的活性或表达量相关的疾病的药物或药物组合物。
在另一优选例中，所述疾病选自下组：癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病、人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮癣。
其中，所述癌症选自下组：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、多发性骨髓瘤。
在另一优选例中，所述JAK激酶的活性或表达量相关的疾病为JAK1相关的障碍。
其中，所述JAK1相关的障碍优选选自下组：I型糖尿病、狼疮、多发性硬化症、类风湿性关节炎、牛皮癣、哮喘、特应性皮炎、自身免疫性甲状腺疾病、溃疡性结肠炎、克罗恩病和斑秃。
在另一优选例中，提供一种第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物的用途，其用于制备抑制JAK激酶活性的药物或药物组合物；其中，所述JAK激酶优选为JAK1激酶。
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针对JAK1的选择性。具体地，本发明化合物，以JAK2/JAK1之比为代表的选择性或以JAK3/JAK1之比或以TYK2/JAK1之比为代表的选择性平均提高约10倍(大部分化合物提高约20-100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
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。也即，本发明所列举的连接基团-L1-没有指明其连接方向时，其连接方向可以按与从左往右的读取顺序相同的方向进行连接，也可以按与上述方向相反的方向进行连接。举例说明如下，
Figure PCTCN2021134880-appb-000034
中连接基团-L1-为-C-D-，若-C-D-按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2021134880-appb-000035
若-C-D-按与上述方向相反的方向连接环A和环B构成
Figure PCTCN2021134880-appb-000036
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必须出现的，并且该描述包括所述事件或状况发生的情况，以及所述事件或状况不发生的情况。
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”。
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 6烷基表示具有1-6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“环烷基”是指包含特定数目的C原子的环状烷基(饱和的或含有双键的)，如“C3-C10环烷基”指具有3-10个(优选3、4、5、6、7或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。本发明中，环烷基意在包含取代环烷基。
如本文所用，术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链的烷氧基；其具有式C1-C6烷基-O-或-C1-C5烷基-O-C1-C5烷基(如，-CH 2-O-CH 2CH 3、-CH 2-O-(CH 2) 2CH 3、-CH 2CH 2-O-CH 2CH 3)结构，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，“杂环(烷)基(heterocyclyl)”是指具有选自N、S和O的杂原子的饱和或部分饱和的环状基团，“3-10元杂环基”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。本发明中，杂环基和杂环烷基具有相同含义，可互换使用。其可以是单环，也可以是双环形式，例如桥环或螺环形式。3-10元杂环(烷)基优选3-8元杂环(烷)基，更优选地为6-8元杂环(烷)基。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、哌嗪基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用，“芳基”是指环上不含杂原子的芳香族环基，“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，所述芳基可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。如苯基(即六元芳环)、萘基等，其中六元芳基还意在包含六元芳基并5-6元环烷基和六元芳基并5-6元杂环烷基。C6-C12芳基优选C6-C10芳基。芳基可以是任选取代的或未取代的。
如本文所用，“杂芳基”指具有1-3个原子为选自下组N、S和O的杂原子的环状芳香基，“5-12元杂芳基”指具有5-12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。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、酰胺基、磺酰胺基、甲酰基、甲酰胺基、羧基和羧酸酯基等。
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。
在本发明中，术语“酰胺基”是指带有结构-CONRR'的基团，其中，R和R'可以独立的代表氢、烷基、环烷基、芳基、杂环基，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。酰胺基的实例包括但不限于：-CONH 2、-CONHCH 3、-CONHCH 2CH 3、-CON(CH 3) 2、-CONH环丙基、-CONH环丁基、-CONH环戊基、-CONH环己基、-CONCH 3环丙基、-CONCH 3环丁基、-CONCH 3环戊基、-CONCH 3环己基。
在本发明中，术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、烷基、环烷基、芳基、杂环基，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。磺酰胺基的实例包括但不限于：-SO 2NH 2、-SO 2NHCH 3、-SO 2NHCH 2CH 3、-SO 2N(CH 3) 2、-SO 2NH环丙基、-SO 2NH环丁基、-SO 2NH环戊基、-SO 2NH环己基、-SO 2NCH 3环丙基、-SO 2NCH 3环丁基、-SO 2NCH 3环戊基、-SO 2NCH 3环己基。
在本发明中，术语“甲酰基”是指包含-CHO的基团。
在本发明中，术语“甲酰胺基”是指包含
Figure PCTCN2021134880-appb-000037
的基团，甲酰胺基还意在包含取代的甲酰胺基，具有式
Figure PCTCN2021134880-appb-000038
其中，R各自独立地代表氢、烷基、环烷基、环烯基、芳基、杂芳基、杂环基，如上文所定义。各R可以相同或不同。
在本发明中，“氨基”是指具有-N-RR'结构，R和R'各自独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义，R和R'可以相同或不同。氨基的实例包括但不限于：-NH 2、-NHCH 3、-NHCH 2CH 3、-N(CH 3) 2、-NH环丙基、-NH环丁基、-NH环戊基、-NH环己基、-NCH 3环丙基、-NCH 3环丁基、-NCH 3环戊基、-NCH 3环己基。
在本发明中，“亚砜基”是指具有-S(O)-R，R独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义。亚砜基的实例包括但不限于：-S(O)-CH 3、-S(O)-CH 2CH 3、-S(O)-CH(CH 3) 2。
在本发明中，“砜基”是指具有-S(O) 2-R，R独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义。砜基的实例包括但不限于：-S(O) 2-CH 3、-S(O) 2-CH 2CH 3、-S(O) 2-CH(CH 3) 2。
在本发明中，“酯基”是指具有-C(O)-O-R或R-C(O)-O-结构，其中，R独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义。酯基的实例包括但不限于：-C(O)-O-CH 3、-C(O)-O-CH 2CH 3、-C(O)-O-CH 2CH 2CH 3、-C(O)-O-CH(CH 3) 2、-O-C(O)-CH 3、-O-C(O)-CH 2CH 3、-O-C(O)-CH 2CH 2CH 3、-O-C(O)-CH(CH 3) 2。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。
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：氘、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
在本发明中，术语“多个”独立指2、3、4、5个。
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。
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化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
本发明的式I化合物具有如下结构，
Figure PCTCN2021134880-appb-000039
Figure PCTCN2021134880-appb-000040
式中，R 1、R 2、R 3、B、C、m、n、k和l的定义如上所述。
优选地，所述的式I化合物具有式II所述的结构，
Figure PCTCN2021134880-appb-000041
式中，R 1、R 2、R 3、R a、q、B和C的定义如上所述。
优选地，式I-II中，B选自下组：C(＝O)O-、
Figure PCTCN2021134880-appb-000042
其中，R b的定义如上所述。
优选地，式I-II中，C选自取代或未取代的下组基团：3-8元杂环烷基、C3-C8环烷基、5-10元杂芳基、C6-C10芳基；优选地，C选自取代或未取代的下组基团：环戊基、环己基、四氢呋喃基、四氢吡咯基、四氢吡喃基、哌嗪基、哌啶基、吗啉基、苯基、吡啶基、嘧啶基、咪唑基、吡唑基、呋喃基、噻唑基、吡咯基、吲哚基、萘基，其中，所述的取代是指被一个或多个R a取代；
R a的定义如上所述。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、 硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements，CAS version，Handbook of Chemistry and Physics，75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”，Thomas Sorrell，University Science Books，Sausalito:1999，也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
化合物的制备方法
以下方案和实例中描述了制备式I的化合物的方法。原料和中间体从商业来源购买，由已知步骤制备，或以其他方式说明。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～150℃，优选10℃～100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
优选地，本发明化合物可同如下步骤制得
在惰性溶剂(如DCM、DMF等)中，催化剂(如HATU、碳酸钾等)存在下，化合物I'发生反应，得到化合物I
Figure PCTCN2021134880-appb-000043
式中，
R 1、R 2、R 3、m、n、k和l的定义如上所述；
R选自取代或未取代的下组基团：C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
B'选自下组：氨基、羟基、羧基、磺酸基、
Figure PCTCN2021134880-appb-000044
-CO-NH-R'；
C'选自：氨基、羟基、羧基、磺酸基、
Figure PCTCN2021134880-appb-000045
CO-O-R'、-CO-NH-R'；
其中，R'选自取代或未取代的下组基团：C1-C6烷基、C2-C6烯基、C2-C6炔基、3-10元杂环基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
所述取代是指被选自下组的一个或多个基团取代：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、 C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基。
本发明化合物合成方法中所用起始原料和试剂均可商业购买或通过文献报道的方法合成。
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，因此本发明化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，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 PCTCN2021134880-appb-000046
)、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JAK抑制剂)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(例如例如JAK抑制剂)。该其他药学上可接受的化合物(例如JAK抑制剂)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JAK激酶的活性或表达量相关的疾病。
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激酶抑制作用；
2.本发明的化合物可以作为JAK激酶抑制剂，尤其是作为JAK1的高选择性抑制剂。
3.本发明的化合物具有较好的药代动力学特性和药效，例如更好的成药性、毒副作用低、生物利用度好等。
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。
实施例
通用材料及测试方法：
本发明的化合物的合成方法示于下面的方案、方法和实施例。起始原料是市售的或可以根据本领域或本文所描述的已知方法制备。本发明的化合物可通过以下所示的具体实施例来说明。然而，这些具体实施例不应被解释为是本发明的唯一种类。这些实施例进一步详细说明本发明化合物的制备。本领域的技术人员将容易理解，条件和过程的已知变化可用于制备这些化合物。
所有的温度均为摄氏度，除非另有说明。
对收率而言的百分比均为质量百分比。
所有的份数均为体积份，所有的百分比均为体积百分比，除非另有说明。
薄层色谱(PTLC)的制备是在20×20cm的板(500微米厚的硅胶)上进行。硅胶层析法用Biotage快速色谱系统。
1H NMR用Bruker AscendTM400光谱仪，400MHz，298K，并且将残余质子在氘化试剂中的化学位移(ppm)给出参考：
CDCl 3δ＝7.26ppm，CD 3ODδ＝3.30ppm，DMSO-d 6δ＝2.50ppm
LCMS色谱采用安捷伦科技1260链接6100四极谱仪。对于LC流动相为0.1％甲酸-水(A)和0.1％甲酸-乙腈(B)，洗脱剂梯度：0-5.5分钟0-95％B，5.5-6分钟95％B，6-8分钟0％B，用SB-Aq50毫米×2.1毫米×3.5微米的毛细管柱。
质谱(MS)通过电喷雾离子质谱法(ESI)进行测定。
HPLC质谱分析条件：
LC1：
柱：SB-Aq 50mm×2.1mm×3.5μm；
温度：40℃；
洗脱液：100:0至5:95体积/体积0.1％甲酸-水/0.1％甲酸-乙腈，8分钟；
流量：1.0mL/min，注射5μL；
检测：VWD，210nm&254nm；
MS：质量范围100-100amu；正离子电喷雾电离。
缩略语表：
AcOH＝乙酸
Alk为烷基
AR为芳基
Boc＝叔丁氧羰基
bs＝宽峰
CH 2Cl 2＝二氯甲烷
d＝双峰
dd＝双二重峰
DBU＝1,8-二氮杂双环[5.4.0]十一-7-烯
DCM＝二氯甲烷
DMF＝N，N-二甲基甲酰胺
DMSO＝二甲基亚砜
EA＝乙酸乙酯
ESI＝电喷雾电离
Et＝乙基
EtOAc＝乙酸乙酯
EtOH＝乙醇
h＝小时
HOAc＝乙酸
LiOH＝氢氧化锂
m＝多重
Me＝甲基
MeCN＝乙腈
MeOH＝甲醇
MgSO 4＝硫酸镁
min＝分钟
MS＝质谱
NaCl＝氯化钠
NaOH＝氢氧化钠
Na 2SO 4＝硫酸钠
NMR＝核磁共振光谱
PE＝石油醚
PG＝保护基
Ph＝苯基
rt＝室温
s＝单峰
t＝三重峰
TFA＝三氟乙酸
THF＝四氢呋喃
实施例1 A1的合成：
Figure PCTCN2021134880-appb-000047
第一步：2-(1,4-二氧杂螺[4.5]癸-8-亚基)乙酸乙酯(A1-2)
氮气保护，1,4-环己二酮单乙二醇缩酮(A1-1，10.0g，64.0mmol)加入无水THF(100ml)中，冰浴搅拌5min，分批加入钠氢(3.07g，76.8mmol，60％dispersion in mineral oil)，继续冰浴搅拌0.5h，然后缓慢加入膦酰乙酸三乙酯(14.78g，65.9mmol)的THF溶液(50ml)，滴毕后自然升至室温继续搅拌2h。TLC确认反应完全后，加水淬灭，浓缩THF，加EA萃取，收集有机层，无水硫酸钠干燥，浓缩EA，得到黄色液体2-(1,4-二氧杂螺[4.5]癸-8-亚基)乙酸乙酯(A1-2，14.38g，crude)，未纯化直接用于下一步。 1H NMR(400MHz,CDCl 3)δ5.69(s,1H),4.17(q,J＝8.0Hz,2H),4.00(s,4H),3.04-3.01(m,2H),2.42-2.39(m,2H),1.82-1.77(m,4H),1.30(t,J＝8.0Hz,3H)。
第二步：2-(8-硝基甲基-1,4-二氧杂螺[4.5]癸-8-基)乙酸乙酯(A1-3)
2-(1,4-二氧杂螺[4.5]癸-8-亚基)乙酸乙酯(A1-2，14.38g，63.6mmol)加入THF(100ml)中，然后依次加入四丁基氟化铵(18.29g，70mmol，70mL，1M in THF)、硝基甲烷(5.82g，95.40mmol)，升温至80℃，搅拌反应16h。TLC确认反应完全后，浓缩THF，加入EA和去离子水，萃取分液，有机层经无水硫酸钠干燥，浓缩EA，得到黄色液体2-(8-(硝基甲基)-1,4-二氧杂螺[4.5]癸-8-基)乙酸乙酯(A1-3，16.68g，crude)，未纯化直接用于下一步。 1H NMR(400MHz,CDCl 3)δ4.75(s,2H),4.21-4.15(q,J＝8.0Hz,2H),3.97(s,4H),2.58(s,2H),1.74-1.72(m,8H),1.31-1.25(m,3H)。
第三步：1,4-二氧杂-10-氮杂二螺[4.2.4 8.2 5]十四烷-11-酮(A1-4)
2-(8-硝基甲基-1,4-二氧杂螺[4.5]癸-8-基)乙酸乙酯(A1-3，16.68g)加入甲醇(150ml)中，然后加入雷尼镍，通入氢气45℃反应48h。LCMS监测反应完全后，过滤，浓缩甲醇， 得到1,4-二氧杂-10-氮杂二螺[4.2.4 8.2 5]十四烷-11-酮(A1-4，11.98g，crude)，未纯化直接用于下一步。 1H NMR(400MHz,CDCl 3)δ5.65(s,1H),3.97(s,4H),3.22(s,2H),2.26(s,2H),1.77-1.74(m,4H),1.69-1.66(m,4H)。
第四步：1,4-二氧杂-10-氮杂螺[4.2.4 8.2 5]十四烷(A1-5)
氮气保护，1,4-二氧杂-10-氮杂二螺[4.2.4 8.2 5]十四烷-11-酮(A1-4，2g，9.47mmol)加入干燥THF(30ml)中，搅拌5min，慢慢加入硼烷THF溶液(47.4ml，47.4mmol，1M)，升温至70℃，搅拌16h。LCMS确认反应完全后，冷却至室温，慢慢加入甲醇淬灭，浓缩溶剂，得到油状1,4-二氧杂-10-氮杂螺[4.2.4 8.2 5]十四烷(A1-5，1.8g，crude)，未纯化直接用于下一步。
第五步：10-(7H-吡咯并[2,3-d]嘧啶-4-基)-1,4-二氧杂-10-氮杂螺[4.2.4 8.2 5]十四烷(A1-6)
1,4-二氧杂-10-氮杂螺[4.2.4 8.2 5]十四烷(A1-5，1.8g，9.13mmol)和4-氯-7H-吡咯并[2,3-d]嘧啶(1.4g，9.13mmol)加入DMF(30ml)中，再加入N,N-二异丙基乙胺(2.36g，18.3mmol)，升温至100℃，搅拌16h。LCMS确认反应完全后，冷却至室温，抽滤，收集滤饼，减压抽干，得到灰白色固体10-(7H-吡咯并[2,3-d]嘧啶-4-基)-1,4-二氧杂-10-氮杂螺[4.2.4 8.2 5]十四烷(A1-6，2.26g，crude)，未纯化直接用于下一步。 1H NMR(400MHz,CDCl 3)δ10.16(br,1H),8.33(s,1H),7.05(d,J＝3.48Hz,1H),6.59(d,J＝3.52Hz,1H),3.99–3.96(m,6H),3.73(s,2H),2.00–1.92(m,2H),1.78–1.71(m,8H)。
第六步：2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂-螺[4.5]癸-8-酮(A1-7)
10-(7H-吡咯并[2,3-d]嘧啶-4-基)-1,4-二氧杂-10-氮杂螺[4.2.4 8.2 5]十四烷(A1-6，2.26g，7.20mmol)加入THF(30ml)中，滴入浓盐酸(10ml)，室温搅拌16h。LCMS确认反应完全后，滴加6mol/L NaOH溶液调节pH＝7～8，抽滤，收集滤饼，减压抽干，得到灰白色固体2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂-螺[4.5]癸-8-酮(A1-7，1.89g，crude)，未纯化直接用于下一步。 1H NMR(400MHz,CDCl 3)δ10.63(br,1H),8.35(s,1H),7.09(d,J＝4Hz,1H),6.61(d,J＝4.0Hz,1H),4.05(s,2H),3.89(s,2H),2.48(t,J＝8.0Hz,4H),2.12(t,J＝8.0Hz,2H),2.07–1.96(m,4H)。
第七步：2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[4.5]癸-8-胺(A1)
2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[4.5]癸-8-酮(A1-7，1g，3.70mmol)加入无水乙醇(30ml)中，再加入7mol/L NH 3的MeOH溶液(29.6ml，0.21mol)和钛酸异丙酯(2.1g，7.40mmol)，室温搅拌6h，再分批加入硼氢化钠(210mg，5.56mmol)，继续搅拌16h。LCMS确认反应完全后，加入氨水(17ml)淬灭反应，室温搅拌15min，抽滤，收集滤液，浓缩后加入EA搅拌10min，抽滤，收集滤饼，真空干燥，得到灰白色固体A1(900mg)。MS(ESI)m/z:calcd 272.19(M+H),found 272.10； 1H NMR(400MHz,DMSO- d6)δ11.55(br,1H),8.06(s,1H),7.09(d,J＝3.32Hz,1H),6.57(s,1H),3.79(s,2H),3.49(s,2H),2.71-2.68(m,1H),1.87(s,2H),1.72-1.69(m,2H),1.64-1.61(m,2H),1.43(s,2H),1.33-1.27(m,2H)。
实施例2 N-(2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[4.5]癸-8-基)乙酰胺(A2)的合成：
Figure PCTCN2021134880-appb-000048
氮气保护，2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[4.5]癸-8-胺(A1，4mg，14.8μmol)加入到MeCN(1ml)中，再加入碳酸氢钠(2mg，23.8μmol)，冷至0℃搅拌5min，再滴入乙酰氯(1.1mg，14.8μmmol)的MeCN溶液，继续冰浴搅拌1h。LCMS确认反应完全后，浓缩MeCN，残余物经制备板纯化得到白色固体A2(3mg，收率64.9％)。MS(ESI)m/z:calcd314.20(M+H),found 314.00； 1H NMR(400MHz,MeOH- d4)δ8.08(s,1H),7.10(d,J＝3.56Hz,1H),6.71(d,J＝3.56Hz,1H),3.91(br,2H),3.73-3.63(m,3H),2.06-2.04(m,2H),1.95(s,3H),1.88-1.85(m,2H),1.79-1.75(m,2H),1.65-1.59(m,2H),1.53-1.45(m,2H)。
实施例3 N-(2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[4.5]癸-8-基)苯磺酰胺(A3的合成：
Figure PCTCN2021134880-appb-000049
氮气保护，2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[4.5]癸-8-胺(A1，10mg，36.9μmol)加入到DMF(2ml)中，搅拌溶解，加入碳酸钾(6.1mg，44.2μmol)，然后滴入苯磺酰氯(7.8mg，44.2μmol)的DMF(0.5ml)溶液，室温搅拌1h。LCMS确认反应完全后，加入EA和去离子水萃取，收集有机相，浓缩EA，残余物经反相柱纯化，得到白色固体A3(5mg，收率33.1％)。MS(ESI)m/z:calcd 412.18(M+H),found 412.20； 1H NMR(400MHz,DMSO- d6)δ12.65(br,1H),8.27(d,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,2H),7.71(d,J＝8.0Hz,1H),7.66-7.58(m,3H),7.43(br,1H),6.88(br,1H),3.99(br,1H),3.63(br,3H),3.02(br,1H),1.92-1.85(m,2H),1.61-1.59(m,4H),1.39-1.32(m,4H)。
实施例4 N-2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[4.5]癸-8-基)-3-溴-5-硝基苯甲酰胺(A4)的合成：
Figure PCTCN2021134880-appb-000050
氮气保护，2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[4.5]癸-8-胺(A1，15mg，55.3μmol)和3-溴-5-硝基苯甲酸(13.5mg，55.3μmol)加入到DCM(2ml)和DMF(0.5ml)的混合溶剂中，再加入HATU(21mg，55.3μmol)，冰浴搅拌5min，然后滴加N,N-二异丙基乙胺(7.1mg，55.3μmol)的DCM(1ml)溶液，冰浴搅拌0.5h。LCMS确认反应完全后，加入二氯甲烷和去离子水，收集有机层，无水Na 2SO 4干燥，浓缩DCM，残余物经反相柱纯化，得到白色固体A4(11mg，收率40.0％)。MS(ESI)m/z:calcd 499.11，501.11(M+H),found 499.21，501.22； 1H NMR(400MHz,DMSO- d6)δ12.66(br,1H),8.74(d,J＝8.0Hz,1H),8.66-8.65(m,1H),8.56(d,J＝1.48Hz,1H),8.49-8.48(m,1H),8.30(d,J＝4.0Hz,1H),7.45(s,1H),6.94(s,1H),4.04-3.87(m,5H),2.05-1.75(m,6H),1.59-1.52(m,4H)。
参照实施例2～4的实验步骤制备，以不同酰化试剂，得到实施例5-75，如下表1所示。
表1
Figure PCTCN2021134880-appb-000051
Figure PCTCN2021134880-appb-000052
Figure PCTCN2021134880-appb-000053
Figure PCTCN2021134880-appb-000054
Figure PCTCN2021134880-appb-000055
Figure PCTCN2021134880-appb-000056
Figure PCTCN2021134880-appb-000057
Figure PCTCN2021134880-appb-000058
Figure PCTCN2021134880-appb-000059
Figure PCTCN2021134880-appb-000060
Figure PCTCN2021134880-appb-000061
Figure PCTCN2021134880-appb-000062
Figure PCTCN2021134880-appb-000063
Figure PCTCN2021134880-appb-000064
实施例76 N-(2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[3.3]庚-6-基)-2-氯-4-硝基苯甲酰胺(76)的合成
Figure PCTCN2021134880-appb-000065
第一步：6-氧代-2-氮杂螺[3.3]庚烷(A76-01)
2-Boc-6-氧代-2-氮杂螺[3.3]庚烷(200mg，0.95mmol)加入DCM(2mL)中，氮气保护下 加入三氟乙酸(2mL)，室温搅拌3.0h。LCMS确认反应完全后，反应液直接旋干，得到黄色油状6-氧代-2-氮杂螺[3.3]庚烷三氟乙酸盐(A76-01，215mg，crude)，未纯化直接用于下一步。MS(ESI)m/z:calcd 112.07(M+H),found 112.14。
第二步：6-氧代-2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[3.3]庚烷(A76-02)
6-氧代-2-氮杂螺[3.3]庚烷三氟乙酸盐(A76-01，215mg，0.95mmol)和4-氯-7H-吡咯并[2,3-d]嘧啶(148mg，0.96mmol)加入N-甲基吡咯烷酮(4ml)中，再加入碳酸钾(900mg，6.5mmol)，升温至80℃，搅拌14h。LCMS确认反应完全后，冷却至室温，抽滤，收集滤饼，减压抽干，得到类白色固体6-氧代-2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[3.3]庚烷(A76-02，40mg，crude)，未纯化直接用于下一步。
第三步：2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[3.3]庚-6-胺(A76-03)
6-氧代-2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[3.3]庚烷(A76-02，40mg，0.18mmol)加入无水乙醇(2ml)中，再加入7mol/L NH 3的MeOH溶液(2ml，14mmol)和钛酸异丙酯(105mg，0.37mmol)，室温搅拌6h，再加入硼氢化钠(67mg，1.8mmol)，继续搅拌16h。LCMS确认反应完全后，加入氨水(2mL)淬灭反应，室温搅拌15min，抽滤，收集滤液，浓缩后加入EA溶解，抽滤，收集滤液，减压旋干，得到淡黄色油状2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[3.3]庚-6-胺(A76-03,35mg，crude)，未进一步处理直接用于下一步。MS(ESI)m/z:calcd 229.13(M+H),found 229.10。
第四步：N-(2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[3.3]庚-6基)-4-氯-2-硝基苯甲酰胺(A76)
2-(7H-吡咯并[2,3-d]嘧啶-4-基)-2-氮杂螺[3.3]庚-6-胺(A76-03,35mg,0.15mmol)和4-氯-2-硝基苯甲酸(30mg，0.15mmol)加入到DMF(1ml)中，再加入HATU(57mg，0.15mmol)，冰浴搅拌5min，然后滴加N,N-二异丙基乙胺(19.35mg，0.15mmol)的DMF(0.5mL)溶液，继续冰浴搅拌1h。LCMS确认反应完全后，反应液直接经反相柱纯化，得到白色固体A76(20mg，收率32.3％)。MS(ESI)m/z:calcd 413.11(M+H),found 413.10； 1H NMR(400MHz,DMSO- d6)δ12.64(s,1H),8.97(d,J＝6.9Hz,1H),8.30(s,1H),8.19(s,1H),7.91(d,J＝8.2Hz,1H),7.67(d,J＝8.2Hz,1H),7.45(s,1H),6.70(s,1H),4.53(m,4H),4.26-4.22(m,1H),2.78–2.64(m,2H),2.35-2.30(m,2H)。
效果例1：生物测试方法
JAK激酶的测活方法是利用均相时间分辨荧光技术。该方法的反应是在384浅孔板中，反应总体积是10μL。激酶蛋白、化合物、ATP和底物的混合液在50mM Hepes(pH7.0)、NaN 3 0.02％、BSA 0.01％、0.1mM原钒酸盐(Orthocanadate)、5mM MgCl 2、1mM DTT的反应缓冲液中进行，反应1小时后，向体系中加入能够识别底物磷酸化的抗体和染料XL-615以及含有EDTA的检测缓冲液(Cisbio)。激酶的反应信号通过PE公司的多孔板检测仪进行检测。参数设置是激发光320nm，发射光615nm和665nm。通过665nm和615nm的信号比值间接反映JAK的活力。反应中设置不加酶的背景孔和不含化合物的全酶活 性孔。
化合物抑制蛋白IC 50的值通过公式：Y＝100/(1+10^((LogIC50-X)*HillSlope))获得。
在JAK1反应体系中，ATP的浓度为2μM，JAK1蛋白浓度是0.2ng/μL。
在JAK2反应体系中，ATP的浓度为2μM，JAK1蛋白浓度是0.01ng/μL。
在JAK3反应体系中，ATP的浓度为2μM，JAK1蛋白浓度是0.04ng/μL。
在TYK2反应体系中，ATP的浓度为2μM，JAK1蛋白浓度是0.2ng/μL。
测试数据分为以下几种：A:IC 50<10nM；B:IC 50 11-100nM；C:IC 50 101-1000nM；D:IC 50 1001-10000nM；E:IC 50>10000nM。
测试结果如表2所示。
表2
Figure PCTCN2021134880-appb-000066
Figure PCTCN2021134880-appb-000067
Figure PCTCN2021134880-appb-000068
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JAK的活性，尤其是JAK1活性。本发明化合物IC50值可以低至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JAK，尤其是JAK1。
(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、JAK2/JAK1的IC50之比、TYK2/JAK1的IC50之比提高约10倍(大部分为约20-100倍)，远远优于目前已上市的药物。
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. 一种式I所示的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，
    Figure PCTCN2021134880-appb-100001
    式中，
    R 1、R 2和R 3各自独立地选自取代或未取代的下组基团：H、D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；其中，所述的取代是指被一个或多个R a取代；
    或者R 1和R 2与它们连接的原子一起构成取代或未取代的下组基团：5-6元芳基或杂芳基、3-10元杂环基、C3-C10环烷基；其中，所述的取代是指被一个或多个R a取代；
    B独立地选自下组：键、-(CH 2) r-、C(＝O)、N-R b、C(＝O)O-、
    Figure PCTCN2021134880-appb-100002
    -(CH 2) p-R c、O、S、SO、SO 2；R c选自：C(＝O)O-、
    Figure PCTCN2021134880-appb-100003
    其中，R b独立地选自下组：H、C1-C6烷基；
    其中，-(CH 2) r-和-(CH 2) p-中的H原子可以任选地被一个或多个R a取代；
    C选自取代或未取代的下组基团：H、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；其中，所述的取代是指被一个或多个R a取代；
    r和p各自独立地为1、2、3、4；
    m、n、k和l各自独立地为0、1、2、3，且m+n≥1，k+l≥1；
    Figure PCTCN2021134880-appb-100004
    部分中的H可以任选地被一个或多个R a取代；
    其中，各R a独立地选自取代或未取代的下组基团：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基；其中，R a中所述的取代是指被选自下组的一个或多个基团取代：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基和C6-C12芳基。
  2. 如权利要求1所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，
    Figure PCTCN2021134880-appb-100005
    部分选自:
    Figure PCTCN2021134880-appb-100006
    Figure PCTCN2021134880-appb-100007
    其中，q为0、1、2、3、4或5；
    R a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光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，其具有式II所示的结构：
    Figure PCTCN2021134880-appb-100008
    其中，q为0、1、2、3、4或5；
    R 1、R 2、R 3、R a、B和C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光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，B选自下组：C(＝O)O-、
    Figure PCTCN2021134880-appb-100009
    其中，R b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光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，C选自取代或未取代的下组基团：3-8元杂环烷基、C3-C8环烷基、5-10元杂芳基、C6-C10芳基；其中，所述的取代是指被一个或多个R a取代；
    R a的定义如权利要求1所述。
  6. 如权利要求1所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，所述化合物满足下述条件中的一个或多个，
    (1)
    Figure PCTCN2021134880-appb-100010
    选自:
    Figure PCTCN2021134880-appb-100011
    Figure PCTCN2021134880-appb-100012
    Figure PCTCN2021134880-appb-100013
    其中，q为0、1、2、3、4或5；R a的定义如权利要求1中所述；
    (2)B选自：-NH-、
    Figure PCTCN2021134880-appb-100014
    -NH-C(＝O)-；任选地，上述基团中的各氢被C1-C6烷基取代；
    (3)C选自：H、甲氧基、苯基、甲基、乙基、噻唑基、吡啶基、环丙基、吡嗪基、环己基、苯并噻吩基、苯并呋喃基、嘧啶基、萘基、环丁基、环戊基、环庚基；其中，任选地，C被选自下述的取代基取代：氟、氯、溴、硝基、氰基、羟基、乙炔基、甲基、甲氧基、甲酸甲酯基、三氟甲基、苯基、磺酰胺基；
    优选地，C选自：H、甲氧基、苯基、甲基、
    Figure PCTCN2021134880-appb-100015
    环丙基、
    Figure PCTCN2021134880-appb-100016
    环己基、
    Figure PCTCN2021134880-appb-100017
    萘基、环丁基、环戊基、环庚基；其中，任选地，C被选自下述的取代基取代：氟、氯、溴、硝基、氰基、羟基、乙炔基、甲基、甲氧基、甲酸甲酯基、三氟甲基、苯基、磺酰胺基；
    更优选地，C选自：H、甲基、甲氧基、
    Figure PCTCN2021134880-appb-100018
    Figure PCTCN2021134880-appb-100019
    苯基、
    Figure PCTCN2021134880-appb-100020
    Figure PCTCN2021134880-appb-100021
    Figure PCTCN2021134880-appb-100022
    (4)R 1为氢；
    (5)R 2为氢；
    (6)R 3为氢；
    特别地，
    Figure PCTCN2021134880-appb-100023
    选自
    Figure PCTCN2021134880-appb-100024
  7. 如权利要求1-5中任一项所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，所述化合物中，各取代基满足下述条件中的一个或多个，
    各C1-C6烷基独立地选自：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基；
    各C1-C6烷氧基独立地选自：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基、叔丁氧基；
    各C2-C6烯基独立地选自：乙烯基、丙烯基、烯丙基；
    各C2-C6炔基独立地选自：乙炔基、丙炔基；
    各3-10元杂环烷基独立地选自：四氢呋喃基、四氢吡咯基、四氢噻吩、四氢吡喃基、哌嗪基、哌啶基、吗啉基；
    各C3-C10环烷基独立地选自：环丙基、环丁基、环戊基、环己基、环庚基；
    各5-12元杂芳基独立地选自：吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基、咪唑基、吡唑基、噻唑基、吲哚基、苯并噻吩基、苯并呋喃基；
    各C6-C12芳基独立地选自：苯基、萘基。
  8. 如权利要求1所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，所述化合物选自下组：
    Figure PCTCN2021134880-appb-100025
    Figure PCTCN2021134880-appb-100026
    Figure PCTCN2021134880-appb-100027
    Figure PCTCN2021134880-appb-100028
  9. 一种药物组合物，其特征在于，其包含权利要求1-8中任一项所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物；和药学上可接受的载体；
    特别地，所述药物组合物用于治疗或预防与JAK激酶的活性或表达量相关的疾病；
    更特别地，所述药物组合物用作JAK激酶抑制剂，优选用作JAK1激酶抑制剂。
  10. 一种如权利要求1-8中任一所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物的用途，其特征在于，
    其用于制备治疗或预防与JAK激酶的活性或表达量相关的疾病的药物或药物组合物；或者，其用于制备抑制JAK激酶活性的药物或药物组合物，所述JAK激酶优选为JAK1激酶；
    特别地，所述疾病选自下组：癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病、人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮癣；其中，所述癌症优选选自下组：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、多发性骨髓瘤；
    特别地，所述与JAK激酶的活性或表达量相关的疾病为JAK1相关的障碍；其中，所述JAK1相关的障碍优选选自下组：I型糖尿病、狼疮、多发性硬化症、类风湿性关节炎、牛皮癣、哮喘、特应性皮炎、自身免疫性甲状腺疾病、溃疡性结肠炎、克罗恩病和斑秃。
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