WO2022117012A1 - Inhibiteur de jak spirocyclique, composition pharmaceutique le contenant, et son application - Google Patents

Inhibiteur de jak spirocyclique, composition pharmaceutique le contenant, et son application Download PDF

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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)
Chinese (zh)
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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/fr

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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

La présente invention concerne un inhibiteur de JAK spirocyclique, une composition pharmaceutique le contenant, et une application de celui-ci. Spécifiquement, la présente invention concerne un composé tel que présenté dans la formule I ou un stéréoisomère ou un isomère optique, un sel, promédicament, ou solvate pharmaceutiquement acceptables de celui-ci, et concerne également une composition pharmaceutique du composé et utilisant le composé comme inhibiteur de JAK, et une utilisation médicale du composé dans la préparation d'un médicament de prévention et/ou de traitement d'une maladie liée au JAK, spécialement le JAK1.
PCT/CN2021/134880 2020-12-02 2021-12-01 Inhibiteur de jak spirocyclique, composition pharmaceutique le contenant, et son application WO2022117012A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732636A (zh) * 2014-12-30 2016-07-06 广东东阳光药业有限公司 杂芳化合物及其在药物中的应用
CN110248663A (zh) * 2017-02-03 2019-09-17 利奥制药有限公司 作为新型JAK激酶抑制剂的5-(7H-吡咯并[2,3-d]嘧啶-4-基)-5-氮杂螺[2.5]辛烷-8-甲酸衍生物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732636A (zh) * 2014-12-30 2016-07-06 广东东阳光药业有限公司 杂芳化合物及其在药物中的应用
CN110248663A (zh) * 2017-02-03 2019-09-17 利奥制药有限公司 作为新型JAK激酶抑制剂的5-(7H-吡咯并[2,3-d]嘧啶-4-基)-5-氮杂螺[2.5]辛烷-8-甲酸衍生物

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 1 September 2017 (2017-09-01), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -2123683-07-6 REGISTRY ED -Entered STN: 01 Sep 2017 CN -5-Azaspiro[3.4]octane, 5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- (CA INDEX NAME)", XP055937863, retrieved from STN Database accession no. 2123683-07-6 *
DATABASE REGISTRY 1 September 2017 (2017-09-01), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -2123894-99-3 REGISTRY ED -Entered STN: 01 Sep 2017 CN -5-Azaspiro[2.5]octane, 5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- (CA INDEX NAME)", XP055937872, retrieved from STN Database accession no. 2123894-99-3 *
DATABASE REGISTRY 1 September 2017 (2017-09-01), ANONYMOUS: "RN: 2123812-98-4", XP055937867, retrieved from STN Database accession no. 2123812-98-4 *
DATABASE REGISTRY 10 July 2016 (2016-07-10), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -1948928-73-1 REGISTRY ED -Entered STN: 10 Jul 2016 CN -2-Azaspiro[3.3]heptane, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-(tetrahydro- 2H-pyran-4-yl)-(CA INDEX NAME)", XP055937853, retrieved from STN Database accession no. 1948928-73-1 *
DATABASE REGISTRY 17 July 2013 (2013-07-17), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -1445146-29-1 REGISTRY ED -Entered STN: 17 Jul 2013 CN -7-Azaspiro[3.5]nonan-1-ol, 3-ethoxy-7-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-(CA INDEX NAME)", XP055937894, retrieved from STN Database accession no. 1445146-29-1 *
DATABASE REGISTRY 18 November 2018 (2018-11-18), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -2249256-59-3 REGISTRY ED -Entered STN: 18 Nov 2018 CN -2-Azaspiro[3.3]heptane, 1-(3-pyridinyl)-2-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-(CA INDEX NAME)", XP055937874, retrieved from STN Database accession no. 2249256-59-3 *
DATABASE REGISTRY 19 July 2016 (2016-07-19), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -1954977-69-5 REGISTRY ED -Entered STN: 19 Jul 2016 CN -6-Azaspiro[3.4]octane, 2-ethoxy-6-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-(CA INDEX NAME)", XP055937855, retrieved from STN Database accession no. 1954977-69-5 *
DATABASE REGISTRY 30 January 2019 (2019-01-30), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -2262280-33-9 REGISTRY ED -Entered STN: 30 Jan 2019 CN -2-Azaspiro[5.5]undecane, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- (CA INDEX NAME)", XP055937883, retrieved from STN Database accession no. 2262280-33-9 *
DATABASE REGISTRY 30 January 2019 (2019-01-30), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -2262281-91-2 REGISTRY ED -Entered STN: 30 Jan 2019 CN -6-Azaspiro[2.5]octane-1-carboxylic acid, 6-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- (CA INDEX NAME)", XP055937885, retrieved from STN Database accession no. 2262281-91-2 *
DATABASE REGISTRY 30 January 2019 (2019-01-30), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -2263101-70-6 REGISTRY ED -Entered STN: 31 Jan 2019 CN -2-Azaspiro[4.5]decane, 2-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- (CA INDEX NAME)", XP055937891, retrieved from STN Database accession no. 2263101-70-6 *
DATABASE REGISTRY 31 August 2017 (2017-08-31), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -2123475-59-0 REGISTRY ED -Entered STN: 31 Aug 2017 CN -2-Azaspiro[3.3]heptane, 5,5-difluoro-2-(2-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-(CA INDEX NAME)", XP055937858, retrieved from STN Database accession no. 2123475-59-0 *
DATABASE REGISTRY 5 July 2016 (2016-07-05), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -1945622-63-8 REGISTRY ED -Entered STN: 05 Jul 2016 CN -2-Azaspiro[3.3]heptane, 2-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1- (tetrahydro-2H-pyran-4-yl)-(CA INDEX NAME)", XP055937849, retrieved from STN Database accession no. 1945622-63-8 *

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