WO2016145935A1 - 优化的联合用药及其治疗癌症和自身免疫疾病的用途 - Google Patents

优化的联合用药及其治疗癌症和自身免疫疾病的用途 Download PDF

Info

Publication number
WO2016145935A1
WO2016145935A1 PCT/CN2016/000149 CN2016000149W WO2016145935A1 WO 2016145935 A1 WO2016145935 A1 WO 2016145935A1 CN 2016000149 W CN2016000149 W CN 2016000149W WO 2016145935 A1 WO2016145935 A1 WO 2016145935A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
compound
pharmaceutical composition
composition according
btk
Prior art date
Application number
PCT/CN2016/000149
Other languages
English (en)
French (fr)
Inventor
何伟
Original Assignee
浙江导明医药科技有限公司
何伟
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2016232923A priority Critical patent/AU2016232923B2/en
Priority to IL254435A priority patent/IL254435B1/en
Priority to EA201792066A priority patent/EA037058B1/ru
Priority to MX2017011836A priority patent/MX2017011836A/es
Priority to CN201680017009.0A priority patent/CN107406454B/zh
Priority to CN202111303221.2A priority patent/CN114790209A/zh
Priority to JP2017549326A priority patent/JP7012534B2/ja
Application filed by 浙江导明医药科技有限公司, 何伟 filed Critical 浙江导明医药科技有限公司
Priority to EP16764117.4A priority patent/EP3272752A4/en
Priority to KR1020227026364A priority patent/KR20220110872A/ko
Priority to BR112017019790-1A priority patent/BR112017019790B1/pt
Priority to CA2980016A priority patent/CA2980016C/en
Priority to KR1020177025465A priority patent/KR102428387B1/ko
Priority to US15/183,340 priority patent/US9717745B2/en
Publication of WO2016145935A1 publication Critical patent/WO2016145935A1/zh
Priority to US15/628,143 priority patent/US10098900B2/en
Priority to US16/123,167 priority patent/US10537587B2/en
Priority to US16/123,203 priority patent/US10596183B2/en
Priority to US16/790,197 priority patent/US11369620B2/en
Priority to AU2020277128A priority patent/AU2020277128B2/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems

Definitions

  • the present invention relates to a series of novel polyfluoro-substituted pyrazolopyrimidines and processes for their preparation, pharmaceutical compositions containing them as active ingredients and methods for inhibiting Bruton's kinase activity.
  • the present invention also relates to a combination of in vitro tumor cell viability and tumor inhibition in vivo for a plurality of classes of drugs.
  • the optimized combination drug of the invention has the synergistic effect, can better inhibit the survival of the tumor than the single targeted drug, can cause some tumors to completely disappear, and the optimized combination drug can better treat the drug resistance of the tumor than the single targeted drug. And cancer recurrence. Optimized combination medications are safer because of lower doses, and better efficacy can result in shorter treatment cycles.
  • Cancer treatment has evolved from toxic chemotherapy to combination chemotherapy (such as CHOP), antibodies (such as rituximab), combination therapy with chemotherapy (R-CHOP), and now exciting immune anticancer therapy (PD) -1 and PD-L1 antibodies) and T cell therapy (CAR-T) of chimeric antigen receptors.
  • combination chemotherapy such as CHOP
  • antibodies such as rituximab
  • R-CHOP combination therapy with chemotherapy
  • CAR-T T cell therapy
  • the life expectancy and quality of life of patients have improved, but due to the complexity of cancer, mutations in a single pathway or signaling pathway can cause some therapies to be ineffective or relapse. Small molecule targeted therapy requires long-term daily dosing, and if the drug is stopped, the cancer will rebound or recur.
  • Antibodies and chemotherapy the mode of administration is complex, the combination can have additive or synergistic effects, but rarely leads to the cure of cancer.
  • Targeted therapy with immunotherapeutic therapy or chimeric antigen receptor T cell therapy is ongoing, but may have safety concerns.
  • Oral therapy has many advantages, such as stopping the administration immediately in the event of serious side effects.
  • Antibody or cell therapy is more difficult to control serious side effects immediately.
  • single-channel targeted therapy or combination therapy of two targeted pathways has certain limitations, so the clinical efficacy (total effective rate-ORR) of cancer is mostly partial (PR) or stable disease (SD), rarely There is a cure (CR). This treatment usually only extends the patient's life for a few months.
  • Ibrutinib is the first FDA-approved Bruton's tyrosine kinase (BTK) inhibitor, which has good effects on B-cell lymphoma, including MCL and CLL, but clinical treatment has produced mutations such as C481s. And cause drug resistance (Furman et al: Ibrutinib resistance in chronic lymphocytic leukemia, N Engl J Med, 2014, 2352).
  • BTK Bruton's tyrosine kinase
  • BTK plays a key role in the B cell signaling pathway from the B cell receptor (BCR) on the cell surface to the downstream intracellular response. It is a key regulator of B cell development, activation, proliferation and survival.
  • Everolimus is an FDA-approved mTOR kinase inhibitor for the treatment of breast, pancreatic, renal cell carcinoma, renal hamartoma and tuberous sclerosis complexes.
  • the mechanistic role of the mTOR protein has been fully elucidated as a key regulator of cell growth, proliferation, metabolism and apoptosis in a very complex signaling pathway.
  • organ transplantation also activates mTOR, and everolimus is used to treat rejection of organ transplants at low doses.
  • Pomalidomide is an immunomodulatory drug approved by the FDA in 2013 for the treatment of multiple myeloma.
  • Pomamide and related iMiDs inhibit the cytokines TNF- ⁇ , IL-1 ⁇ , IL-6, IL-12 and GM-CSF.
  • TNF- ⁇ , IL-1 ⁇ , IL-6, IL-12 and GM-CSF In addition to their anti-angiogenic, anti-proliferative and pro-apoptotic properties, they also stimulate T lymphocytes to induce their proliferation, production of T-cell factors, and T-cell toxicity, thereby increasing the anti-cancer activity of T cells.
  • Venetoclax or ABT-199 is a bcl-2 inhibitor in clinical research.
  • B lymphocyte tumor-2 (bcl-2) protein plays a key role in apoptosis.
  • ABT-199 has caused tumor lysis syndrome (TLS) in the clinic and caused death.
  • TLS tumor lysis syndrome
  • Methotrexate is an anti-folate antitumor drug and a therapeutic rheumatoid arthritis drug, which inhibits cell synthesis and inhibits cell growth and reproduction mainly by inhibiting dihydrofolate reductase.
  • Bruton's tyrosine kinase belongs to the Tec family. It consists of a unique N-terminal domain, namely the PH (pleckstrin homology) domain, the TH (Tec homology) homology region, the SH3 (Src homology 3) domain, the SH2 (Src homology 2) domain, and the catalytic domain.
  • the SH 1/TK (Src homologyl/Tyrosine kinase) domain or kinase domain composition is referred to (Akinley et al: Ibrutinib and novel BTK inhibitors in clinical development, Journal of Hematology & Oncology 2013, 6:59).
  • B lymphocytes the correct expression of different protein regions of BTK gene plays a key role in the function of B cells and various transduction pathways.
  • BTK Downstream of the BTK function, there are a variety of receptors, including growth factors, B cell antigens, chemokines and innate immune receptors, which initiate a diverse range of cellular processes such as cell proliferation, survival, differentiation, exercise, angiogenesis, Cytokine production, antigen expression, etc. Therefore, BTK plays an important role in many hematopoietic signaling pathways, and is also important in B cell activation, development, survival, and signaling (Kurosaki, Molecular mechanisms in B cell antigen receptor signaling. Curr OP Imm, 1997, 9 (3): 309-18).
  • the CD20 antibody rituximab (Rituxan) is a protein-based therapeutic agent that depletes B cells and is used as an inflammatory disease such as rheumatoid arthritis for the treatment of autoimmune diseases such as chronic lymphocytic leukemia and autoantibodies. Therefore, protein kinases that play a key role in inhibiting B cell activation should be helpful for pathology of B cell-associated diseases.
  • BTK-deficient mice BTK-deficient mice and BTK-sufficient mouse model tests
  • Kil LP et al: Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia .Am J Blood Res 2013, 3(1): 71-83.
  • CLL chronic lymphocytic leukemia
  • BTK-deleted mice completely abolish chronic lymphocytic leukemia, and overexpression of BTK accelerates the onset of leukemia and increases mortality.
  • BTK inhibitors are not ideal: in addition to inhibiting BTK, it also inhibits other various kinases (such as ETK, EGF, BLK, FGR, HCK, YES, BRK and JAK3, etc.), which may cause more side effects. Side effects of better selective inhibitors may be smaller.
  • various kinases such as ETK, EGF, BLK, FGR, HCK, YES, BRK and JAK3, etc.
  • BTK inhibitors produce a variety of derivatives in vivo, which also affects the efficacy and side effects.
  • the pharmacokinetics of BTK inhibitors are also known to be improved.
  • the present invention relates to a BTK inhibitor for use as a method of treating or inhibiting an autoimmune disease or condition, a xenogenic immune disease or condition, an inflammatory disease, and a cancer or condition.
  • This includes administering to the patient an effective amount of a compound expressed by the general formulae (I), (II), (Ia), (IIa), (Ib) and (IIb), or a pharmaceutically acceptable salt thereof.
  • R 1 is a fluorine atom; n is 1, 2, 3 or 4;
  • R 2 is a fluorine atom; m is 1 or 2;
  • R 3 is a hydrogen atom or a halogen atom.
  • the term "pharmaceutically acceptable salt” refers to a salt which exists in the form of an acid or a base, and a non-limiting example thereof is (a) an acid addition salt, a mineral acid (for example, hydrochloric acid, hydrobromic acid) , sulfuric acid, phosphoric acid, nitric acid, etc.), organic acid salts, organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid (benzoic acid) Acid), tannic acid, pamoic acid, alginic acid, poly glutamic acid, and salicylic acid; (b) base addition salts ), formed with metal cations such as zinc, calcium, sodium, potassium, and the like.
  • a mineral acid for example, hydrochloric acid, hydrobromic acid
  • sulfuric acid sulfuric acid
  • phosphoric acid phosphoric acid
  • nitric acid etc.
  • organic acid salts organic acids such as acetic
  • the invention is exemplified by the examples and the compounds disclosed herein.
  • Particular compounds of the invention are selected from the group consisting of the compounds of the disclosed examples and their pharmaceutically acceptable salts and their individual diastereomeric compounds or salts.
  • R1, R2, R3, m, n are as defined above.
  • the fluorine-substituted starting material A1 may form the intermediate C1 with the substituted phenol B1 in the presence of a base such as potassium carbonate and in a suitable solvent such as DMF.
  • a suitable base such as potassium acetate
  • a suitable solvent such as 1,4-dioxane
  • intermediate C1 can be combined with a bis-pinacol borate in a suitable catalyst (eg [1]
  • the reaction is carried out by the action of 1'-bis(diphenylphosphino)ferrocene]palladium dichloride to provide intermediate D1.
  • the starting material 1H-pyrazolo[3,4-d]pyrimidin-4-amine can be reacted with NIS to obtain intermediate F1, and then intermediate G1 is formed via Mitsunobu reaction or substitution reaction.
  • intermediate G1 can interact with the boronate D1 in a suitable catalyst such as Pd-118.
  • the reaction is carried out to obtain intermediate H1.
  • the Boc group of H1 was removed under acidic conditions to give the amine compound I1.
  • the amine compound I1 can be reacted with an electrophile to give the product I.
  • the optically active compounds Ia and Ib can be obtained by SFC chiral resolution.
  • Intermediate C2 is formed in the presence of a base such as potassium carbonate in a suitable solvent such as DMF, 3-fluoro-4-bromophenol and 1-fluoro-3-nitrobenzene.
  • a suitable reducing agent such as iron powder and ammonium chloride
  • a suitable solvent such as ethanol and water
  • the nitro compound C2 can be reduced to the amine D2, which can be formed by the action of sodium nitrite and pyridine hydrogen fluoride.
  • Fluorine substituted intermediate E2 Fluorine substituted intermediate E2.
  • E2 can be combined with a bis-pinacol borate in a suitable catalyst (eg [1, 1
  • a suitable catalyst eg [1, 1
  • the reaction is carried out under the action of '-bis(diphenylphosphino)ferrocene]palladium dichloride) to provide a borate F2.
  • a suitable base such as potassium phosphate
  • a suitable solvent such as 1,4-dioxane and water
  • intermediate H1 can interact with the boronate F2 in a suitable catalyst (eg, Pd-118). The reaction is carried out to provide intermediate G2.
  • the amine compound H2 can be reacted with an electrophile to give the product I2.
  • the optically active compounds J2 and K2 can be obtained by SFC chiral resolution when I2 is a racemate.
  • 3-Fluoro-4-bromophenol and 3-fluoro-phenylboronic acid are formed under the action of a suitable catalyst (such as copper acetate) to form intermediate B3, and then B3 can be combined with a bis-pinacol borate in a suitable catalyst (eg [ The reaction is carried out under the action of 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride to provide a boronic ester C3.
  • a suitable catalyst such as copper acetate
  • intermediate G1 can be combined with the boronic ester C3 in a suitable catalyst (eg [1, 1').
  • a suitable catalyst eg [1, 1'
  • the reaction is carried out by the action of bis(diphenylphosphino)ferrocene]palladium dichloride to provide intermediate D3.
  • the Boc group of D3 was removed under acidic conditions to give the amine compound E3.
  • the amine compound E3 can be reacted with an electrophile to give the product F3.
  • the optically active compounds H3 and I3 can be obtained by SFC chiral resolution when F3 is a racemate.
  • the amine compound I1 can be reacted with butane-2-alkynoic acid to give the product II.
  • the optically active compounds IIa and IIb can be obtained by SFC chiral resolution.
  • the intermediate F1 forms an optically active intermediate A5 via a Mitsunobu reaction or a substitution reaction.
  • a suitable base such as potassium phosphate
  • a suitable solvent such as 1,4-dioxane and water
  • intermediate A5 can be reacted with borate D1 in a suitable catalyst such as Pd-118.
  • the reaction is carried out to obtain intermediate B5.
  • the Boc group of B5 was removed under acidic conditions to give the amine compound C5.
  • the amine compound C5 can be reacted with an electrophile to give the product Ia.
  • the amine compound C5 can be reacted with butane-2-alkynoic acid to give the product IIa.
  • the present invention provides compounds of the formulae (I), (II), (Ia), (IIa), (Ib) and (IIb), and their enantiomers and diastereomers or pharmaceutically acceptable thereof Salt.
  • the compounds of the formula (I), (II), (Ia), (IIa), (Ib) and (IIb) of the present invention comprise one or more stable isotopes or radioisotopes, said isotopes comprising However, it is not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, and the like.
  • the present invention introduces the 1 H isotope 2 H into a BTK inhibitor for the first time.
  • the double bond terminal 1 H of the vinyl group of the compound of the formula (I), (II), (Ia), (IIa), (Ib) and (IIb) can be replaced by 2 H, thereby reducing
  • the drug is inactivated by the redox of the bond.
  • the present invention provides a process for the preparation of the compounds of the formulae (I), (II), (Ia), (IIa), (Ib) and (IIb), and their enantiomers and diastereomers.
  • the present invention provides a method for modulating the activity of BTK and treating or inhibiting a disease associated with BTK activity. It has been confirmed that the compounds of the present invention have an inhibitory effect on BTK activity, and the present invention provides compounds for use in the treatment of the compounds of the formulae (I), (II), (Ia), (IIa), (Ib) and (IIb). And/or an active ingredient in a medicament for preventing a disease caused by unfavorable cytokine signaling, including but not limited to:
  • autoimmune diseases such as chronic lymphatic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritis syndrome (goodpasture syndrome), pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple cerebrospinal sclerosing, acute idiopathic polyneuritis, systemic lupus erythematosus, rheumatoid arthritis, Psoriasis (psoriasis), systemic vasculitis, scleroderma, pemphigus, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, ulcerative colitis, etc.
  • pulmonary hemorrhagic nephritis syndrome goodpasture syndrome
  • pemphigus vulgaris pemphigoid
  • abnormal immune diseases such as serum diseases, asthma, allergic rhinitis and drug allergies
  • inflammatory diseases such as keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, bronchitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, etc.;
  • Cancer includes, but is not limited to, various B cell malignancies (including small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), and Waldorf macroglobulin blood. Diseases (Waldenstrom Macroglobulinemia), Follicular Lymphom, Mantle Cell Lymphoma (MCL), and other diseases that inhibit BTK kinase activity in patients;
  • diseases that inhibit BTK kinase activity are beneficial to patients including, but not limited to, brain tumors, bladder cancer, stomach cancer, ovarian cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, and renal cancer.
  • esophageal cancer pre-existing adenocarcinoma, thyroid cancer, bone cancer, skin cancer, colon cancer, female genital tract tumor, lymphoma, multiple myeloma (MM) and testicular cancer.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of claims 1-2.
  • compositions of the compounds of the invention may be used alone or in combination with one or more additional agents, depending on standard pharmaceutical practice, the pharmaceutical formulation of the BTK inhibitor and the additional agent
  • additional agents include, but are not limited to:
  • Tyrosine kinase inhibitors eg, axitinib, dasatinib, ectinib, etc.
  • Topoisomerase inhibitors such as topotecan, etc.
  • Protein kinase C inhibitors eg AEB-071, etc.
  • a sphingosine-1-phosphate receptor agonist eg, fingolimod, KRP-203, etc.
  • Anti-T cell immunoglobulin such as AtGam, etc.
  • An antibody against the IL-2 receptor eg, daclizumab, etc.
  • CX Carboplatin
  • MTX Aminopterin cyclosporin A, tacrolimus, sirolimus, everolimus, azathioprine, buquina, leflunomide, LEA-29Y, anti-CD3 antibody (eg 0KT3) Etc.), aspirin;
  • B7-CD28 blocking molecules such as Beltacept, Abatacept, etc.
  • a CD40-CD154 blocking molecule eg, an anti-CD40 antibody, etc.
  • Paracetamol, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids eg prednisolone or dexamethasone;
  • Bruton's tyrosine kinase (BTK) inhibitors including all known but not limited to: Ibrutinib Ibrutinib, Compounds 3 and 5, ACP-196 (Acerta Pharma), BGB-3111 (BeiGene), AVL-292 (Celgene), ONO-4059 (One Pharmaceutical), HM71224 (Hanmi Pharmaceutical), RN486 (Roche), CNX-774 and CGI-11746, and the like.
  • mTOR inhibitors include all known but not limited to: everolimus, rapamycin, XL388, GDC-0349, AZD2014, AZD8055, GSK105965, MLN0128 and Ridaforlimus.
  • Immunomodulatory drugs include all known but not limited to: Thalidomide (Thalidomide), Revlimid (Lenalidomide), Pomalidomide (Pomamidamine), CC-122, CC-220.
  • PI3K kinase inhibitors include all known but not limited to: BTG226, PF-05212384 (Gedatolisib), GDC-0980 (Apitolisib), GSK2126458, BEZ235, IPI-145 (Duvelisib) and CAL-101 (Idelalisib) and the like.
  • Bcl-2 inhibitors include all known but not limited to: ABT-199 (Venetoclax) and BI-97C1 (sabutoclax) and the like.
  • TOPK inhibitors include all known but not limited to: OTS964 (Oncotherapy Science).
  • JAK3 kinase inhibitors include all known but not limited to: Tofactinib.
  • JAK1/2 kinase inhibitors including all known, but not limited to: Roxolitinib.
  • ALK kinase inhibitors include all known, but not limited to, crizotinib, Ceritinib, and CH5424802 (Alectinib).
  • the invention also relates to a specific screening of a plurality of combination drugs in a tumor model in vitro in vitro and in vivo.
  • Compounds or combinations of compounds that kill tumor cells in vitro are not necessarily effective in animal tumor models because of their pharmacological problems. Therefore, in the absence of tumor suppression in animals, only in vitro cell data can not prove whether the compound or combination of compounds can be used as a drug.
  • the invention adopts a total oral administration mode (rather than intraperitoneal injection or intravenous injection) to solve the uncertainty factor of the drug replacement, and optimizes the compound or compound combination in various animal tumor models to achieve the drug-making property. evaluation of.
  • JAK2 inhibitors and BTK inhibitors synergistically inhibit tumor cell effects in vitro, but the present invention shows the opposite result: the JAK1/2 inhibitor Ruxolitinib is not only associated with BTK inhibitors, mTOR inhibitors, The immunomodulatory drug IMiD has no synergistic effect on tumor cells and has no inhibitory effect on TMD-8 tumor cells.
  • the present invention discloses a combination of two-in-one and three-in-one (combination or combination) superior to a single targeted drug.
  • the combination of two-in-one and three-in-one has a synergistic effect at lower doses.
  • the proportions of the combination formulations contemplated by the present invention are not limited to the specific ratios of the in vitro and in vivo experiments disclosed herein.
  • the present invention simultaneously optimizes combined screening for targeting multiple key signaling pathways that control cell growth, proliferation, survival, and apoptosis.
  • Single-targeted therapies often produce resistance due to genetic mutations that render the drug ineffective and cause disease recurrence.
  • Combination therapy can overcome drug resistance and achieve better therapeutic effects or cure.
  • the present invention shows that the combination has a synergistic effect on the tumor cells and a synthetic lethal ability, and its in vitro potency is up to 100-fold more than that of the single targeted drug.
  • the combination also demonstrates superior efficacy in combination with much lower doses than each single targeted drug (eg, 10 of BTK inhibitor 3)
  • a single targeted drug eg, 10 of BTK inhibitor 3
  • Efficacy. A two-in-one combination can cause complete tumor regression during a 15-day treatment cycle, while a three-in-one combination can result in complete tumor regression in a shorter treatment cycle (9 days) and no 12 days after discontinuation of dosing Observing tumor rebound, the effect is significantly better than single-targeted therapy.
  • Single-targeted therapy not only requires long-term treatment, but also often has tumor rebound and drug resistance and cancer recurrence.
  • Combination therapy because of the much lower dose than a single targeted drug and at the same time exhibits superior efficacy will result in an optimized combination of drugs with better safety and a wider therapeutic window than each single drug.
  • the above unique properties of the combination of the present invention may bring new hope to cancer patients who are difficult to treat.
  • the three-in-one drug combination of the present invention can be as high as 95% inhibition of tumor cell viability at concentrations as low as 10 nM for BTK inhibitors, which is unexpected, and is not speculated or directed by the prior invention.
  • Cell viability inhibition was tested after 48 hours of incubation, and if the incubation time increased to 72-96 hours, the combination drug will show greater inhibition of cell viability.
  • the present invention shows that inhibition of cell viability in vitro corresponds to tumor suppression in vivo, and inhibition of cell viability in vitro can predict tumor suppressive effects in vivo. High-effect in vitro cell viability inhibition at the lowest concentration (eg, 10 nM) in the test can result in tumor regression or complete disappearance.
  • the invention of high tumor cell viability inhibition as low as 10 nM kills tumor cells has enormous clinical therapeutic applications.
  • the combination of drugs in the tumor cells of the human body can easily reach a concentration of 10-100 nM, thereby obtaining a better therapeutic effect.
  • single targeted therapy or two-way combination therapy usually achieves a concentration of about 1000 nM in order to effectively Inhibit the growth of tumor cells.
  • ABT-199 inhibited TMD-8 cell viability at 37 nM, 100 nM and 10 nM concentrations of 37.6%, 18.8% and 11.1%, respectively.
  • the inhibition of TMD-8 cell viability with the BTK inhibitor 3 was 85.97%, 79.99% and 65.36%, respectively.
  • the high-efficiency inhibition of TMD-8 cell viability with the BTK inhibitor 3 and PI3K inhibitors was 95.56%, 95.30% and 94.62%, respectively.
  • the activity of the triad pair of TMD-8 cells with BTK inhibitor 3 and the mTOR inhibitor everolimus was also highly potent, 93.44%, 94.73% and 94.65%, respectively.
  • the superior synergistic effects of the present invention are not speculative or instructive in the prior art.
  • the present invention provides (1) one of the best combinations of Bruton's tyrosine kinase (BTK) inhibitor and mTOR kinase inhibitor and IMiD immunomodulatory drug in combination; the other two are best
  • the combined three-in-one drug combination is (2) Luton's tyrosine kinase (BTK) inhibitor and mTOR kinase inhibitor and Bcl-2 inhibitor; (3) Luton's tyrosine kinase (BTK) inhibition And PI3K inhibitors and Bcl-2 inhibitors.
  • a two-in-one combination of Bruton's tyrosine kinase (BTK) inhibitor and mTOR kinase inhibitor Bruton's tyrosine kinase (BTK) inhibitor and immunomodulatory drug IMiD.
  • Drug combination two-in-one combination of Bruton's tyrosine kinase (BTK) inhibitor and TOPK inhibitor, two-in-one combination of TOPK inhibitor and PI3K kinase inhibitor, Bruton's tyrosine kinase
  • a two-in-one combination of a (BTK) inhibitor and a PI3K kinase inhibitor two-in-one combination of a (BTK) inhibitor and a PI3K kinase inhibitor.
  • the present invention shows that certain combinations inhibit synergistic effects, some combinations have no synergistic effects and the opposite effect.
  • Cellular molecular signal channels are too numerous and intersecting and complex, while suppressing the combination of multiple signal channels is more complicated. Therefore, the super synergy effect of the three optimal three-in-one combinations described in the present invention is not speculated or directed by the prior art.
  • the invention provides a combined screening method for inhibiting cell viability in vitro and tumor inhibition in an animal and a plurality of tumor models, and solves the problem of drug-like evaluation of the combined compound.
  • the present invention shows that there is only a three-in-one drug combination in the oral gavage animal tumor model [Bruton's tyrosine kinase (BTK) inhibitor, mTOR kinase inhibitor and IMiD immunomodulatory drug] and 2-in-1 drug
  • BTK Brun's tyrosine kinase
  • mTOR kinase inhibitor 2-in-1 drug
  • the combination of [Button's tyrosine kinase (BTK) inhibitor and mTOR kinase inhibitor] resulted in complete tumor disappearance and no tumor rebound growth was observed after discontinuation of dosing.
  • Other combination drugs only inhibit tumor growth and must be administered continuously to inhibit tumor growth.
  • the single-agent everolimus can cause complete tumor disappearance at medium and high doses, the tumor rapidly rebounds after stopping the administration, which is a feature and defect of targeted therapy.
  • the present invention solves this drawback and is expected to personalize the cure of cancer.
  • the present invention not only demonstrates the excellent therapeutic effect of tumor suppression on a sensitive TMD-8 tumor model, but also demonstrates that the three-in-one combination drug is good in the insensitive DoHH2 tumor model and the resistant and refractory WSU-DLCL tumor model, respectively. Efficacy. Although the tumors did not completely disappear in the two models, the efficacy of the three-in-one combination drug was the best.
  • Epizyme's paper shows that compound EZ-6438 (histone methyltransferase) on the WSU-DLCL tumor model. Histone Methyltransferase EZH2 inhibitor) requires a very high dose (480 mg/kg) per day to achieve similar efficacy.
  • the three-in-one combination drug of the present invention only needs to administer 21 mg per kilogram per day to the mice.
  • the present invention proves for the first time that the multi-targeted combination has a better therapeutic effect and greatly reduces the dose of a single drug, thereby further reducing the side effects of each single drug and making the combination safer and more effective.
  • the multi-targeting combination of the present invention can be used not only for malignant lymphoid tumors and blood cancers caused by B-cells, but also for cancers and solid tumors caused by T-cells.
  • the multi-targeted combination of the present invention can also be used for the treatment of autoimmune diseases such as rheumatoid arthritis.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising Bruton's tyrosine kinase (BTK) inhibitor, mTOR kinase inhibitor and IMiD immunomodulator as active ingredients.
  • BTK Bruton's tyrosine kinase
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising Bruton's tyrosine kinase (BTK) inhibitor, mTOR kinase inhibitor and Bcl-2 inhibitor as active ingredients.
  • BTK Bruton's tyrosine kinase
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising Bruton's tyrosine kinase (BTK) inhibitor, PI3K kinase inhibitor and Bcl-2 inhibitor as active ingredients.
  • BTK Bruton's tyrosine kinase
  • the present invention also provides the use of the compounds represented by the general formulae (I), (II), (Ia), (IIa), (Ib) and (IIb) for the preparation of a medicament for regulating BTK activity, treating or inhibiting diseases associated with BTK activity.
  • the use of the drug is not limited to the group consisting of the compounds represented by the general formulae (I), (II), (Ia), (IIa), (Ib) and (IIb)
  • the present invention also provides for the preparation of a compound represented by the general formulae (I), (II), (Ia), (IIa), (Ib) and (IIb) in combination with an mTOR kinase inhibitor and/or an IMiD immunomodulatory drug.
  • a medicament for modulating BTK activity treating or inhibiting a disease associated with BTK activity.
  • the present invention also provides a combination of a Bruton's tyrosine kinase (BTK) inhibitor and a mTOR kinase inhibitor and an IMiD immunomodulatory drug, or a combination of the two, for the preparation of a modulated BTK activity, treatment or inhibition.
  • BTK Bruton's tyrosine kinase
  • the present invention also provides a combination of a Bruton's tyrosine kinase (BTK) inhibitor and a mTOR kinase inhibitor and a Bcl-2 inhibitor for the preparation of a BTK activity or a Bcl-2 activity, treatment or inhibition.
  • BTK Bruton's tyrosine kinase
  • the present invention also provides a combination of a Bruton's tyrosine kinase (BTK) inhibitor and a PI3K kinase inhibitor and a Bcl-2 inhibitor for the preparation of a BTK activity or a PI3K activity or a Bcl-2 activity.
  • BTK Bruton's tyrosine kinase
  • PI3K kinase inhibitor a PI3K kinase inhibitor
  • Bcl-2 inhibitor for the preparation of a BTK activity or a PI3K activity or a Bcl-2 activity.
  • Carriers, excipients, and other additives commonly used in pharmaceutical formulations can be used to prepare one or two or more of formula (I), (II), (Ia), (IIa), (Ib), and A pharmaceutical composition comprising the compound of (IIb) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a dosage form for parenteral administration such as a nasal preparation or an inhalation is administered for therapeutic administration.
  • the symptoms, age, sex, and the like of each patient to be treated should be considered in order to appropriately determine the dose of the compound.
  • an adult patient takes a daily dose of a compound of about 0.001 mg/kg to 100 mg/kg, and the dose is taken once or divided into 2 to 4 times.
  • adult patients are administered once or more times per day in a dose range of 0.0001 mg/kg to 10 mg/kg. Further, in the case of administration by inhalation, in general, an adult patient is administered once or more times per day in a dose range of 0.0001 mg/kg to 1 mg/kg.
  • the solid composition for oral administration may be in the form of a tablet, a powder, a granule or the like.
  • one or more active substances are combined with at least one inert excipient (eg, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, poly Mixing with vinylpyrrolidone, magnesium aluminum silicate, etc.).
  • the composition may also contain inert additives such as a lubricant (e.g., magnesium stearate), a disintegrant (e.g., sodium carboxymethyl starch), and a dissolution aid, according to a conventional method.
  • Tablets or pills may also be coated with a sugar coating or a gastric or enteric coating as needed.
  • the liquid composition for oral administration includes a pharmaceutically acceptable emulsion, solution, suspension, syrup, or elixir, and the like, and contains an inert diluent (e.g., purified water, ethanol) which can be usually used.
  • an inert diluent e.g., purified water, ethanol
  • the composition may also contain adjuvants such as solubilizers, wetting agents, suspending agents, and sweetening, flavoring, perfuming, and preservatives.
  • Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, emulsions.
  • the diluent for the aqueous solution may, for example, include distilled water for injection and physiological saline.
  • the diluent for the non-aqueous solution may, for example, include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
  • Such compositions may also contain additives such as isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers, solubilizers.
  • compositions may be sterilized by filtration through a bacteria-retaining filter, addition of a bactericide, or light irradiation. Further, these compositions may be prepared into a sterile solid composition which is dissolved or suspended by using sterile water or a sterile injectable solvent before use.
  • Transmucosal agents such as inhalants and nasal sprays can be used in a solid, liquid, or semi-solid state, and these transmucosal agents can be prepared according to a conventionally known method.
  • excipients such as lactose and starch
  • pH adjusters such as lactose and starch
  • antiseptic agents such as lactose and starch
  • surfactants such as surfactants
  • lubricating agents such as sodium bicarbonate
  • stabilizers such as a metered dose inhalation device or a nebulizer.
  • the compound may be combined with a pharmaceutically acceptable carrier and administered as a solution or suspension.
  • a dry powder inhaler or the like can be used for single administration or multiple administrations. Dry powder or capsules containing powder can also be used. Alternatively, it may be administered by a pressurized aerosol spray or the like by using a suitable propellant (for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide).
  • a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.
  • FIG. 1A Tumor volume inhibition in multiple doses of Compounds 1 and 3 in the TMD-8 model of SCID mice
  • FIG. 1B Tumor weight inhibition in multiple doses of Compounds 1 and 3 in the TMD-8 model of SCID mice
  • reaction solution was poured into ice water (300 mL), and then extracted four times with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness.
  • reaction mixture was stirred at 0 ° C for 1 hour, then quenched with water (5mL), then diluted with dichloromethane (50mL), twice with water (30mL) and brine (30mL). The organic phase was dried over anhydrous sodium sulfate (MgSO4). Rate: 64%).
  • reaction solution was stirred at 60 ° C overnight under a nitrogen atmosphere. After cooling to room temperature, it was filtered through Celite. The filtrate was concentrated to dryness, and water (300 mL) was added to the residue, and then extracted three times with ethyl acetate. The combined organic layers were dried with anhydrous sodium
  • reaction solution was stirred at 0 ° C for 1 hour, then warmed to 60 ° C and stirred for 12 hours. After cooling to room temperature, saturated brine (10 mL) was added, and the mixture was extracted three times with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and evaporated to dryness crystals. 0.8 g, yield: 71%).
  • the reaction solution was stirred at 80 ° C for 30 minutes under microwave irradiation. After cooling to room temperature, it was filtered through Celite. The filtrate was concentrated and dried, and the obtained crude product was separated by high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 10% to 100% (volume ratio)), and evaporated under reduced pressure. The volatile component was lyophilized to give the title compound (38 mg, yield: 28%).
  • the crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.7 %NH 4 HCO 3 , gradient elution 10% to 100% by volume), the volatile component was evaporated under reduced pressure, and the title compound (19 g, yield: 23%).
  • the reaction solution was stirred at room temperature for 12 hours, concentrated and dried, and the obtained crude product was separated by high-performance liquid chromatography on a C18 reverse phase column (instrument: LC 8A & Gilson 215, component collection column: Synergi Max-RP150*30 mm*4u, flowing Phase A: water (0.5% HCl), mobile phase B: acetonitrile, flow rate: 30 mL/min, gradient: B36% to 37%, 0-17 minutes), the volatile components were evaporated under reduced pressure and lyophilized to obtain the target.
  • the compound hydrochloride (76 mg, yield: 13%).
  • the obtained crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 36% to 37% (volume)
  • the title compound hydrochloride (228 mg, yield: 20%) was obtained by evaporation of the volatile component.
  • the reaction solution was stirred at 15-18 ° C for 2 hours and concentrated to dryness.
  • the obtained crude product was separated by high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 22% to 52% by volume), and the volatile components were distilled off under reduced pressure. After lyophilization, the title compound hydrochloride (82 mg, yield: 33%) was obtained.
  • the enzymatic reaction solution of the BTK wild type kinase standard HTRF assay consisted of 1 nM BTK wild type kinase, 1 ⁇ M biotin-TK1 polypeptide, 30 ⁇ MATP and 50 mM HEPES (pH 7.5) buffer. After the mixture was incubated at room temperature for 60 minutes, the reaction was stopped by the addition of EDTA. The inhibitor (5 L) was then added to a final concentration of 2 nM antibody and 62.5 nM XL665. The plates were incubated for 60 minutes at room temperature and the results were read using an Envision multi-label microplate reader. The test data was converted to the percent inhibition (%) by the formula (Min Ratio) / (Max-Min) * 100%, and then the IC50 value of the test compound was obtained by fitting four parameter curves.
  • Tumor cells (TMD-8, DoHH2 and WSU-DLCL2) were transferred and attached to 96-well plates. After overnight, a blank control buffer and a test compound solution of selected concentration (0.01 nM - 100 ⁇ M) were added. After 48 hours of incubation, cells were lysed by the addition of CellTiter-Go reagent. The luminescence signal was recorded and the percent inhibition of cell viability was calculated.
  • Rat pharmacokinetic experiments The pharmacokinetic tests of male SD rats within 24 hours were divided into two groups: intravenous and oral, with 3 animals in each group.
  • the time of blood collection in the intravenous group was before administration, 0.0833, 0.167 after administration. , 0.5, 1, 2, 4, 8, 24 hours; the time of blood in the oral group was 0.167, 0.5, 1, 2, 4, 8, 24 hours before administration.
  • bioassay was performed by HPLC-MS/MS to report the plasma concentration of the compound.
  • the calculated pharmacokinetic parameters were the mean clearance rate (Clp) of the intravenous group animals, and the average apparent volume of distribution (Vdss).
  • AUC Average retention time
  • Cmax mean maximum drug concentration
  • MRT mean residence time
  • Canine pharmacokinetic experiments The pharmacokinetic test within 24 hours of Beagle dogs is divided into two groups: intravenous (1 mg per kg) and oral (3 mg/kg) groups of 3 animals per group. Before administration, 0.033, 0.083, 0.25, 0.5, 1, 3, 6, 9, 24 hours after administration; the time of blood collection in the oral group was before administration, 0.083, 0.25, 0.5, 1, 3 after administration. , 6, 9, 24 hours. After blood collection, bioassay was performed by HPLC-MS/MS to report the plasma concentration of the compound. The calculated pharmacokinetic parameters were the mean clearance rate (Clp) of the intravenous group animals, and the average apparent volume of distribution (Vdss).
  • AUC Average retention time
  • Cmax average drug concentration
  • MRT mean residence time
  • TMD-8 DoHH2, WSU-DLCL2 tumor cells were seeded in RPMI-1640 medium containing 10% heat-inactivated fetal bovine serum and cultured at 37 ° C, 5% CO 2 . Tumor cells are routinely subcultured twice a week. Tumor inoculation is performed when cells grow into the exponential growth phase and are harvested and counted. Right side of each mouse inoculated subcutaneously with 02mL PBS suspension of tumor cells (10x 10 6) and Matrigel (1/1). Dosing begins when the average tumor volume is approximately 100-200 mm 3 .
  • Each group consisted of 6-10 tumor-bearing mice.
  • the test group (including the blank control group, the single drug group, and the co-administration group) was orally administered at a predetermined dose for 14 days or 21 days.
  • Mouse body weight and tumor volume were measured every two or three days during the experiment.
  • mice were divided into 8 groups, including one normal group, one solvent control group, and five treatment groups. All mice (except the normal group) were immunized with 200 ⁇ g of bovine collagen (type II) on days 0 and 21. Seven days after the booster immunization (28 days), the animals began to show symptoms of the disease with an average clinical score of about 1. On the same day, the immunized mice were randomly divided into 7 groups: compound 3 (1.5 mpk) and compound 14 (0.15 mpk) were administered in combination twice a day; compound 3 (4.5 mpk) and compound 14 (0.45 mpk) were administered in combination, one day.
  • the in vivo inhibitory effect of the combination of Compound 3 and Compound 14 was evaluated using a female Lewis rat collagen-induced arthritis model. All rats (except the normal group) were immunized with complete Freund's adjuvant (CFA) on the left hind limb on day 0. Six days after immunization, some rats began to show clinical signs of arthritis, such as erythema and swelling.
  • CFA complete Freund's adjuvant
  • the "two-in-one" combination drug has significant tumor cell viability inhibition.
  • the drug combinations of Compound 8+ Compound 13, Compound 14+ Compound 13, Compound 15+ Compound 13 and Compound 3+ Compound 13 all exhibited high potency inhibition of TMD-8 cell viability.
  • the "three-in-one" combination drug has significant tumor cell viability inhibition.
  • the drug combination of Compound 3+ Compound 14+ Compound 12 and Compound 3+ Compound 8+ Compound 12 still has up to 95% inhibition of tumor cell viability at a concentration of BTK inhibitor as low as 10 nM.
  • the "three-in-one" drug combination of Compound 3 + Compound 15 + Compound 14 has a good cell viability inhibitory effect on multi-drug resistant WSU-DLCL2 cells and is significantly superior to each single targeted drug. .
  • the "three-in-one" drug combination of Compound 3 + Compound 15 + Compound 14 has a good cell viability inhibitory effect on refractory DoHH-2 cells and is significantly superior to each single targeted drug.
  • the combination has synergistic effect on the tumor cells and the ability to synthesize lethality. Under the combined administration conditions of much lower dose than each single targeted drug, the efficacy of the combination is far superior to that of each single.
  • the efficacy of targeted drugs For example, a combination of Compound 3+ Compound 14 "two-in-one" can lead to complete tumor regression during a 15-day treatment cycle, while Compound 3+ Compound 14+ Compound 15 "Three-in-one" combination is used in a shorter treatment cycle. (9 days) can lead to The tumor completely resolved, and no tumor rebound was observed within 12 days after the administration was stopped, and the effect was significantly better than that of single-targeted therapy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Endocrinology (AREA)
  • Neurology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

本发明提供一系列新的多氟取代的吡唑并嘧啶类化合物或盐。这类化合物是酪氨酸激酶(BTK)的抑制剂。这类化合物可具有更好的激酶抑制选择性和药代药谢性质。本发明公开了所述化合物的制备方法。本发明也公开了包含所属化合物与其他靶向药物组合物或其他药物相互组合的联合用药。优化的联合用药具有协同作用、比单一靶向药物能更好地抑制肿瘤的生存，可造成某些肿瘤完全消失。优化的联合用药比单一靶向药物能更好治疗肿瘤的耐药性和癌症复发，治疗周期更短。本发明还涉及组合化合物及其作为活性成分的药物制剂，在更低剂量下更安全并有协同效应的疗效。本发明还包括使用这些化合物和它们的制剂来治疗和抑制自身免疫性疾病或病症、异种免疫性疾病或病症、炎性疾病以及癌症或病症的方法。

Description

优化的联合用药及其治疗癌症和自身免疫疾病的用途
发明的技术领域
本发明涉及一系列新的多氟取代的吡唑并嘧啶类化合物及其制备方法，包含它们作为有效成份的药物组合物及其抑制布鲁顿氨酸激酶活性的方法。本发明还涉及多类药物的体外肿瘤细胞活力和体内肿瘤抑制的联合用药优化筛选。本发明的优化联合用药具有协同作用、比单一靶向药物能更好地抑制肿瘤的生存，可造成某些肿瘤完全消失，优化的联合用药比单一靶向药物能更好治疗肿瘤的耐药性和癌症复发。优化的联合用药因剂量低而更安全，并且更好的疗效可造成治疗周期更短。
发明背景
癌症治疗已经从有毒性化疗发展到联合化疗(如CHOP)，抗体(如利妥昔单抗)，以抗体与化疗联合治疗(R-CHOP)，到现在令人兴奋的免疫抗癌疗法(PD-1和PD-L1抗体)和嵌合抗原受体的T细胞疗法(CAR-T)。患者的寿命和生活质量已有所改善，但由于癌症的复杂性，单一途径或信号通路的突变可以引起一些疗法是无效的或复发。小分子靶向治疗需要每天长期给药，如果停止给药，癌症会反弹或复发。抗体和化疗，给药方式复杂，联合用药可具有累加或协同效应，但很少导致癌症的治愈。靶向治疗与免疫抗癌疗法或嵌合抗原受体的T细胞疗法(CAR-T)是正在进行中的，但可能具有安全性的担忧。口服疗法有许多优点，比如在遇到严重副作用时可以立即停止给药。抗体或细胞疗法则比较困难马上控制严重副作用。目前单通路靶向治疗或二个靶向通路的联合疗法有一定的局限性，因此癌症的临床疗效(总有效率-ORR)大都是部分缓解(PR)或稳定的疾病(SD)，很少有治愈(CR)。这种治疗通常会只延长患者生命几个月。此外，细胞疗法的复杂性或抗体化疗的组合也具有安全性问题，以及这些疗法限制于医院环境，不仅导致癌症治疗成本较高，而且影响患者的求治愿望和依从性，及普及到广大患者的局限性。此外，单剂靶向治疗价格每名患者为10-20万美元，新的联合治疗的价格会成倍或更高，这种昂贵的治疗是不可持续发展的。因此，患者和市场都有明确的需要来寻求更好的组合疗法。新的组合疗法或联合用药希望是更为有效与更小的副作用，治疗时间更短。加上合适的伴侣诊断，优化的组合疗法(个性化治疗或精准治疗)，可能会治愈癌症亚型，或更有抗耐药性。
Ibrutinib(依鲁替尼)是首个被FDA批准的布鲁顿酪氨酸激酶(BTK)抑制剂，对B细胞淋巴瘤，包括MCL和CLL等有良好疗效，但临床治疗已产生C481s等突变而造成耐药性(Furman et al：Ibrutinib resistance in chronic lymphocytic leukemia，N Engl J Med，2014，2352)。此外，依鲁替尼的药代在患者差异巨大(Marostica et al：Population harmacokinetic model of ibrutinib，a Bruton tyrosine kinase inhibitor，in patients with B cell malignancies，Cancer Chemother Pharmacol(2015)75：111-121)，它的毒理动力学研究发现AUC在鼠和犬都较低1000h*ng/mL(雄鼠，40mg/kg)和3300h*ng/mL(雌鼠，40mg/kg)及1780h*ng/mL(雄犬，24mg/kg)和1850h*ng/mL(雌犬，24mg/kg)(FDA’s NDA Application Number 205552Orig1s000_pharmacological review)。BTK起着从细胞表面的B细胞受体(BCR)至下游细胞内反应的B细胞信号传导途径的关键作用。它是B细胞发育，活化，增殖和存活的关键调节剂。
Everolimus(依维莫司)是FDA批准用于乳腺癌，胰腺癌，肾细胞癌，肾错构瘤和结节性硬化症复合物的治疗mTOR激酶抑制剂。mTOR蛋白的机制作用已被完全阐明，它是在一个非常复杂的信号传导途径中控制细胞生长，增殖，代谢和细胞凋亡的关键调节剂。此外器官移植也会激活mTOR，依维莫司在低剂量下用于治疗器官移植的排斥。
Pomalidomide(泊马度胺)是在2013年FDA批准治疗多发性骨髓瘤的免疫调节药物。泊马度胺和有关同类IMiDs抑制细胞因子TNF-α，IL-1β，IL-6，IL-12和GM-CSF。除了它们的抗血管生成，抗增殖和促凋亡性质外，它们也刺激T淋巴细胞诱导其增殖，T细胞因子的产生，和T细胞毒性，从而增加了T细胞的抗癌活性。
Venetoclax或ABT-199是处于临床研究中的bcl-2抑制剂。B淋巴细胞瘤-2(bcl-2)蛋白对细胞凋亡有关键作用。ABT-199临床中曾引发肿瘤溶解综合症(TLS)而导致患者死亡。
Methotrexate(甲氨蝶呤)为抗叶酸类抗肿瘤药和治疗类风湿关节炎药物，主要通过对二氢叶酸还原酶的抑制而达到阻碍细胞的合成，而抑制细胞的生长与繁殖。
布鲁顿氨酸激酶(Bruton’s tyrosine kinase，BTK)属于Tec家族的成员。它由独特的N-端结构域即PH(pleckstrin homology)结构域、TH(Tec homology)同源区、SH3(Src homology 3)结构域、SH2(Src homology 2)结构域和催化结构域，也称SH 1/TK(Src homologyl/Tyrosine kinase)结构域或者激酶结构域组成(Akinleye et al：Ibrutinib and novel BTK inhibitors in clinical development，Journal of Hematology&Oncology 2013，6：59)。在B淋巴细胞正常发育过程中，BTK基因不同蛋白区域的正确表达在B细胞的功能及多种转导途径中具有关键性作用。
BTK功能下游有多种受体，包括生长因子，B细胞抗原，趋化因子和先天免疫受体，从而启动一个多元化范围内的细胞过程，如细胞增殖，存活，分化，运动，血管生成，细胞因子生产，抗原表达等。因此BTK在许多造血细胞信号传输途径中起重要作用，同时在B细胞激活，发育，存活和信号传导中也至关重要(Kurosaki，Molecular mechanisms in B cell antigen receptor signaling.Curr OP Imm，1997，9(3)：309-18)。
已有证据证明B细胞对自身免疫应答和炎性反应有免疫调节作用。如CD20抗体利妥昔单抗(Rituxan)是消耗B细胞的基于蛋白质的治疗剂，用作治疗自身免疫性疾病如慢性淋巴细胞白血病和自身抗体导致的炎性疾病如类风湿关节炎。因此通过抑制B细胞活化过程中发挥关键作用的蛋白质激酶应该可以对于B细胞相关疾病病理有帮助。
BTK在自身免疫疾病中的作用的证据已经由BTK-缺失型小鼠和BTK-充足型小鼠模型试验提供(Kil LP，et al：Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia.Am J Blood Res 2013，3(1)：71-83.)。在慢性淋巴细胞白血病(CLL)小鼠模型中，BTK-缺失型小鼠完全废止慢性淋巴细胞白血病，BTK过度表达会加速白血病发病，增加死亡率。
已知BTK抑制剂的选择性不理想：除了抑制BTK，还抑制其他多种激酶(如ETK，EGF，BLK，FGR，HCK，YES，BRK和JAK3等)，从而可能产生较多的副作用。选择性更好的抑制剂副作用可能更小。
已知BTK抑制剂体内生成多种衍生物，这也会影响药效和副作用。已知BTK抑制剂的药代动力学也可改善。
发明内容
本发明涉及BTK抑制剂用作治疗或抑制自身免疫性疾病或病症、异种免疫性疾病或病症、炎性疾病以及癌症或病症的方法。包括给所述患者施用有效剂量由通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)表达的化合物，或它们的药学上可接受的盐。
Figure PCTCN2016000149-appb-000001
Figure PCTCN2016000149-appb-000002
其中：
R1为氟原子；n为1，2，3或4；
R2为氟原子；m为1或2；
R3为氢原子或氘原子。
本发明中，术语“药学上可接受的盐”指的是以酸或碱形式存在的盐，其非受限的实例为(a)酸性加成盐，无机酸(例如，盐酸、氢溴酸、硫酸、磷酸、硝酸等)，有机酸的盐，有机酸例如醋酸、草酸(oxalicacid)、酒石酸(tartaric acid)、琥珀酸(succinic acid)、苹果酸(malic acid)、抗坏血酸、苯甲酸(benzoic acid)、鞣酸(tannic acid)、扑酸(pamoic acid)、海藻酸(alginic acid)、聚麸胺酸(poly glutamicacid)及水杨酸等；(b)碱性加成盐(base addition salts)，形成有金属阳离子，如锌、钙、钠、钾等。
合成方法
本发明通过实施例和本文中所公开的化合物来示例。在本发明的具体化合物选自下组被公开的实施例中的化合物和它们的药学上可接受的盐及它们的单独的非对映体的化合物或盐。
本发明对合成路径进行了积极探索，成功设计了合成吡唑并嘧啶类化合物的新方法(见方案1-2和具体反应实例)。
除非另有说明，在下面的反应方案和讨论中，R1，R2，R3，m，n的定义如上所述。
反应式方案1
Figure PCTCN2016000149-appb-000003
在碱的存在下，如碳酸钾，并在适当的溶剂中，如DMF，氟取代的起始材料A1可以与取代的苯酚B1生成中间体C1。在适当的碱，如醋酸钾的存在下，并在适当的溶剂，如1，4-二氧六环中，中间体C1可与双联频哪醇硼酸酯在适当的催化剂(如[1，1′-双(二苯基磷)二茂铁]二氯化钯)作用下进行反应以提供中间D1。在适当的溶剂中，如DMF，起始原料1H-吡唑并[3，4-d]嘧啶-4-胺可与NIS进行反应得到中间体F1，然后经由Mitsunobu反应或者取代反应形成中间体G1。在适当的碱，如磷酸钾的存在下，并在适当的溶剂，如1，4-二氧六环和水中，中间体G1可与硼酸酯D1在适当的催化剂(如Pd-118)作用下进行反应得到中间H1。在酸性条件下脱去H1的Boc基团，得到胺化合物I1。胺化合物I1可以与亲电子试剂反应，得到产物I。当I为外消旋体时可通过SFC手性拆分得到具有光学活性的化合物Ia和Ib。
反应式方案2
Figure PCTCN2016000149-appb-000004
在碱的存在下，如碳酸钾，并在适当的溶剂中，如DMF，3-氟-4-溴苯酚与1-氟-3硝基苯生成中间体C2。在适当的还原剂，如铁粉和氯化铵，并在适当的溶剂中，如乙醇和水，硝基化合物C2可被还原成胺D2，随后在亚硝酸钠和吡啶氟化氢的作用下可生成氟取代的中间体E2。在适当的碱，如醋酸钾的存在下，并在适当的溶剂，如1，4-二氧六环中，E2可与双联频哪醇硼酸酯在适当的催化剂(如[1，1′-双(二苯基磷)二茂铁]二氯化钯)作用下进行反应以提供硼酸酯F2。在适当的碱，如磷酸钾的存在下，并在适当的溶剂，如1，4-二氧六环和水中，中间体H1可与硼酸酯F2在适当的催化剂(如Pd-118)作用下进行反应以提供中间G2。在酸性条件下脱去G2的Boc基团得到胺化合物H2。胺化合物H2可以与亲电子试剂反应，得到产物I2。当I2为外消旋体时可通过SFC手性拆分得到光学活性的化合物J2和K2。
反应式方案3
Figure PCTCN2016000149-appb-000005
3-氟-4-溴苯酚与3-氟-苯硼酸在适当的催化剂(如醋酸铜)作用下生成中间体B3，随后B3可与双联频哪醇硼酸酯在适当的催化剂(如[1，1′-双(二苯基磷)二茂铁]二氯化钯)作用下进行反应以提供硼酸酯C3。在适当的碱，如醋酸钾的存在下，并在适当的溶剂，如1，4-二氧六环和水中，中间体G1可与硼酸酯C3在适当的催化剂(如[1，1′-双(二苯基磷)二茂铁]二氯化钯)作用下进行反应以提供中间D3。在酸性条件下脱去D3的Boc基团得到胺化合物E3。胺化合物E3可以与亲电子试剂反应，得到产物F3。当F3为外消旋体时可通过SFC手性拆分得到光学活性的化合物H3和I3。
反应式方案4
Figure PCTCN2016000149-appb-000006
胺化合物I1可以与丁-2炔酸反应，得到产物II。当II为外消旋体时可通过SFC手性拆分得到具有光学活性的化合物IIa和IIb。
反应式方案5
Figure PCTCN2016000149-appb-000007
中间体F1经由Mitsunobu反应或者取代反应形成有光学活性的中间体A5。在适当的碱，如磷酸钾的存在下，并在适当的溶剂，如1，4-二氧六环和水中，中间体A5可与硼酸酯D1在适当的催化剂(如Pd-118)作用下进行反应得到中间B5。在酸性条件下脱去B5的Boc基团，得到胺化合物C5。胺化合物C5可以与亲电子试剂反应，得到产物Ia。
反应式方案6
Figure PCTCN2016000149-appb-000008
胺化合物C5可以与丁-2炔酸反应，得到产物IIa。
本发明提供了由通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)所述化合物，及它们的对映体和非对映体或其可药用的盐。
本发明由通式通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)所述化合物包括含有一个或者多个稳定同位素或放射同位素，所述同位素包括，但不仅限于2H，3H，13C，14C，15N，18O等。
本发明首次将1H的同位素2H引入BTK抑制剂。
本发明由通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)所述的化合物乙烯基的双键末端1H可被2H替代，从而降低由双键氧化还原而导致的药物失活。
本发明提供了制备由通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)所述化合物，及它们的对映体和非对映体的方法。
本发明提供了一种用于调节BTK的活性，并且治疗或抑制与BTK活性相关的疾病的方法。经证实，本发明的化合物对BTK活性具有抑制作用，本发明提供了由通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)所述化合物用于治疗和/或预防以下疾病的药剂中的活性成分，所述的疾病为由不利的细胞因子信号传导引发的疾病，这些疾病包括，但不限于：
(1)自身免疫性疾病(autoimmune diseases)如慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征(goodpasture syndrome)、寻常天皰疮、类天皰疮、原发性胆汁性肝硬变、多发性脑脊髓硬化症、急性特发性多神经炎等，系统性红斑狼疮、类风湿关节炎、银屑病(psoriasis)、系统性脉管炎、硬皮病、天疱疮、混合结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、溃疡性结肠炎等；
(2)异常免疫性疾病如血清病、哮喘、过敏性鼻炎和药物过敏等；
(3)炎性疾病如角膜炎、鼻炎、口腔炎、腮腺炎、咽炎、扁桃体炎、气管炎、支气管炎、肺炎、心肌炎、胃炎、肠胃炎、胆囊炎、阑尾炎等；
(4)癌症包括，但不限于各种B细胞恶性肿瘤(包括小淋巴细胞淋巴瘤(SLL)、慢性淋巴细胞白血病(CLL)、弥漫性大B细胞淋巴瘤(DLBCL)、华氏巨球蛋白血症(Waldenstrom Macroglobulinemia)、滤泡性淋巴瘤(Follicular Lymphom)、套细胞淋巴瘤(MCL))以及其他抑制BTK激酶活性对病人有益处的疾病；
其他抑制BTK激酶活性对病人有益处的疾病包括但不限于：脑瘤，膀胱癌，胃癌，卵巢癌，胰腺癌，乳腺癌，头颈癌，子宫颈癌，子宫内膜癌，直肠癌，肾癌，食道癌，前例腺癌，甲状腺癌，骨癌，皮肤癌，结肠癌，雌性生殖道瘤，淋巴瘤，多发性骨髓瘤(MM)和睾丸癌等。
所述方法包括给需要的患者有效剂量的如权利要求1-2中的化合物。
可以根据标准的药学实践，将本发明的化合物(BTK抑制剂)的药物制剂单独使用或者与一种或多种另外的药剂联合使用，所述BTK抑制剂的药物制剂与所述另外的药剂的给药途径可以相同或不同，并且给药时间可以相同或不同。所述的另外的药剂包括(但不限于)：
酪氨酸激酶抑制剂(如阿西替尼、达沙替尼、埃克替尼等)；
拓扑异构酶抑制剂(如托泊替康等)；
蛋白激酶C抑制剂(如AEB-071等)；
鞘氨醇-1-磷酸受体激动剂(如芬戈莫德、KRP-203等)；
抗T细胞免疫球蛋白(如AtGam等)；
抗IL-2受体的抗体(如达利珠单抗等)；
酰胺(CTX)、异环磷酰胺(IFO)、阿霉素(ADM)、柔红霉素(DNR)、长春新碱(VCR)、长春花碱(VBL)、依托泊甙(VP16)、威猛(Vumon)、卡铂(CBP)和甲 氨蝶呤(MTX)环孢菌素A、他克莫司、西罗莫司、依维莫司、硫唑嘌呤、布喹那、来氟米特、LEA-29Y、抗CD3抗体(如0KT3等)、阿司匹林；
B7-CD28阻断分子(如Belatacept、Abatacept等)；
CD40-CD154阻断分子(例如抗CD40抗体等)；
扑热息痛、布洛芬、萘普生、吡罗昔康和抗炎甾体类(例如氢化泼尼松或地塞米松)；
布鲁顿的酪氨酸激酶(BTK)抑制剂，包括所有已知的、但不仅限于：依鲁替尼Ibrutinib，化合物3和5，ACP-196(Acerta Pharma)，BGB-3111(BeiGene)，AVL-292(Celgene)，ONO-4059(One Pharmaceutical)，HM71224(Hanmi Pharmaceutical)，RN486(Roche)，CNX-774和CGI-11746等。
mTOR抑制剂，包括所有已知的、但不仅限于：依维莫司，雷帕霉素，XL388，GDC-0349，AZD2014，AZD8055，GSK105965，MLN0128和Ridaforlimus等。
免疫调节药物IMiDs，包括所有已知的、但不仅限于：Thalidomide(沙利度胺)，Revlimid(来那度胺)，Pomalidomide(泊马度胺)，CC-122，CC-220。
PI3K激酶抑制剂，包括所有已知的、但不仅限于：BTG226，PF-05212384(Gedatolisib)，GDC-0980(Apitolisib)，GSK2126458，BEZ235，IPI-145(Duvelisib)和CAL-101(Idelalisib)等。
Bcl-2抑制剂，包括所有已知的、但不仅限于：ABT-199(Venetoclax)和BI-97C1(sabutoclax)等。
TOPK抑制剂，包括所有已知的、但不仅限于：OTS964(Oncotherapy Science)。
JAK3激酶抑制剂，包括所有已知的、但不仅限于：托法替尼(Tofactinib)。
JAK1/2激酶抑制剂，包括所有已知的、但不仅限于：鲁索替尼(Ruxolitinib)。
ALK激酶抑制剂，包括所有已知的、但不仅限于：克唑替尼(Crizotinib)，色瑞替尼(Ceritinib)和CH5424802(Alectinib)。
本发明也涉及具体的多种组合药物在体外细胞和动物体内肿瘤模型优化筛选。体外能杀死肿瘤细胞的化合物或化合物组合，因为药代药谢问题，并不一定在动物肿瘤模型中有效。因此在没有动物体内肿瘤抑制前提下、仅有体外细胞数据不能证明化合物或化合物组合能否成药。本发明采取全为口服灌胃的给药方式(而非腹腔注射或静脉注射)而解决了药代药谢不确定因素，对化合物或化合物组合在多种动物肿瘤模型进行筛选优化而达到成药性的评估。
现有技术声称ALK抑制剂和BTK抑制剂有协同抑制体外肿瘤细胞效应，但本发明显示了相反结果：ALK抑制剂色瑞替尼(Ceritinib)和BTK抑制剂依鲁替尼Ibrutinib没有协同效应。
现有技术也声称JAK2抑制剂和BTK抑制剂有协同抑制体外肿瘤细胞效应，但本发明显示了相反结果：JAK1/2抑制剂鲁索替尼(Ruxolitinib)不但和BTK抑制剂、mTOR抑制剂、免疫调节药物IMiD对肿瘤细胞都没有协同效应，对TMD-8肿瘤细胞基本上无抑制作用。
本发明公开了优越于单一靶向药物的二合一和三合一的联合用药(复方用药或组合药物)。二合一和三合一的联合用药在更低剂量具有协同效应。本发明涉及的联合用药配方比例不仅限于本发明公开的体外和体内实验的具体比例。
本发明同时对控制细胞生长，增殖，存活和凋亡的多个关键信号通路靶向进行优化组合筛选。单一靶向治疗经常因基因突变而产生耐药性造成药无效并导致疾病复发。联合用药可以克服耐药性而达到更好的治疗效果或治愈。本发明显示联合用药对肿瘤细胞有协同效应和合成致死能力，其的体外效力比单一靶向药物的活性高达100倍的增加。在多种移植瘤模型抑制口服灌胃给药，联合用药还展示了更卓越的疗效，在比每个单一靶向药物剂量低得多的组合给药条件下(例如：BTK抑制剂3的十八分之一剂量，mTOR抑制剂依维莫司的六分之一剂量，IMiD免疫调节剂泊马度胺的六分之一剂量)，联合用药的疗效远远优于每个单一靶向药物的疗效。二合一的联合用药在15天的治疗周期可以导致肿瘤完全消退，而三合一的联合用药在更短的治疗周期(9天)可以导致肿瘤完全消退，并且在停止给药后12天内没有观察肿瘤反弹，疗效显著优于比单一靶向治疗。单一靶向治疗不但需要长期治疗，而且常有肿瘤的反弹和耐药性的产生以及癌症复发。联合用药因为使用比单一靶向药物低得多的剂量并同时展现更卓越的疗效将使优化的联合用药比每个单药都拥有更好的安全性和更广泛的治疗窗。本发明联合用药的上述独特性能可能为难以治疗的癌症患者带来新希望。
本发明三合一药物组合在BTK抑制剂低至10nM浓度下可高达95％肿瘤细胞活力抑制是意想不到的，不是现有发明可推测或指导的。细胞活力抑制是在温育48小时后测试，如果温育时间增长到72-96小时，组合药物将显示更强的细胞活力抑制。本发明显示体外细胞活力抑制与体内肿瘤抑制相对应，体外细胞活力抑制可以预测体内肿瘤抑制效果。测试中最低浓度下(如10nM)的高效应体外细胞活力抑制可导致肿瘤消褪或者完全消失。低至10nM浓度下有很高肿瘤细胞活力抑制可杀死肿瘤细胞的发明具有巨大的临床治疗应用。在治疗患者疗程中，人体的肿瘤细胞内组合药物很容易到达10-100nM浓度，从而得到更好的治疗效果。目前单一靶向治疗或双向联合治疗通常在化合物浓度达到1000nM左右才能有效地 抑制肿瘤细胞的生长。比如ABT-199在1000nM、100nM和10nM浓度下抑制TMD-8细胞活力分别为37.6％、18.8％和11.1％。在和BTK抑制剂3的二合一对TMD-8细胞活力抑制分别为85.97％、79.99％和65.36％。而在和BTK抑制剂3及PI3K抑制剂的三合一对TMD-8细胞活力高效抑制分别为95.56％、95.30％和94.62％。和BTK抑制剂3及mTOR抑制剂依维莫司的三合一对TMD-8细胞活力也有高效抑制，分别为93.44％、94.73％和94.65％。本发明的超强协同效应不是现有技术可推测或指导的。
本发明提供了(1)布鲁顿的酪氨酸激酶(BTK)抑制剂和mTOR激酶抑制剂及IMiD免疫调节药物的三合一药物组合为联合用药最佳组合之一；另外两个最佳组合的三合一药物组合分别为(2)鲁顿的酪氨酸激酶(BTK)抑制剂和mTOR激酶抑制剂及Bcl-2抑制剂；(3)鲁顿的酪氨酸激酶(BTK)抑制剂和PI3K抑制剂及Bcl-2抑制剂。其次分别为布鲁顿的酪氨酸激酶(BTK)抑制剂和mTOR激酶抑制剂的二合一药物组合、布鲁顿的酪氨酸激酶(BTK)抑制剂和免疫调节药物IMiD的二合一药物组合、布鲁顿的酪氨酸激酶(BTK)抑制剂和TOPK抑制剂的二合一药物组合、TOPK抑制剂和PI3K激酶抑制剂的二合一药物组合、布鲁顿的酪氨酸激酶(BTK)抑制剂和PI3K激酶抑制剂的二合一药物组合。
本发明显示了某些组合抑制有协同效应，某些组合没有协同效应和起相反作用。细胞分子信号通道过多并交叉而复杂，同时抑制多信号通道的组合更多更复杂。因此本发明所述三种最佳三合一组合的超强协同效应不是现有技术可推测或指导的.
本发明提供了体外细胞活力抑制和动物体内肿瘤抑制及多种肿瘤模型的结合优化筛选方法，解决了组合化合物成药性评价的难题。
本发明显示，在口服灌胃动物肿瘤模型中只有三合一的药物组合[布鲁顿的酪氨酸激酶(BTK)抑制剂、mTOR激酶抑制剂和IMiD免疫调节药物]和二合一的药物组合[布鲁顿的酪氨酸激酶(BTK)抑制剂和mTOR激酶抑制剂]的联合用药可以导致肿瘤完全消失，而且在停止给药后没有观察到肿瘤反弹生长。其他组合药物只抑制肿瘤增长，必须持续给药才能抑制肿瘤增长。虽然单药依维莫司在中高剂量也可导致肿瘤完全消失，但在停止给药后肿瘤快速反弹生长，这是靶向治疗的特征和缺陷。本发明解决了该缺陷，有望个体化治愈癌症。
本发明不仅在敏感的TMD-8肿瘤模型上验证了肿瘤抑制的卓越疗效，也在不敏感的DoHH2肿瘤模型和耐药而难治的WSU-DLCL肿瘤模型分别证明了三合一组合药物的良好疗效。虽然在该二种模型上没有导致肿瘤完全消失，三合一组合药物的疗效也是最优秀的。比如Epizyme公司论文显示在WSU-DLCL肿瘤模型上，化合物EZ-6438(组蛋白甲基转移酶 Histone Methyltransferase EZH2抑制剂)需每天给小鼠灌胃非常高剂量(每公斤480毫克)才能达到类似疗效。而本发明三合一组合药物用药仅需每天给小鼠灌胃每公斤21毫克。
本发明第一次证明多靶向联合用药具有更好的疗效，并大大降低了单一药物的剂量，因此可以进一步降低每个单药的副作用，而使联合用药更安全更有效。
本发明的多靶向联合用药不仅可用于B-细胞引起的恶性淋巴肿瘤和血癌等，也可治疗T-细胞引起的癌症及固体肿瘤等。
本发明的多靶向联合用药也可用于治疗类风湿关节炎等自身免疫疾病。
本发明还提供了含有布鲁顿的酪氨酸激酶(BTK)抑制剂、mTOR激酶抑制剂和IMiD免疫调节剂的三者作为活性成分的药物组合物。
本发明还提供了含有布鲁顿的酪氨酸激酶(BTK)抑制剂、mTOR激酶抑制剂和Bcl-2抑制剂的三者作为活性成分的药物组合物。
本发明还提供了含有布鲁顿的酪氨酸激酶(BTK)抑制剂、PI3K激酶抑制剂和Bcl-2抑制剂的三者作为活性成分的药物组合物。
本发明还提供了将通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)表示的化合物用于制备调节BTK活性、治疗或者抑制与BTK活性相关疾病的药物的用途。
本发明还提供了将通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)表示的化合物与mTOR激酶抑制剂和/或IMiD免疫调节药物联合用于制备调节BTK活性、治疗或者抑制与BTK活性相关疾病的药物的用途。
本发明还提供了将布鲁顿的酪氨酸激酶(BTK)抑制剂和mTOR激酶抑制剂和IMiD免疫调节药物的三者组合、或者其中两者组合，用于制备调节BTK活性、治疗或者抑制与BTK活性相关疾病的药物的用途。
本发明还提供了将布鲁顿的酪氨酸激酶(BTK)抑制剂和mTOR激酶抑制剂和Bcl-2抑制剂的三者组合，用于制备调节BTK活性或Bcl-2活性、治疗或者抑制与BTK或Bcl-2活性相关疾病的药物的用途。
本发明也提供了将布鲁顿的酪氨酸激酶(BTK)抑制剂和PI3K激酶抑制剂和Bcl-2抑制剂的三者组合，用于制备调节BTK活性或PI3K活性或Bcl-2活性、治疗或者抑制与BTK活性或PI3K活性或Bcl-2活性相关疾病的药物的用途。
可使用载体、赋形剂和其它通常用于药物制剂的添加剂，来制备含有一种或两种或多种通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)所示的化合物或其可药用盐作为活性成分的药物组合物。
可采用片剂、丸剂、胶囊、颗粒剂、散剂、乳剂、糖浆、混悬剂或液体制剂等的口服给药的剂型，或者采用静脉注射或肌肉注射、栓剂、皮下剂、透皮剂、经鼻剂、吸入剂等的非经口给药的剂型，来进行治疗给药。应考虑要治疗的各个患者的症状、年龄、性别等以便适当地确定化合物的剂量。通常来说，在口服给药的情况下，成人患者每日服用的化合物剂量为0.001mg/kg至100mg/kg左右，并将该剂量一次服用或分为2～4次服用。在根据症状需要采用静脉给药的情况中，通常来说，成人患者按照每次0.0001mg/kg至10mg/kg的剂量范围，每日一次至多次给药。另外，在采用吸入剂给药的情况中，通常来说，成人患者按照每次0.0001mg/kg至1mg/kg的剂量范围，每日一次至多次给药。
在本发明中，用于经口给药的固体组合物可以采用片剂、散剂、颗粒剂等剂型。在这种固体组合物中，将一种或一种以上的活性物质与至少一种惰性赋形剂(例如乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、硅酸镁铝等)混合。按照常规方法，组合物中也可以含有惰性添加剂，如润滑剂(如硬脂酸镁)、崩解剂(如羧甲基淀粉钠)和溶解助剂。根据需要，片剂或丸剂也可以被糖衣或者胃溶性或肠溶性包衣剂所包覆。
用于经口给药的液体组合物包括可药用的乳液剂、溶液制剂、混悬剂、糖浆剂、或酏剂等，并含有通常可使用的惰性稀释剂(例如纯化水、乙醇)。除所述惰性稀释剂以外，该组合物中也可以含有诸如增溶剂、润湿剂、悬浮剂之类的助剂以及甜味剂、矫味剂、芳香剂、防腐剂。
用于非经口给药的注射剂包括无菌的水性或非水性溶液制剂、混悬剂、乳剂。用于水性溶液的稀释剂可(例如)包括注射用蒸馏水和生理盐水。用于非水性溶液的稀释剂可(例如)包括丙二醇、聚乙二醇、植物油(如橄榄油)、醇类(如乙醇)和聚山梨醇酯80。这样的组合物中还可以含有诸如等渗剂、防腐剂、润湿剂、乳化剂、分散剂、稳定剂、溶解助剂之类的添加剂。可以采用通过可截留细菌的过滤器进行过滤、添加杀菌剂或进行光辐射的方法来对所述组合物进行灭菌。此外，也可以将这些组合物制成无菌的固体组合物，在使用前再用无菌水或无菌的注射用溶剂来使其溶解或混悬而使用。
诸如吸入剂和经鼻剂之类的经粘膜剂，可以以固体、液体、或半固体的状态使用，并且可以按照以往公知的方法来制备这些经粘膜剂。例如，可以根据需要而添加赋形剂(如乳糖和淀粉)、pH调节剂、防腐齐IJ、表面活性剂、润滑齐IJ、稳定剂和增稠剂等。给药时可以使用合适的吸入或吹送用装置。例如，可以使用计量给药吸入装置等公知的装置或喷雾器，将化合物单独地或作为配方后的混合物粉末来给药。此外，也可以将化合物与可药用的载体组合后，作为溶液或混悬液来给药。干燥粉末吸入器等可以用于单次给药或多次给药， 并可以使用干燥粉末或含有粉末的胶囊。另外，也可以采用加压气溶胶喷雾等形式，通过使用适当的抛射剂(例如，氯氟烷烃、氢氟烷烃、或二氧化碳等适当的气体)来给药。
表1.BTK抑制剂的化合物
Figure PCTCN2016000149-appb-000009
Figure PCTCN2016000149-appb-000010
注：如果在画出的结构和给出的该结构的名称之间有差异，则以画出的结构为准。
附图说明
图1-A.化合物1和3多剂量在SCID小鼠体内TMD-8模型中的肿瘤体积抑制作用
图1-B.化合物1和3多剂量在SCID小鼠体内TMD-8模型中的肿瘤重量抑制作用
图2.化合物3和15及联合用药在SCID小鼠体内TMD-8肿瘤模型中的抗肿瘤作用
图3.化合物3、8、15及联合用药在SCID小鼠体内TMD-8肿瘤模型中的抗肿瘤作用
图4.化合物3、14、16及联合用药在SCID小鼠体内TMD-8肿瘤模型中的抗肿瘤作用
图5.化合物3、14、15及联合用药在SCID小鼠体内TMD-8肿瘤模型中的抗肿瘤作用
图6.化合物3、14、15及联合用药在SCID小鼠体内DoHH-2肿瘤模型中的抗肿瘤作用
图7.化合物3、14、15及联合用药在SCID小鼠体内DoHH-2肿瘤模型中的抗肿瘤作用
图8.化合物3和9在耐药性的WSU-DLCL2肿瘤模型中的抗肿瘤作用
图9.化合物3、14、15及联合用药在SCID小鼠体内耐药性的WSU-DLCL2肿瘤模型中的抗肿瘤作用
图10.化合物3、14和15的“三合一”联合用药在小鼠体内TMD-8肿瘤模型中的抗肿瘤作用
图11.化合物3、14、15与化合物9、14、15的“三合一”联合用药在小鼠体内DoHH2肿瘤模型中的抗肿瘤作用
图12.化合物3、8、12及“二合一”或“三合一”联合用药在小鼠体内TMD-8肿瘤模型中的抗肿瘤作用
图13.足体积--佐剂诱发关节炎
图14.病理组织切片--佐剂诱发关节炎
图15.临床评分--胶原诱导性关节炎
图16.病理组织切片--胶原诱导性关节炎
实施例1
化合物1和2
Figure PCTCN2016000149-appb-000011
1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-三氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮
Figure PCTCN2016000149-appb-000012
1-[(S)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-三氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮
步骤A：
Figure PCTCN2016000149-appb-000013
3-(4-溴-3-氟苯氧基)-1，2，4，5-四氟苯
操作步骤：
向化合物3-氟-4-溴苯酚(47.0g，246.1mmol，1.0eq.)的DMF(500mL)溶液中加入碳酸钾(68.0g，492.1mmol，2.0eq.)和化合物1，2，3，4，5-五氟苯(49.6g，295.3mmol，1.2eq.)。反应液在100℃搅拌12小时，减压蒸除溶剂。将残余物溶于乙酸乙酯(300mL)中，用水(100mL)洗两次，饱和食盐水(100mL)洗一次。有机相用无水硫酸钠干燥，浓缩旋干得到目标化合物(78g，收率：93％)。
步骤B：
Figure PCTCN2016000149-appb-000014
2-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷
操作步骤：
将化合物3-(4-溴-3-氟苯氧基)-1，2，4，5-四氟苯(73g，215.3mmol，1.0eq.)，双联频哪醇硼酸酯(65.6g，258.4mmol，1.2eq.)，醋酸钾(31.6g，322.9mmol，1.5eq.)和[1，1′-双(二苯基磷)二茂铁]二氯化钯(9.4g，12.8mmol，0.06eq.)溶于1，4-二氧六环(1L)中，反应液在80℃，并在氮气保护下搅拌14小时。冷却至室温后，反应液用硅藻土过滤，滤液旋干，得到的粗品用硅胶柱层析纯化分离(展开剂：石油醚)得到目标化合物(60g，收率：72％)。
步骤C：
Figure PCTCN2016000149-appb-000015
3-碘-1H-吡唑并[3，4-d]嘧啶-4-胺
操作步骤：
向1H-吡唑并[3，4-d]嘧啶-4-胺(100g，0.74mol，1.0eq.)的DMF(800mL)溶液中加入NIS(250g，1.11mol，1.5eq.)。反应液在氮气保护下在80～85℃搅拌16小时。反应液过滤，滤饼用乙醇洗涤三次，每次1000mL，得到目标化合物(184g，收率：95％)。
步骤D：
Figure PCTCN2016000149-appb-000016
3-(甲基磺酰氧基)哌啶-1-甲酸叔丁酯
操作步骤：
在0℃下向3-羟基哌啶-1-甲酸叔丁酯(10.0g，50mmol，1.0eq.)的二氯甲烷(100mL)溶液中依次滴加三乙胺(15g，150mmol，3.0eq.)和甲基磺酰氯(6.3g，55mmol，1.1eq.)。反应液在20℃搅拌1小时，加入饱和NaHCO3(100mL)，然后用二氯甲烷(200mL)萃取三次。有机相用无水硫酸钠干燥，浓缩旋干得到目标化合物(13g，收率：95％)。
步骤E：
Figure PCTCN2016000149-appb-000017
3-(4-氨基-3-碘-1H-吡唑并[3，4-d]-嘧啶-1-基)哌啶-1-甲酸叔丁酯
操作步骤：
在0℃下向3-碘-1H-吡唑并[3，4-d]-嘧啶-4-胺(8.1g，31mmol，1.0eq.)的DMF(50mL)溶液中加入碳酸铯(20.2g，62mmol，2.0eq.)和3-(甲基磺酰氧基)哌啶-1-甲酸叔丁酯(13g，46.5mmol，1.5eq.)。反应液在80℃搅拌过夜，用硅藻土过滤，浓缩旋干，得到的粗品用硅胶柱层析纯化分离(洗脱剂：乙酸乙酯)得到目标化合物(5g，收率：25％)。
步骤F：
Figure PCTCN2016000149-appb-000018
3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]哌啶-1-甲酸叔丁酯
操作步骤：
将化合物3-(4-氨基-3-碘-1H-吡唑并[3，4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(7.6g，17.1mmol，1.0eq.)，2-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷(8.6g，22.3mmol，1.3eq.)，磷酸钾(7.3g，34.2mmol，2.0eq.)和Pd-118(0.56g，0.855mmol，0.05eq.)溶于1，4-二氧六环/水(240mL，5∶1，v/v)中。反应在氮气保护下，在60℃反应12小时。冷却至室温后，将反应液倾入冰水(300mL)中，然后用乙酸乙酯(100mL)萃取四次。合并的有机相用无水硫酸钠干燥，浓缩旋干，得到的粗品用硅胶柱层析纯化分离(展开剂：乙酸乙酯)得到目标化合物(6.8g，收率：69％)。
步骤G：
Figure PCTCN2016000149-appb-000019
3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-(哌啶-3-基)-1H-吡唑并[3，4-d]嘧啶-4-胺
操作步骤：
在0℃下向3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]哌啶-1-甲酸叔丁酯(6.8g，11.8mmol)的乙酸乙酯(50mL)溶液中加入HCl/EA(20mL，4mol/L)。反应液在室温下搅拌1小时，浓缩旋干得到目标化合物的盐酸盐(5.2g，收率：86％)。
步骤H：
Figure PCTCN2016000149-appb-000020
1-[3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮
操作步骤：
在0℃下向3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-(哌啶-3-基)-1H-吡唑并[3，4-d]嘧啶-4-胺(1.5g，2.9mmol，1.0eq.)的二氯甲烷(10mL)溶液中依次滴加三乙胺(887mg，8.7mmol，3.0eq.)和丙烯酰氯(0.26g，2.9mmol，1.0eq.)。反应液在0℃搅拌1小时，用水(5mL)淬灭，然后用二氯甲烷(50mL)稀释，水(30mL)洗两次，饱和食盐水(30mL)洗一次。有机相用无水硫酸钠干燥，浓缩旋干，所得粗品用硅胶柱层析分离纯化(洗脱剂：石油醚∶乙酸乙酯＝1∶0～1∶1)得到目标化合物(0.94g，收率：64％)。
光谱数据：
LC/MS(方法：UFLC)：RT＝3.130分钟；m/z＝531.1[M+H]+；总的运行时间为7分钟。
1H NMR(400MHz，DMSO-d6)δ8.22(s，1H)，8.00-7.91(m，1H)，7.55-7.46(m，1H)，7.27(dd，J＝2.4，10.8Hz，1H)，7.12(dd，J＝2.4，8.8Hz，1H)，6.88-6.65(m，1H)，6.13-6.02(m，1H)，5.70-5.56(m，1H)，4.71-4.65(m，1H)，4.54-4.51(m，0.5H)，4.20-4.17(m，1H)，4.07-4.04(m，0.5H)，3.67-3.60(m，0.5H)，3.17-3.12(m，1H)，2.98-2.94(m，0.5H)，2.26-2.21(m，1H)，2.11-2.06(m，1H)，1.92-1.89(m，1H)，1.58-1.54(m，1H).
步骤I：
Figure PCTCN2016000149-appb-000021
1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-三氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮
Figure PCTCN2016000149-appb-000022
1-[(S)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-三氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮
操作步骤：
将化合物1-[3-[4-氨基-3-[2-氟-4-(2，3，5，6-三氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮(750mg)进行手性SFC分离(Chiralcel OJ，20μm；Supercritical CO2：C2H5OH(0.2％DEA)，v/v，200ml/min)得到目标化合物1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-三氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮(280mg，ee：100％)和1-[(S)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-三氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮(330mg，ee：98％)。
光谱数据：
化合物1：
LC/MS(方法：UFLC)：RT＝3.002分钟；m/z＝531.1[M+H]+；总的运行时间为7分钟。
1H NMR(400MHz，CDCl3)δ8.36(s，1H)，7.58(t，J＝8.4Hz，1H)，7.09-7.04(m，1H)，6.94-6.88(m，2H)，6.62-6.54(m，1H)，6.32-6.25(m，1H)，5.73-5.63(m，1H)，5.56-5.51(m，1H)，4.90-4.85(m，1.5H)，4.59-4.56(m，0.5H)，4.21-4.17(m，0.5H)，4.04-4.01(m，0.5H)，3.76-3.71(m，0.5H)，3.40-3.35(m，0.5H)，3.22-3.15(m，0.5H)，2.93-2.87(m，0.5H)，2.39-2.27(m，2H)，2.04-1.68(m，2H).
化合物2：
LC/MS(方法：UFLC)：RT＝3.006分钟；m/z＝531.1[M+H]+；总的运行时间为7分钟。
1H NMR(400MHz，CD3OD)δ8.24(s，1H)，7.62(t，J＝8.4Hz，1H)，7.50-7.45(m，1H)，7.09-7.01(m，2H)，6.85-6.63(m，1H)，6.21-6.09(m，1H)，5.77-5.61(m，1H)，4.63-4.59(m，1H)，4.23-4.07(m，1.5H)，3.90-3.85(m，0.5H)，3.51-3.45(m，0.5H)，3.34-3.17(m，1.5H)，2.40-2.23(m，2H)，2.08-2.05(m，1H)，1.75-1.71(m，1H).
实施例2
化合物3
Figure PCTCN2016000149-appb-000023
1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮
方法一：
步骤A：
Figure PCTCN2016000149-appb-000024
(R)-3-(4-氨基-3-碘-1H-吡唑并[3，4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯
操作步骤：
在0℃并在氮气保护下，向化合物3-碘-1H-吡唑并[3，4-d]嘧啶-4-胺(24g，92mmol，1.0eq.)，化合物(S)-3-羟基-吡咯烷-1-甲酸叔丁酯(26g，137.5mmol，1.5eq)和PPh3(36g，137.5mmol，1.5eq.)的四氢呋喃(720mL)溶液中滴加DIAD(27.6g，137.5mmol，1.5eq.)。反应液在0℃搅拌1小时，然后在室温下搅拌过夜。减压蒸除溶剂，向反应瓶中加入乙腈(200mL)，然后室温下搅拌2小时，过滤，滤饼用乙腈(20mL)洗涤，干燥得到目标化合物(25g，收率：63％)。
步骤B：
Figure PCTCN2016000149-appb-000025
(3R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]吡咯烷-1-甲酸叔丁酯
操作步骤：
将化合物(R)-3-(4-氨基-3-碘-1H-吡唑并[3，4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯(25g，58mmol，1.0eq.)，化合物2-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷(30g，75.4mmol，1.3eq.)，磷酸钾(25g，116mmol，2.0eq.)和Pd-118(750mg，1.16mmol，0.02eq.)溶于1，4-二氧六环/水(600mL，5∶1，v/v)中。反应液在氮气保护下，在60℃搅拌过夜。冷却至室温后，用硅藻土过滤。滤液浓缩旋干，向剩余物中加入水(300mL)，然后用乙酸乙酯萃取三次，每次300mL。合并的有机相用无水硫酸钠干燥，浓缩旋干得到目标化合物(60g，粗品)。
步骤C：
Figure PCTCN2016000149-appb-000026
3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-[(R)-吡咯烷-3-基]-1H-吡唑并[3，4-d]嘧啶-4-胺
操作步骤：
在0℃下向(3R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]吡咯烷-1-甲酸叔丁酯(60g，粗品)的乙酸乙酯(100mL)溶液中加入HCl/EA(100mL，4mol/L)。反应液在室温下搅拌1小时，浓缩旋干得到目标化合物的盐酸盐。向反应瓶中加入水(500mL)，用乙酸乙酯萃取三次，每次300mL。水相调节pH＝9，用乙酸乙酯萃取三次，每次300mL。合并的有机相用无水硫酸钠干燥，浓缩旋干得到目标化合物(24g，两步收率：90％)。
步骤D：
Figure PCTCN2016000149-appb-000027
1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮
操作步骤：
在-5℃下向3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-[(R)-吡咯烷-3-基]-1H-吡唑并[3，4-d]嘧啶-4-胺(23.5g，50.75mmol，1.0eq.)的四氢呋喃(470mL)溶液中加入NaOH(10％，94mL)，然后滴加丙烯酰氯(5.97g，66mmol，13eq.)。反应液在-5℃搅拌1小时，用饱和食盐水(100mL)淬灭，用乙酸乙酯萃取三次，每次200mL。合并的有机相用无水硫酸钠干燥，浓缩旋干，得到的粗品用硅胶柱层析分离纯化(洗脱剂：石油醚∶乙酸乙酯＝1∶3～1∶ 1)，得到产品溶于甲醇(500mL)，过滤。向搅拌的滤液中加水(1500mL)，然后搅拌2小时，过滤，滤饼减压干燥得到目标化合物3(16.5g，收率：63％)。
光谱数据：
LC/MS(方法：UFLC)：RT＝3.764分钟；m/z＝517.0[M+H]+；总的运行时间为7分钟。
1H NMR(400MHz，CD3OD)δ8.45(s，1H)，7.70(t，J＝8.4Hz，1H)，7.55-7.46(m，1H)，7.12-7.05(m，2H)，6.70-6.55(m，1H)，6.33-6.26(m，1H)，5.81-5.75(m，1H)，4.23-3.83(m，5H)，2.68-2.55(m，2H).
方法二：
操作步骤：
在0℃下向3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-[(R)-吡咯烷-3-基]-1H-吡唑并[3，4-d]嘧啶-4-胺(1.0g，2.16mmol，1.0eq.)的四氢呋喃(50mL)和水(10mL)溶液中加入NaOH(216mg，5.40mmol，2.5eq.)，然后滴加氯丙酰氯(288mg，2.27mmol，1.05eq.)的四氢呋喃溶液(10mL)。反应液在0℃搅拌1小时，然后升温至60℃搅拌12小时。冷却至室温后加饱和食盐水(10mL)，用乙酸乙酯萃取三次，每次50mL。合并的有机相用无水硫酸钠干燥，浓缩旋干，得到的粗品用硅胶柱层析分离纯化(洗脱剂：石油醚∶乙酸乙酯＝1∶3～1∶1)得到目标化合物3(0.8g，收率：71％)。
方法三：
操作步骤：
将化合物(R)-[3-(4-氨基-3-碘-1H-吡唑并[3，4-d]嘧啶-1-基)-1-吡咯烷基]-2-丙烯-1-酮(100g，0.26mmol，1.0eq.)，化合物2-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷(120mg，0.31mmol，1.2eq.)，碳酸钠(55mg，0.52mmol，2.0eq.)和Pd(PPh3)4(30mg，0.026mmol，0.01eq.)溶于1，4-二氧六环/水(5mL，1∶1，v/v)中。反应液在微波照射下在80℃搅拌30分钟。冷却至室温后，用硅藻土过滤。滤液浓缩旋干，得到的粗品采用高效液相色谱在C18反相柱上分离(流动相：乙腈/水/0.5％HCl，梯度洗脱10％至100％(体积比))，减压蒸除易挥发的组分后冻干得到目标化合物(38mg，产率：28％)。
方法四：
化合物3和化合物4
Figure PCTCN2016000149-appb-000028
1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮
Figure PCTCN2016000149-appb-000029
1-[(S)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮
步骤A：
Figure PCTCN2016000149-appb-000030
3-(甲基磺酰氧基)吡咯烷-1-甲酸叔丁酯
操作步骤：
在0℃下向3-羟基吡咯烷-1-甲酸叔丁酯(30.0g，163mmol，1.0eq.)的二氯甲烷(200mL)溶液中依次滴加三乙胺(35g，346mmol，2.1eq.)和甲基磺酰氯(36.6g，321mmol，1.9eq.)。反应液在0℃搅拌3小时，用水(20mL)淬灭，然后用水(100mL)洗两次，饱和食盐水(100mL)洗一次。有机相用无水硫酸钠干燥，浓缩旋干得到目标化合物(45.6g，收率：100％)。
步骤B：
Figure PCTCN2016000149-appb-000031
3-(4-氨基-3-碘-1H-吡唑并[3，4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯
操作步骤：
向化合物3-(甲基磺酰氧基)吡咯烷-1-甲酸叔丁酯(35g，134mmol，3.5eq.)的DMF(300mL)溶液中加入碳酸铯(37g，115mmol，3.0eq.)和化合物3-碘-1H-吡唑并[3，4-d]嘧啶-4-胺(10g，38mmol，1.0eq.)。反应液在85℃搅拌12小时，冷却至室温后过滤。滤液浓缩旋干，所得粗品用硅胶柱层析纯化分离(洗脱剂：石油醚∶乙酸乙酯＝1∶1)得到目标化合物(7.0g，收率：44％)。
步骤C：
Figure PCTCN2016000149-appb-000032
3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]吡咯烷-1-甲酸叔丁酯
操作步骤：
将化合物3-(4-胺-3-碘-1H-吡唑并[3，4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯(8g，18mmol，1.0eq.)，2-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷(10.7g，27mmol，1.5eq.)，磷酸钾(7.6g，36mmol，2.0eq.)和Pd-118(1.2g，1.8mmol，0.1eq.)溶于1，4-二氧六环/水(180mL，5∶1，v/v)中。反应在氮气保护下，在60℃搅拌14小时。冷却至室温后，将反应液倾入冰水(50mL)中，用乙酸乙酯(100mL)萃取三次。合并的有机相用无水硫酸钠干燥，浓缩旋干，得到的粗品用硅胶柱层析分离纯化(洗脱剂：乙酸乙酯∶石油醚＝1∶1)得到目标化合物(2.5g，收率：25％)。
步骤D：
Figure PCTCN2016000149-appb-000033
3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-(吡咯烷-3-基)-1H-吡唑并[3，4-d]嘧啶-4-胺
操作步骤：
在0℃下向3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]吡咯烷-1-甲酸叔丁酯(2.5g，4.4mmol)的二氯甲烷(20mL)溶液中加入HCl/EA(20mL，4mol/L)。反应液在室温下搅拌1小时，浓缩旋干得到目标化合物的盐酸盐(2.2g，收率：100％)。
步骤E：
Figure PCTCN2016000149-appb-000034
1-[3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮
操作步骤：
在0℃下向3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-(吡咯烷-3-基)-1H-吡唑并[3，4-d]嘧啶-4-胺(2.2g，4.4mmol，1.0eq.)的二氯甲烷(50mL)溶液中依次滴加三乙胺(1.4g，12.8mmol，3.0eq.)和丙烯酰氯(0.38g，4.2mmol，0.95eq.)。反应液在0℃搅拌1小时，用水(30mL)淬灭，分液，水相用二氯甲烷(30mL)萃取三次。合并的有机相用无水硫酸钠干燥，浓缩旋干，得到的粗品用硅胶柱层析纯化分离(洗脱剂：乙酸乙酯)得到目标化合物(1.0g，收率：45％)。
光谱数据：
LC/MS(方法：UFLC)：RT＝2.810分钟；m/z＝517.1[M+H]+；总的运行时间为7分钟。
步骤F：
Figure PCTCN2016000149-appb-000035
1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮
Figure PCTCN2016000149-appb-000036
1-[(S)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮
操作步骤：
化合物1-[3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]吡咯烷-1-基]丙-2-烯-1-酮通过SFC手性拆分得到化合物3(270mg)和化合物4(320mg)。
光谱数据：
LC/MS(方法：UFLC)：RT＝2.808分钟；m/z＝517.1[M+H]+；总的运行时间为7分钟。
实施例3
化合物5
Figure PCTCN2016000149-appb-000037
1-[(R)-3-[4-氨基-3-[2-氟-4-(3-氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-2-丙烯-1-酮
步骤A：
Figure PCTCN2016000149-appb-000038
1-(3-氟-4-溴苯氧基)-3-硝基苯
操作步骤：
向化合物3-氟-4-溴苯酚(40g，210mmol，1.0eq.)的DMF(400mL)溶液中加入1-氟-3硝基苯(29.6g，210mmol，1.0eq.)和碳酸钾(58g，420mmol，2.0eq.)。反应液在氮气保护下并在90℃搅拌12小时，减压蒸除溶剂。向剩余物中加水(300mL)然后用乙酸乙酯(300mL)萃取三次。合并的有机相用无水硫酸钠干燥，浓缩旋干得到目标化合物(65g，收率：100％)。
步骤B：
Figure PCTCN2016000149-appb-000039
3-(3-氟-4-溴苯氧基)苯胺
操作步骤：
向化合物1-(3-氟-4-溴苯氧基)-3-硝基苯(65g，210mmol，1.0eq.)的乙醇(300mL)和水(60mL)溶液中加入氯化铵(28g，525mmol，2.5eq.)和铁粉(58.8g，1.05mol，5.0eq.)。反应液在氮气保护下回流搅拌12小时，冷却至室温后用硅藻土过滤，滤液浓缩旋干，得到的粗品采用高效液相色谱在C18反相柱上分离(流动相：乙腈/水/0.7％NH4HCO3，梯度 洗脱10％至100％(体积比))，减压蒸除易挥发的组分后冻干得到目标化合物(19g，产率：23％)。
步骤C：
Figure PCTCN2016000149-appb-000040
1-溴-2-氟-4-(3-氟苯氧基)苯
操作步骤：
在-10℃向吡啶-氟化氢溶液(30mL)中分批加入化合物3-(3-氟-4-溴苯氧基)苯胺(9g，32mmol，1.0eq.)。所得反应液在0℃搅拌30分钟，然后冷却在-10℃分批加入亚硝酸钠(2.42g，35mmol，1.1eq.)。反应液在20℃搅拌30分钟，然后在60℃搅拌14小时。冷却至室温后，将反应液倾入冰-乙醇(50mL)中，加入NaHCO3饱和溶液(50mL)，然后用乙酸乙酯(50mL)萃取三次，合并的有机相用无水硫酸钠干燥，浓缩旋干，得到的粗品用硅胶柱层析分离纯化(洗脱剂：石油醚)得到目标化合物(5.8g，产率：64％)。
步骤D：
2-[2-氟-4-(3-氟苯氧基)苯基]-4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷
操作步骤：
将化合物1-溴-2-氟-4-(3-氟苯氧基)苯(5.8g，20mmol，1.0eq.)，双联频哪醇硼酸酯(6.1g，24mmol，1.2eq.)，醋酸钾(3.9g，40mmol，2.0eq.)和[1，1′-双(二苯基磷)二茂铁]二氯化钯(0.89g，1.2mmol，0.06eq.)溶于1，4-二氧六环(100mL)中，反应液在85℃，并在氮气保护下搅拌14小时。冷却至室温后，反应液用硅藻土过滤，滤液旋干，得到的粗品用硅胶柱层析纯化分离(洗脱剂：石油醚)得到目标化合物(6.5g，收率：100％)。
步骤E：
Figure PCTCN2016000149-appb-000042
(3R)-3-[4-氨基-3-[2-氟-4-(3-氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]吡咯烷-1-甲酸叔丁酯
操作步骤：
将化合物3-(4-氨基-3-碘-1H-吡唑并[3，4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯(6.5g，15.0mmol，1.0eq.)，化合物2-[2-氟-4-(3-氟苯氧基)苯基]-4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷(6.5g，19.6mmol，1.3eq.)，磷酸钾(6.4g，30.1mmol，2.0eq.)和Pd-118(0.25g，0.39mmol，0.01eq.)溶于1，4-二氧六环/水(16mL，1∶1，v/v)中。反应液在氮气保护下，在85℃搅拌12小时。冷却至室温后，反应液用水(50mL)稀释，然后用乙酸乙酯(100mL)萃取三次。合并的有机相用无水硫酸钠干燥，浓缩旋干，得到的粗品采用硅胶柱层析分离纯化(洗脱剂：乙酸乙酯)得到目标化合物(4.2g，产率：55％)。
步骤F：
Figure PCTCN2016000149-appb-000043
3-[2-氟-4-(3-氟苯氧基)苯基]-1-[(R)-吡咯烷-3-基]-1H-吡唑并[3，4-d]嘧啶-4-胺
操作步骤：
在0℃下向(3R)-3-[4-氨基-3-[2-氟-4-(3-氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]吡咯烷-1-甲酸叔丁酯(4.2g，8.27mmol)的二氯甲烷(15mL)溶液中加入HCl/EA(10mL，4mol/L)。反应液在室温下搅拌1小时，浓缩旋干得到目标化合物的盐酸盐(3.7g，收率：92％)。
步骤G：
Figure PCTCN2016000149-appb-000044
1-[(R)-3-[4-氨基-3-[2-氟-4-(3-氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶 -1-基]-1-吡咯烷基]-2-丙烯-1-酮
操作步骤：
在0℃下向3-[2-氟-4-(3-氟苯氧基)苯基]-1-[(R)-吡咯烷-3-基]-1H-吡唑并[3，4-d]嘧啶-4-胺(3.7g，8.27mmol，1.0eq.)的四氢呋喃(20mL)溶液中依次滴加氢氧化钠溶液(10％，15.3mL)和丙烯酰氯(0.67g，7.44mmol，0.9eq.)。反应液在室温下搅拌10分钟，用饱和NaHCO3(20mL)淬灭，用二氯甲烷(30mL)萃取三次。合并的有机相用无水硫酸钠干燥，浓缩旋干，得到的粗品采用硅胶柱层析分离纯化(洗脱剂：石油醚∶乙酸乙酯＝1∶0～1∶1)得到目标化合物(2.5g，产率：65％)。
光谱数据：
LC/MS(方法：UFLC)：RT＝3.178分钟；m/z＝463.0[M+H]+；总的运行时间为7分钟。
1H NMR(400MHz，CDCl3)δ8.36(s，1H)，7.53-7.49(m，1H)，7.40-7.35(m，1H)，6.95-6.81(m，4H)，6.41-6.39(m，2H)，5.69-5.55(m，3H)，4.14-3.98(m，3H)，3.78-3.72(m，1H)，2.71-2.54(m，2H).
实施例4
化合物6
Figure PCTCN2016000149-appb-000045
(E)-1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-3-氘-2-丙烯-1-酮
步骤A：
Figure PCTCN2016000149-appb-000046
(E)-3-溴丙烯酸
操作步骤：
化合物丙炔酸(1g，14.28mmol，1.0eq.)和HBr(40％水溶液，1.7mL，0.88eq.)的混合液在140℃搅拌过夜。减压蒸除溶剂，所得粗品用水结晶三次，每次4mL，得到目标化合物(0.76g，产率：35％)。
光谱数据：
1H NMR(400MHz，CDCl3)δ7.76(d，J＝14Hz，1H)，6.55(d，J＝14Hz，1H).
步骤B：
Figure PCTCN2016000149-appb-000047
(E)-3-氘丙烯酸
操作步骤：
在0～5℃下向化合物(E)-3-溴丙烯酸(3g，19.87mmol，1.0eq.)的D2O(30mL)中加入Na-Hg(6g，49.67mmol，2.5eq.)。反应液在室温下搅拌36小时。分液，水相用1M的盐酸调pH＝5，然后用乙醚萃取五次，每次20mL。合并的有机相用无水硫酸钠干燥，减压蒸除溶剂得到目标化合物(0.52g，产率：36％)。
光谱数据：
1H NMR(400MHz，CDCl3)δ7.76(d，J＝17.2Hz，1H)，6.55(d，J＝17.2Hz，1H).
步骤C：
Figure PCTCN2016000149-appb-000048
(E)-1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-3-氘-2-丙烯-1-酮
操作步骤：
向化合物3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-[(R)-吡咯烷-3-基]-1H-吡唑并[3，4-d]嘧啶-4-胺(500mg，1.08mmol，1.0eq.)的二氯甲烷(50mL)溶液中加入(E)-3-氘丙烯酸(76mg，1.08mmol，1.0eq.)，HATU(530mg，1.40mmol，1.3eq.)和N，N-二异丙基乙胺(419mg， 3.24mmol，3.0eq.)。反应液在室温下搅拌12小时，浓缩旋干，得到的粗品采用高效液相色谱在C18反相柱上分离(仪器：LC 8A&Gilson 215，组分收集柱：Synergi Max-RP150*30mm*4u，流动相A：水(0.5％HCl)，流动相B：乙腈，流速：30mL/min，梯度：B36％至37％，0-17分钟)，减压蒸除易挥发的组分后冻干得到目标化合物盐酸盐(76mg，产率：13％)。
光谱数据：
LC/MS(方法：UFLC)：RT＝2.765分钟；m/z＝518.1[M+H]+；总的运行时间为7分钟。
1H NMR(400MHz，CD3OD)δ8.41(s，1H)，7.66(t，J＝8.4Hz，1H)，7.51-7.44(m，1H)，7.09-7.01(m，2H)，6.66-6.56(m，1H)，6.28-6.23(m，1H)，5.75-5.66(m，1H)，4.19-4.16(m，1H)，4.06-4.02(m，1.5H)，3.89-3.85(m，1H)，3.78-3.72(m，0.5H)，2.63-2.49(m，2H).
实施例5
化合物7
Figure PCTCN2016000149-appb-000049
(Z)-1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-3-氘-2-丙烯-1-酮
步骤A：
Figure PCTCN2016000149-appb-000050
(Z)-3-溴丙烯酸
操作步骤：
化合物丙炔酸(1g，14.28mmol，1.0eq.)和HBr(40％水溶液，1.7mL，0.88eq.)的混合液在55℃搅拌过夜。减压蒸除溶剂，所得粗品用石油醚结晶三次，每次4mL，得到目标化合物(0.3g，产率：14％)。
光谱数据：
1H NMR(400MHz，CDCl3)δ7.16(d，J＝8.4Hz，1H)，6.67(d，J＝8.4Hz，1H).
步骤B：
Figure PCTCN2016000149-appb-000051
(Z)-3-氘丙烯酸
操作步骤：
在0～5℃下向化合物(Z)-3-溴丙烯酸(3g，19.87mmol，1.0eq.)的D2O(30mL)中加入Na-Hg(6g，49.67mmol，2.5eq.)。反应液在室温下搅拌36小时。分液，水相用1M的盐酸调pH＝5，然后用乙醚萃取五次，每次20mL。合并的有机相用无水硫酸钠干燥，减压蒸除溶剂得到目标化合物(0.34g，产率：23％)。
光谱数据：
1H NMR(400MHz，CDCl3)δ6.14(d，J＝10.4Hz，1H)，5.96(d，J＝10.4Hz，1H).
步骤C：
Figure PCTCN2016000149-appb-000052
(Z)-1-[(R)-3-[4-氨基-3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]-3-氘-2-丙烯-1-酮
操作步骤：
向化合物3-[2-氟-4-(2，3，5，6-四氟苯氧基)苯基]-1-[(R)-吡咯烷-3-基]-1H-吡唑并[3，4-d]嘧啶-4-胺(1.0g，2.16mmol，1.0eq.)的二氯甲烷(50mL)溶液中加入(Z)-3-氘丙烯酸(151mg，2.16mmol，1.0eq.)，HATU(1.06g，2.80mmol，1.3eq.)和N，N-二异丙基乙胺(838mg，6.48mmol，3.0eq.)。反应液在室温下搅拌12小时，浓缩旋干，得到的粗品采用高效液相色谱在C18反相柱上分离(流动相：乙腈/水/0.5％HCl，梯度洗脱36％至37％(体积比))，减压蒸除易挥发的组分后冻干得到目标化合物盐酸盐(228mg，产率：20％)。
光谱数据：
LC/MS(方法：UFLC)：RT＝2.775分钟；m/z＝518.1[M+H]+；总的运行时间为7分钟。
1H NMR(400MHz，CD3OD)δ8.45(s，1H)，7.70(t，J＝8.4Hz，1H)，7.52-7.46(m，1H)，7.13-7.05(m，2H)，6.71-6.61(m，1H)，5.80-5.73(m，2H)，4.23-4.20(m，1H)，4.09-4.04(m，1.5H)，3.93-3.90(m，1H)，3.80-3.75(m，0.5H)，2.67-2.56(m，2H).
实施例6
化合物7x
Figure PCTCN2016000149-appb-000053
1-[(R)-3-[4-氨基-3-[2-氟-4-(3-氟苯氧基)苯基]-1H-吡唑并[3，4-d]嘧啶-1-基]-1-吡咯烷基]丁-2-炔-1-酮
操作步骤：
向3-[2-氟-4-(3-氟苯氧基)苯基]-1-[(R)-吡咯烷-3-基]-1H-吡唑并[3，4-d]嘧啶-4-胺(200.00mg，489.72umol，1.00eq.)的二氯甲烷(5.0mL)溶液中依次加入丁-2炔酸(41.17mg，489.72umol，1.00eq.)HATU(93.10mg，244.86umol，0.50eq.)和DIPEA(75.95mg，587.66umol，102.64uL，1.20eq.)。反应液在15-18℃搅拌2小时，浓缩旋干。得到的粗品采用高效液相色谱在C18反相柱上分离(流动相：乙腈/水/0.5％HCl，梯度洗脱22％至52％(体积比))，减压蒸除易挥发的组分后冻干得到目标化合物盐酸盐(82mg，产率：33％)。
光谱数据：
LC/MS(方法：UFLC)：RT＝3.057分钟；m/z＝475.0[M+H]+；总的运行时间为7分钟。
1H NMR(400MHz，CDCl3)δ9.92(s，1H)，8.34(d，J＝8.8Hz，1H)，7.56(br，1H)，7.41-7.36(m，1H)，7.00-6.86(m，5H)，6.58(br，1H)，5.62-5.58(m，1H)，4.22-3.74(m，4H)，2.65-2.50(m，2H)，2.02-1.96(m，3H).
生物体外实验部分
BTK激酶活性抑制实验：
BTK野生型激酶标准HTRF实验的酶反应液组成为1nM BTK野生型激酶，1μM生物素-TK1多肽，30μMATP和50mM HEPES(pH值7.5)缓冲液。混合物在室温下孵育60分钟后，加入EDTA将反应停止。然后将抑制剂(5L)中加入终浓度为2nM抗体和62.5nM的XL665。将板在室温下孵育60分钟后使用Envision多标记微孔板检测仪读取实验结果。检测数据通过公式(Min Ratio)/(Max-Min)*100％转化为抑制百分率(％)，随后通过四个参数曲线拟合得到测试化合物的IC50值。
体外肿瘤细胞活力抑制实验：
肿瘤细胞(TMD-8，DoHH2和WSU-DLCL2)转移并附着到96孔板。过夜后，加入空白对照缓冲液和选择浓度(0.01nM-100μM)的测试化合物溶液。在48小时温育后，再加入CellTiter-Go试剂裂解细胞。记录发光信号并计算细胞活力的抑制百分比。
动物实验方法
鼠药代实验：雄性SD大鼠24小时内的药物代谢动力学试验共分为静脉和口服两组，每组3只动物.静脉组取血时间点为给药前，给药后0.0833，0.167，0.5，1，2，4，8，24小时；口服组取血时间点为给药前，给药后0.167，0.5，1，2，4，8，24小时。采血完毕后，利用HPLC-MS/MS进行生物分析，报告化合物的血药浓度.计算出的药物代谢动力学参数为静脉组动物的平均清除率(Clp)，平均表观分布容积(Vdss)，0-24h曲线下分布面积(AUC)，0-24小时的平均滞留时间(MRT)，半衰期T1/2；口服组动物在给药后的平均最大药物浓度(Cmax)，0-24h曲线下分布面积(AUC)，0-24小时的平均滞留时间(MRT)；本次试验的平均相对生物利用度。
犬药代实验：比格犬24小时内的药物代谢动力学试验共分为静脉(每公斤1毫克)和口服(每公斤3毫克)两组，每组3只动物.静脉组取血时间点为给药前，给药后0.033，0.083，0.25，0.5，1，3，6，9，24小时；口服组取血时间点为给药前，给药后0.083，0.25，0.5，1，3，6，9，24小时。采血完毕后，利用HPLC-MS/MS进行生物分析，报告化合物的血药浓度.计算出的药物代谢动力学参数为静脉组动物的平均清除率(Clp)，平均表观分布容积(Vdss)，0-24h曲线下分布面积(AUC)，0-24小时的平均滞留时间(MRT)，半衰期T1/2；口服组动物在给药后的平均最高药物浓度(Cmax)，0-24h曲线下分布面积(AUC)，0-24小时的平均滞留时间(MRT)；平均相对生物利用度。
单药及联合用药在动物体内TMD-8，DoHH2或WSU-DLCL2肿瘤模型中的抑制作用：
实验结果显示，联合给药具有协同药效作用，对敏感的(TMD-8)、难治性的(DoHH-2)以及多耐药性的(WSU-DLCL2)肿瘤模型均表现出优于单一药物的抑制效果。
采用雌性CB-17SCID小鼠异种移植模型评估化合物(3，9，14及其他表中列出的化合物)及其联合用药的抑瘤效果。将TMD-8，DoHH2，WSU-DLCL2肿瘤细胞接种于含有10％热灭活胎牛血清的RPMI-1640培养基中，在37℃，5％CO2条件下培养。肿瘤细胞常规传代培养，每周两次。当细胞生长进入指数生长期时收获并计数，以进行肿瘤接种。每只小鼠右侧皮下接种02mL肿瘤细胞PBS悬液(10x 106)和基质胶(1∶1)。当平均肿瘤体积大约为100-200mm3时开始给药。每组由6-10只荷瘤小鼠组成。测试组(包括空白对照组、单药组、联合给药组)按照预定剂量口服给药，连续给药14天或者21天。实验过程中，小鼠体重和肿瘤体积每两天或三天测量一次。
胶原诱导性关节炎模型：
采用雄性DBA/1小鼠胶原诱导性关节炎模型评估化合物3和化合物14联合用药的体内抑制效果。小鼠分为8组，包括一个正常组、一个溶剂对照组、5个治疗组。所有小鼠(除正常组)在第0天和21天用200μg牛胶原(II型)免疫。加强免疫后七天(28天)，动物开始表现出症状的疾病，平均临床评分约1。同日，免疫小鼠随机分为7组：化合物3(1.5mpk)和化合物14(0.15mpk)联合给药，一天两次；化合物3(4.5mpk)和化合物14(0.45mpk)联合给药，一天两次；化合物3(1.5mpk)和化合物14(0.15mpk)联合给药，一天一次；化合物3(1.5mpk)单药，一天一次；化合物14(1.5mpk)单药，一天一次；阳性对照组(0.2mg/kg地塞米松)，并开始给药。口服给药两周，记录体重和临床评分。在研究结束时，处死动物，收集后肢进行组织病理学分析。
佐剂性关节炎模型：
采用雌性Lewis大鼠胶原诱导性关节炎模型评估化合物3和化合物14联合用药的体内抑制效果。所有大鼠(除正常组)在第0天左后肢注射完全弗氏佐剂(CFA)进行免疫。在免疫后6天，一些大鼠开始显示关节炎的临床症状，如红斑和肿胀。在第13天，免疫的动物被重新组合为7组：溶剂对照组，化合物3(5mpk)和化合物14(0.5mpk)联合给药，一天两次；化合物3(15mpk)和化合物14(1.5mpk)联合给药，一天两次；化合物3(30mpk)和化合物14(3mpk)联合给药，一天一次；化合物3(5mpk)单药，一天两次；化合物14(0.5mpk)单药，一天两次；阳性对照组(化合物11，3mpk，一天两次)，并开始给药。口 服给药三周，每隔一天记录体重、爪体积和临床评分。在研究结束时，处死动物，收集右后爪，采用H.E.染色进行组织病理学分析。
表2.本发明实施例化合物抑制BTK酶的活性数据表
Figure PCTCN2016000149-appb-000054
表3.单一化合物对TMD-8细胞株抑制百分比(Inh％)
Figure PCTCN2016000149-appb-000055
Figure PCTCN2016000149-appb-000056
注：本表中的化合物3、6、7、8-19对应于相应的“化合物中文名或英文名”中所指明的化合物，其中3、6、7指代本发明实施例中的化合物，8-19指代现有技术中相应的化合物。为了便于行文，下文以编号表示相应的化合物，因此，以下化合物编号具有相同的含义。
表4.二合一组合化合物对TMD-8细胞株抑制百分比(Inh％)
Figure PCTCN2016000149-appb-000057
Figure PCTCN2016000149-appb-000058
由表4可以看出，“二合一”联合用药具有显著肿瘤细胞活力抑制作用。其中，化合物8+化合物13，化合物14+化合物13，化合物15+化合物13以及化合物3+化合物13的药物组合均呈现了对TMD-8细胞活力的高效抑制作用。
表5.三合一组合化合物对TMD-8细胞株抑制百分比(Inh％)
Figure PCTCN2016000149-appb-000059
Figure PCTCN2016000149-appb-000060
由表5可以看出，“三合一”联合用药具有显著肿瘤细胞活力抑制作用。其中，化合物3+化合物14+化合物12和化合物3+化合物8+化合物12的药物组合在BTK抑制剂低至10nM浓度下仍具有高达95％肿瘤细胞活力抑制作用。
表6.单一化合物和三合一组合化合物对耐药性的WSU-DLCL2细胞株抑制百分比(Inh％)
Figure PCTCN2016000149-appb-000061
由表6可以看出，化合物3+化合物15+化合物14的“三合一”药物组合对多耐药性的WSU-DLCL2细胞具有良好细胞活力抑制作用，并且明显优于每个单一靶向药物。
表7.单一化合物和三合一组合化合物对DoHH-2细胞株抑制百分比(Inh％)
Figure PCTCN2016000149-appb-000062
由表7可以看出，化合物3+化合物15+化合物14的“三合一”药物组合对难治性的DoHH-2细胞具有良好细胞活力抑制作用，并且明显优于每个单一靶向药物。
表8.不同比例组合化合物对TMD-8细胞株抑制百分比(Inh％)
Figure PCTCN2016000149-appb-000063
由表8可以看出，不同比例的“三合一”药物组合对敏感的TMD-8细胞均具有显著细胞活力抑制作用
表9.化合物3在大鼠体内的PK参数
Figure PCTCN2016000149-appb-000064
表10.化合物3在犬体内的PK参数
Figure PCTCN2016000149-appb-000065
表11.化合物3在大鼠体内的TK参数
Figure PCTCN2016000149-appb-000066
表12.化合物3在犬体内的TK参数
Figure PCTCN2016000149-appb-000067
表13.单药及联合用药在动物体内肿瘤模型中的抑瘤作用
Figure PCTCN2016000149-appb-000068
Figure PCTCN2016000149-appb-000069
Figure PCTCN2016000149-appb-000070
Figure PCTCN2016000149-appb-000071
由表13可以看出，联合用药对肿瘤细胞有协同效应和合成致死能力，在比每个单一靶向药物剂量低得多的组合给药条件下，联合用药的疗效远远优于每个单一靶向药物的疗效。例如，化合物3+化合物14“二合一”的联合用药在15天的治疗周期可以导致肿瘤完全消退，而化合物3+化合物14+化合物15“三合一”的联合用药在更短的治疗周期(9天)可以导致 肿瘤完全消退，并且在停止给药后12天内没有观察肿瘤反弹，疗效显著优于比单一靶向治疗。
表14.联合用药在动物体内肿瘤模型中体重影响
Figure PCTCN2016000149-appb-000072
由表14可以看出，各组动物体重无差异，低剂量联合用药安全。
表15.联合用药3/14/15在动物体内肿瘤模型中体重影响
Figure PCTCN2016000149-appb-000073
由表15可以看出，各组动物体重无差异，低剂量联合用药安全。
表16.足体积--佐剂诱发关节炎
Figure PCTCN2016000149-appb-000074
由表16可以看出，“二合一”联合用药比单药更有效。
表17.病理评分--佐剂诱发关节炎
Figure PCTCN2016000149-appb-000075
由表17可以看出，“二合一”联合用药比单药更有效。
表18.初次免疫后第21天之后的平均临床评分--胶原诱导性关节炎
Figure PCTCN2016000149-appb-000076
由表18可以看出，“二合一”联合用药比单药更有效。
表19.病理评分--胶原诱导性关节炎
Figure PCTCN2016000149-appb-000077
由表19可以看出，“二合一”联合用药比单药更有效。

Claims (72)

  1. 由通式(I)、(II)、(Ia)、(IIa)、(Ib)和(IIb)表示的化合物，它们的对映体和非对映体或其可药用的盐。
    Figure PCTCN2016000149-appb-100001
    其中：
    R1为氟原子；n为1，2，3或4；
    R2为氟原子；m为1或2；
    R3为氢原子或氘原子。
  2. 由下列结构式表示的化合物，它们的消旋物或其可药用的盐
    Figure PCTCN2016000149-appb-100002
  3. 一种药物组合物，它包括一种惰性载体和权利要求1-2中任一项所述的化合物或其可药用的盐，优选权利要求2的化合物。
  4. 一种药物，它包括一种惰性载体和权利要求1-2中任意一项所述的化合物或其可药用的盐作为活性成分，优选权利要求2的化合物。
  5. 一种抑制在患者体内BTK活性的方法，包括给予所述患者有效剂量的如权利要求1-2中的化合物。
  6. 一种用于治疗或抑制自身免疫性疾病(autoimmune diseases)或病症的方法，所述方法包括给需要的患者有效剂量的如权利要求1-2中的化合物或权利要求3的组合物，所述自身免疫性疾病包括，但不限于器官特异性自身免疫疾病，如慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征(goodpasture syndrome)、寻常天皰疮、类天皰疮、原发性胆汁性肝硬变、多发性脑脊髓硬化症、急性特发性多神经炎等；系统性自身免疫疾病，如系统性红斑狼疮、类风湿关节炎、银屑病(psoriasis)、系统性脉管炎、硬皮病、天疱疮、混合结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、溃疡性结肠炎等。
  7. 一种用于治疗或抑制异常免疫性疾病或病症的方法，所述方法包括给需要的患者有效剂量的如权利要求1-2中的化合物或权利要求3的组合物，所述异常免疫性疾病包括，但不限于血清病、哮喘、过敏性鼻炎和药物过敏等。
  8. 一种用于治疗或抑制炎性疾病或病症的方法，所述方法包括给需要的患者有效剂量的如权利要求1-2中的化合物或权利要求3的组合物，所述炎性疾病包括，但不限于角膜炎、鼻炎、口腔炎、腮腺炎、咽炎、扁桃体炎、气管炎、支气管炎、肺炎、心肌炎、胃炎、肠胃炎、胆囊炎、阑尾炎等。
  9. 一种用于治疗或抑制癌症或其他疾病的方法，所述方法包括给需要的患者有效剂量的如权利要求1-2中的化合物或权利要求3的组合物，所述癌症或其他疾病包括，但不限于各种B细胞恶性肿瘤(包括小淋巴细胞淋巴瘤(SLL)、慢性淋巴细胞白血病(CLL)、弥漫性大B细胞淋巴瘤(DLBCL)、华氏巨球蛋白血症(Waldenstrom Macroglobulinemia)、滤泡性淋巴瘤(Follicular Lymphom)、套细胞淋巴瘤(MCL)和多发性骨髓瘤(MM))以及其他抑制BTK激酶活性对病人有益处的疾病。
  10. 权利要求1-2的化合物在制备治疗或抑制自身免疫性疾病(autoimmune diseases)的药物中的用途，所述自身免疫性疾病包括，但不限于器官特异性自身免疫疾病，如慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶 性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征(goodpasture syndrome)、寻常天皰疮、类天皰疮、原发性胆汁性肝硬变、多发性脑脊髓硬化症、急性特发性多神经炎等，系统性自身免疫疾病，如系统性红斑狼疮、类风湿关节炎、银屑病(psoriasis)、系统性脉管炎、硬皮病、天疱疮、混合结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫疾病、溃疡性结肠炎等。
  11. 权利要求1-2的化合物在制备治疗或抑制异常免疫性疾病的药物中的用途，所述异常免疫性疾病包括，但不限于血清病、哮喘、过敏性鼻炎和药物过敏等。
  12. 权利要求1-2的化合物在制备治疗或抑制炎性疾病的药物中的用途，所述炎性疾病包括，但不限于角膜炎、鼻炎、口腔炎、腮腺炎、咽炎、扁桃体炎、气管炎、支气管炎、肺炎、心肌炎、胃炎、肠胃炎、胆囊炎、阑尾炎等。
  13. 权利要求1-2的化合物在制备治疗癌症或其他疾病的药物中的用途，其中所述癌症或其他疾病包括，但不限于各种B细胞恶性肿瘤(包括小淋巴细胞淋巴瘤(SLL)、慢性淋巴细胞白血病(CLL)、弥漫性大B细胞淋巴瘤(DLBCL)、华氏巨球蛋白血症(Waldenstrom Macroglobulinemia)、滤泡性淋巴瘤(Follicular Lymphom)、套细胞淋巴瘤(MCL)和多发性骨髓瘤(MM))以及其他抑制BTK激酶活性对病人有益处的疾病。
  14. 权利要求1-2的化合物和各种CD20抗体联合用药在制备治疗癌症或其他疾病的药物中的用途，其中所述癌症或其他疾病包括，但不限于各种B细胞恶性肿瘤(包括小淋巴细胞淋巴瘤(SLL)、慢性淋巴细胞白血病(CLL)、弥漫性大B细胞淋巴瘤(DLBCL)、华氏巨球蛋白血症(Waldenstrom Macroglobulinemia)、滤泡性淋巴瘤(Follicular Lymphoma)、、套细胞淋巴瘤(MCL)和多发性骨髓瘤(MM))以及其他抑制BTK激酶活性对病人有益处的疾病。
  15. 一种三合一的药物组合物，其中含有BTK抑制剂、mTOR抑制剂以及IMiD免疫调节剂。
  16. 如权利要求15所述的三合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)、mTOR抑制剂Everolimus(依维莫司)以及IMiD免疫调节剂Thalidomide(沙利度胺)/Revlimid(来那度胺)/Pomalidomide(泊马度胺)/CC-122/CC-220。
  17. 如权利要求15所述的三合一药物组合物，其含有权利要求2中所述的化合物3、mTOR抑制剂Everolimus(依维莫司)以及IMiD免疫调节剂Thalidomide(沙利度胺)/Revlimid(来那度胺)/Pomalidomide(泊马度胺)/CC-122/CC-220。
  18. 如权利要求15所述的三合一药物组合物，其含有权利要求2中所述的化合物5、mTOR抑制剂Everolimus(依维莫司)以及IMiD免疫调节剂Thalidomide(沙利度胺)/Revlimid(来那度胺)/Pomalidomide(泊马度胺)/CC-122/CC-220。
  19. 如权利要求15所述的三合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)、mTOR抑制剂Rapamycin(雷帕霉素)以及IMiD免疫调节剂Thalidomide(沙利度胺)/Revlimid(来那度胺)/Pomalidomide(泊马度胺)/CC-122/CC-220。
  20. 如权利要求15所述的三合一药物组合物，其含有权利要求2中所述的化合物3、mTOR抑制剂Rapamycin(雷帕霉素)以及IMiD免疫调节剂Thalidomide(沙利度胺)/Revlimid(来那度胺)/Pomalidomide(泊马度胺)/CC-122/CC-220。
  21. 如权利要求15所述的三合一药物组合物，其含有权利要求2中所述的化合物5、mTOR抑制剂Rapamycin(雷帕霉素)以及IMiD免疫调节剂Thalidomide(沙利度胺)/Revlimid(来那度胺)/Pomalidomide(泊马度胺)/CC-122/CC-220。
  22. 一种三合一的药物组合物，其中含有BTK抑制剂、mTOR抑制剂以及Bcl-2抑制剂。
  23. 如权利要求22所述的三合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)、mTOR抑制剂Everolimus(依维莫司)以及Bcl-2抑制剂ABT-199。
  24. 如权利要求22所述的三合一药物组合物，其含有权利要求2中所述的化合物3、mTOR抑制剂Everolimus(依维莫司)以及Bcl-2抑制剂ABT-199。
  25. 如权利要求22所述的三合一药物组合物，其含有权利要求2中所述的化合物5、mTOR抑制剂Everolimus(依维莫司)以及Bcl-2抑制剂ABT-199。
  26. 如权利要求22所述的三合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)、mTOR抑制剂Rapamycin(雷帕霉素)以及Bcl-2抑制剂ABT-199。
  27. 如权利要求22所述的三合一药物组合物，其含有权利要求2中所述的化合物3、mTOR抑制剂Rapamycin(雷帕霉素)以及Bcl-2抑制剂ABT-199。
  28. 如权利要求22所述的三合一药物组合物，其含有权利要求2中所述的化合物5、mTOR抑制剂Rapamycin(雷帕霉素)以及Bcl-2抑制剂ABT-199。
  29. 一种三合一的药物组合物，其中含有BTK抑制剂、Bcl-2抑制剂以及PI3K抑制剂。
  30. 如权利要求29所述的三合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)、Bcl-2抑制剂ABT-199以及PI3K抑制剂Idelalisib。
  31. 如权利要求29所述的三合一药物组合物，其含有BTK抑制剂权利要求2中所述的化合物3、Bcl-2抑制剂ABT-199以及PI3K抑制剂Idelalisib。
  32. 如权利要求29所述的三合一药物组合物，其含有BTK抑制剂权利要求2中所述的化合物5、Bcl-2抑制剂ABT-199以及PI3K抑制剂Idelalisib。
  33. 如权利要求29所述的三合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)、Bcl-2抑制剂ABT-199以及PI3K抑制剂Duvelisib。
  34. 如权利要求29所述的三合一药物组合物，其含有BTK抑制剂权利要求2中所述的化合物3、Bcl-2抑制剂ABT-199以及PI3K抑制剂Duvelisib。
  35. 如权利要求29所述的三合一药物组合物，其含有BTK抑制剂权利要求2中所述的化合物5、Bcl-2抑制剂ABT-199以及PI3K抑制剂Duvelisib。
  36. 一种三合一的药物组合物，其中含有BTK抑制剂、mTOR抑制剂以及Methotrexate(甲氨蝶呤)。
  37. 如权利要求36所述的三合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)、mTOR抑制剂Everolimus(依维莫司)以及Methotrexate(甲氨蝶呤)。
  38. 如权利要求36所述的三合一药物组合物，其含有权利要求2中所述的化合物3、mTOR抑制剂Everolimus(依维莫司)以及Methotrexate(甲氨蝶呤)。
  39. 如权利要求36所述的三合一药物组合物，其含有权利要求2中所述的化合物5、mTOR抑制剂Everolimus(依维莫司)以及Methotrexate(甲氨蝶呤)。
  40. 如权利要求36所述的三合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)、mTOR抑制剂Rapamycin(雷帕霉素)以及Methotrexate(甲氨蝶呤)。
  41. 如权利要求36所述的三合一药物组合物，其含有权利要求2中所述的化合物3、mTOR抑制剂Rapamycin(雷帕霉素)以及Methotrexate(甲氨蝶呤)。
  42. 如权利要求36所述的三合一药物组合物，其含有权利要求2中所述的化合物5、mTOR抑制剂Rapamycin(雷帕霉素)以及Methotrexate(甲氨蝶呤)。
  43. 一种二合一的药物组合物，其中含有BTK抑制剂和mTOR抑制剂。
  44. 如权利要求43所述的二合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)和mTOR抑制剂Everolimus(依维莫司)。
  45. 如权利要求43所述的二合一药物组合物，其含有权利要求2中所述的化合物3和mTOR抑制剂Everolimus(依维莫司)。
  46. 如权利要求43所述的二合一药物组合物，其含有权利要求2中所述的化合物5和mTOR抑制剂Everolimus(依维莫司)。
  47. 如权利要求43所述的二合一药物组合物，其含有为BTK抑制剂Ibrutinib(依鲁替尼)和mTOR抑制剂Rapamycin(雷帕霉素)。
  48. 如权利要求43所述的二合一药物组合物，其含有权利要求2中所述的化合物3和mTOR抑制剂Rapamycin(雷帕霉素)。
  49. 如权利要求43所述的二合一药物组合物，其含有权利要求2中所述的化合物5和mTOR抑制剂Rapamycin(雷帕霉素)。
  50. 一种二合一的药物组合物，其中含有BTK抑制剂和TOPK抑制剂。
  51. 如权利要求50所述的二合一药物组合物，其含有BTK抑制剂Ibrutinib(依鲁替尼)和TOPK抑制剂OTS964。
  52. 如权利要求50所述的二合一药物组合物，其含有权利要求2中所述的化合物3和TOPK抑制剂OTS964。
  53. 如权利要求50所述的二合一药物组合物，其含有权利要求2中所述的化合物5和TOPK抑制剂OTS964。
  54. 一种二合一的药物组合物，其中含有PI3K抑制剂和TOPK抑制剂。
  55. 如权利要求54所述的二合一药物组合物，其含有PI3K抑制剂Idelalisib和TOPK抑制剂OTS964。
  56. 如权利要求54所述的二合一药物组合物，其含有PI3K抑制剂Duvelisib和TOPK抑制剂OTS964。
  57. 一种二合一的药物组合物，其中含有权利要求2中所述的化合物3和PI3K抑制剂Idelalisib。
  58. 一种二合一的药物组合物，其中含有权利要求2中所述的化合物5和PI3K抑制剂Idelalisib。
  59. 一种二合一的药物组合物，其中含有权利要求2中所述的化合物3和PI3K抑制剂Duvelisib。
  60. 一种二合一的药物组合物，其中含有权利要求2中所述的化合物5和PI3K抑制剂Duvelisib。
  61. 一种二合一的药物组合物，其中含有权利要求2中所述的化合物3和Bcl-2抑制剂ABT-199。
  62. 一种二合一的药物组合物，其中含有权利要求2中所述的化合物5和Bcl-2抑制剂ABT-199。
  63. 权利要求15-62的药物组合物在制备治疗或抑制癌症或其他疾病的药物中的用途，其中所述癌症或其他疾病包括，但不限于各种B细胞恶性肿瘤(包括小淋巴细胞淋巴瘤(SLL)、慢性淋巴细胞白血病(CLL)、弥漫性大B细胞淋巴瘤(DLBCL)、华氏巨球蛋白血症(Waldenstrom Macroglobulinemia)、滤泡性淋巴瘤(Follicular Lymphoma)、套细胞淋巴瘤(MCL)和多发性骨髓瘤(MM))以及其他抑制BTK激酶活性对病人有益处的疾病。
  64. 权利要求15-62的药物组合物在制备治疗或抑制自身免疫性疾病(autoimmune diseases)的药物中的用途，所述自身免疫性疾病包括，但不限于器官特异性自身免疫疾病，如慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征(goodpasture syndrome)、寻常天皰疮、类天皰疮、原发性胆汁性肝硬变、多发性脑脊髓硬化症、急性特发性多神经炎等，系统性自身免疫疾病，如系统性红斑狼疮、类风湿关节炎、系统性脉管炎、硬皮病、天疱疮、混合结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫疾病、溃疡性结肠炎等。
  65. 如权利要求64所述的用途，其中所述自身免疫性疾病选自类风湿关节炎。
  66. 权利要求15-62的药物组合物在制备治疗或抑制异常免疫性疾病的药物中的用途，所述异常免疫性疾病包括，但不限于血清病、哮喘、过敏性鼻炎和药物过敏等。
  67. 权利要求15-62的药物组合物在制备治疗或抑制炎性疾病的药物中的用途，所述炎性疾病包括，但不限于角膜炎、鼻炎、口腔炎、腮腺炎、咽炎、扁桃体炎、气管炎、支气管炎、肺炎、心肌炎、胃炎、肠胃炎、胆囊炎、阑尾炎等。
  68. 权利要求15-62的药物组合物治疗或抑制癌症或其他疾病的方法，其中所述癌症或其他疾病包括，但不限于各种B细胞恶性肿瘤(包括小淋巴细胞淋巴瘤(SLL)、慢性淋巴细胞白血病(CLL)、弥漫性大B细胞淋巴瘤(DLBCL)、华氏巨球蛋白血症(Waldenstrom Macroglobulinemia)、滤泡性淋巴瘤(Follicular Lymphoma)、套细胞淋巴瘤(MCL)和多发性骨髓瘤(MM))以及其他抑制BTK激酶活性对病人有益处的疾病。
  69. 权利要求15-62的药物组合物治疗或抑制自身免疫性疾病(autoimmune diseases)的方法，所述自身免疫性疾病包括，但不限于器官特异性自身免疫疾病，如慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征(goodpasture syndrome)、寻常天皰疮、类天皰疮、原发性胆汁性肝硬变、多发性脑脊髓硬化症、急性特发性多神经炎等，系统性自身免疫疾病，如系统性红斑狼疮、类风湿关节炎、银屑病(psoriasis)、系统性脉管炎、硬皮病、天疱疮、混合结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫疾病、溃疡性结肠炎等。
  70. 如权利要求68所述的方法，其中所述自身免疫性疾病选自类风湿关节炎。
  71. 权利要求15-62的药物组合物治疗或抑制异常免疫性疾病的方法，所述异常免疫性疾病包括，但不限于血清病、哮喘、过敏性鼻炎和药物过敏等。
  72. 权利要求15-62的药物组合物治疗或抑制炎性疾病的药物中的的方法，所述炎性疾病包括，但不限于角膜炎、鼻炎、口腔炎、腮腺炎、咽炎、扁桃体炎、气管炎、支气管炎、肺炎、心肌炎、胃炎、肠胃炎、胆囊炎、阑尾炎等。
PCT/CN2016/000149 2015-03-19 2016-03-18 优化的联合用药及其治疗癌症和自身免疫疾病的用途 WO2016145935A1 (zh)

Priority Applications (18)

Application Number Priority Date Filing Date Title
IL254435A IL254435B1 (en) 2015-03-19 2016-03-18 A combination of a BTK inhibitor, an mTOR kinase inhibitor and an immunomodulatory drug and its uses in the treatment of lymphoid malignancy
EA201792066A EA037058B1 (ru) 2015-03-19 2016-03-18 Оптимизированная комбинированная терапия и ее применение для лечения злокачественной опухоли и аутоиммунного заболевания
MX2017011836A MX2017011836A (es) 2015-03-19 2016-03-18 Terapia de combinacion optimizada y uso de la misma para tratar cancer y enfermedad autoinmunitaria.
CN201680017009.0A CN107406454B (zh) 2015-03-19 2016-03-18 优化的联合用药及其治疗癌症和自身免疫疾病的用途
CN202111303221.2A CN114790209A (zh) 2015-03-19 2016-03-18 优化的联合用药及其治疗癌症和自身免疫疾病的用途
JP2017549326A JP7012534B2 (ja) 2015-03-19 2016-03-18 癌および自己免疫疾患を治療するための最適化された組合せ療法およびその使用
BR112017019790-1A BR112017019790B1 (pt) 2015-03-19 2016-03-18 Uso de um inibidor bruton tirosina quinase (btk)
EP16764117.4A EP3272752A4 (en) 2015-03-19 2016-03-18 Optimised combination therapy and use thereof to treat cancer and autoimmune disease
KR1020227026364A KR20220110872A (ko) 2015-03-19 2016-03-18 암 및 자가면역 질환을 치료하기 위한 최적화된 조합 요법 및 그의 용도
AU2016232923A AU2016232923B2 (en) 2015-03-19 2016-03-18 Optimised combination therapy and use thereof to treat cancer and autoimmune disease
CA2980016A CA2980016C (en) 2015-03-19 2016-03-18 Optimized combination therapy and use thereof to treat cancer and autoimmune disease
KR1020177025465A KR102428387B1 (ko) 2015-03-19 2016-03-18 암 및 자가면역 질환을 치료하기 위한 최적화된 조합 요법 및 그의 용도
US15/183,340 US9717745B2 (en) 2015-03-19 2016-06-15 Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
US15/628,143 US10098900B2 (en) 2015-03-19 2017-06-20 Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
US16/123,167 US10537587B2 (en) 2015-03-19 2018-09-06 Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
US16/123,203 US10596183B2 (en) 2015-03-19 2018-09-06 Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
US16/790,197 US11369620B2 (en) 2015-03-19 2020-02-13 Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
AU2020277128A AU2020277128B2 (en) 2015-03-19 2020-11-24 Optimised combination therapy and use thereof to treat cancer and autoimmune disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510119944.5 2015-03-19
CN201510119944.5A CN106146508A (zh) 2015-03-19 2015-03-19 优化的联合用药及其治疗癌症和自身免疫疾病的用途

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US15/628,143 Continuation-In-Part US10098900B2 (en) 2015-03-19 2017-06-20 Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/183,340 Continuation-In-Part US9717745B2 (en) 2015-03-19 2016-06-15 Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases

Publications (1)

Publication Number Publication Date
WO2016145935A1 true WO2016145935A1 (zh) 2016-09-22

Family

ID=56918303

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/000149 WO2016145935A1 (zh) 2015-03-19 2016-03-18 优化的联合用药及其治疗癌症和自身免疫疾病的用途

Country Status (11)

Country Link
EP (1) EP3272752A4 (zh)
JP (2) JP7012534B2 (zh)
KR (2) KR102428387B1 (zh)
CN (4) CN106146508A (zh)
AU (2) AU2016232923B2 (zh)
BR (1) BR112017019790B1 (zh)
CA (2) CA2980016C (zh)
EA (2) EA202092671A1 (zh)
IL (1) IL254435B1 (zh)
MX (1) MX2017011836A (zh)
WO (1) WO2016145935A1 (zh)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017218844A3 (en) * 2016-06-15 2018-02-22 Zhejiang DTRM Biopharma Co. Ltd. Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
WO2018090792A1 (zh) * 2016-11-15 2018-05-24 杭州和正医药有限公司 一种选择性布鲁顿酪氨酸激酶抑制剂及其应用
CN111212839A (zh) * 2017-09-15 2020-05-29 艾杜罗生物科技公司 吡唑并嘧啶酮化合物及其用途
EP3138842B1 (en) * 2014-04-29 2020-12-09 Zhejiang DTRM Biopharma Co., Ltd. Polyfluorinated compounds acting as bruton's tyrosine kinase inhibitors
JP2021501140A (ja) * 2017-10-27 2021-01-14 チョーチアン ディーティーアールエム バイオファーマ コーポレーション リミテッド リンパ球悪性疾患を治療するための方法
JP2021512059A (ja) * 2018-01-29 2021-05-13 ダナ−ファーバー キャンサー インスティテュート，インコーポレイテッド ブルトン型チロシンキナーゼ（ｂｔｋ）阻害剤のｅ３リガーゼリガンドとのコンジュゲーションによるｂｔｋの分解および使用方法
WO2023197914A1 (zh) * 2022-04-12 2023-10-19 安徽中科拓苒药物科学研究有限公司 一种吡唑并嘧啶类化合物的新用途

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146508A (zh) * 2015-03-19 2016-11-23 浙江导明医药科技有限公司 优化的联合用药及其治疗癌症和自身免疫疾病的用途
CN106831788B (zh) * 2017-01-22 2020-10-30 鲁南制药集团股份有限公司 伊布替尼精制方法
WO2019127008A1 (zh) * 2017-12-26 2019-07-04 清华大学 一种靶向降解btk的化合物及其应用
CN108992454B (zh) * 2018-06-20 2020-06-02 合肥医工医药股份有限公司 一种治疗皮肤炎症性疾病的复方药物组合物
CN110772521A (zh) * 2018-07-31 2020-02-11 苏州亚盛药业有限公司 Bcl-2抑制剂或Bcl-2/Bcl-xL抑制剂与BTK抑制剂的组合产品及其用途
CN109369654A (zh) * 2018-11-20 2019-02-22 山东大学 1，3-二取代-4-氨基吡唑并嘧啶类化合物及其制备方法和应用
KR20200114776A (ko) * 2019-03-29 2020-10-07 한미약품 주식회사 퓨로피리미딘 화합물의 산 부가염의 결정형
CN110845500B (zh) * 2019-10-09 2021-05-11 清华大学 靶向btk降解化合物在治疗自身免疫系统疾病中的应用
CN110724143B (zh) * 2019-10-09 2021-03-23 清华大学 一种靶向btk蛋白降解化合物的制备及其在治疗自身免疫系统疾病与肿瘤中的应用
CN115701996A (zh) * 2020-06-25 2023-02-14 托雷莫治疗股份公司 用于治疗EGFR突变型NSCLC的CBP/p300溴结构域抑制剂和EGFR抑制剂的组合
CN114507236A (zh) * 2022-02-28 2022-05-17 山东中医药大学 mTOR蛋白降解靶向嵌合体及其制备方法和应用
CN117045800A (zh) * 2022-05-06 2023-11-14 上海科技大学 mTOR抑制剂增强靶向蛋白降解药物功效的应用
CN117510494B (zh) * 2023-11-07 2024-04-19 桂林医学院附属医院 β-咔啉-沙利度胺偶联物及其在制备逆转ABT-199耐药的药物中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008058944A1 (en) * 2006-11-13 2008-05-22 Aeterna Zentaris Gmbh Microorganisms as carriers of nucleotide sequences coding for antigens and protein toxins, process of manufacturing and uses thereof
US20120108612A1 (en) * 2006-09-22 2012-05-03 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2014143807A2 (en) * 2013-03-15 2014-09-18 Stromatt Scott Anti-cd37 antibody and bcr pathway antagonist combination therapy for treatment of b-cell malignancies and disorders
CN105017256A (zh) * 2014-04-29 2015-11-04 浙江导明医药科技有限公司 多氟化合物作为布鲁顿酪氨酸激酶抑制剂

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2561875A3 (en) * 2007-03-28 2013-06-12 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2010009342A2 (en) * 2008-07-16 2010-01-21 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors
US7718662B1 (en) 2009-10-12 2010-05-18 Pharmacyclics, Inc. Pyrazolo-pyrimidine inhibitors of bruton's tyrosine kinase
AU2012255860C1 (en) 2011-05-17 2015-12-10 Principia Biopharma Inc. Tyrosine kinase inhibitors
EA201490265A1 (ru) 2011-07-13 2014-12-30 Фармасайкликс, Инк. Ингибиторы тирозинкиназы брутона
CN104487441B (zh) 2012-06-18 2018-06-01 普林斯匹亚生物制药公司 有用于治疗癌症和自身免疫性疾病的可逆的共价吡咯并嘧啶或吡唑并嘧啶
CA2879400A1 (en) 2012-07-30 2014-02-06 Concert Pharmaceuticals, Inc. Deuterated ibrutinib
WO2014022569A1 (en) 2012-08-03 2014-02-06 Principia Biopharma Inc. Treatment of dry eye
EP2914296B2 (en) 2012-11-01 2021-09-29 Infinity Pharmaceuticals, Inc. Treatment of cancers using pi3 kinase isoform modulators
WO2014113942A1 (en) * 2013-01-23 2014-07-31 Merck Sharp & Dohme Corp. Btk inhibitors
US8957080B2 (en) * 2013-04-09 2015-02-17 Principia Biopharma Inc. Tyrosine kinase inhibitors
MX2015014596A (es) * 2013-04-17 2016-03-03 Signal Pharm Llc Terapia de combinacion que comprende un inhibidor de tor cinasa y un compuesto imid para tratar cancer.
JP6139782B2 (ja) * 2013-05-21 2017-05-31 チャンスー メドリューション リミテッド 置換ピラゾロピリミジン化合物、及びその薬学的に許容される塩、並びにこれらの溶媒和物、立体異性体、及び互変異性体、並びにこれらを含む医薬組成物
CN106146508A (zh) * 2015-03-19 2016-11-23 浙江导明医药科技有限公司 优化的联合用药及其治疗癌症和自身免疫疾病的用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120108612A1 (en) * 2006-09-22 2012-05-03 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2008058944A1 (en) * 2006-11-13 2008-05-22 Aeterna Zentaris Gmbh Microorganisms as carriers of nucleotide sequences coding for antigens and protein toxins, process of manufacturing and uses thereof
WO2014143807A2 (en) * 2013-03-15 2014-09-18 Stromatt Scott Anti-cd37 antibody and bcr pathway antagonist combination therapy for treatment of b-cell malignancies and disorders
CN105017256A (zh) * 2014-04-29 2015-11-04 浙江导明医药科技有限公司 多氟化合物作为布鲁顿酪氨酸激酶抑制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3272752A4 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3138842B1 (en) * 2014-04-29 2020-12-09 Zhejiang DTRM Biopharma Co., Ltd. Polyfluorinated compounds acting as bruton's tyrosine kinase inhibitors
WO2017218844A3 (en) * 2016-06-15 2018-02-22 Zhejiang DTRM Biopharma Co. Ltd. Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
WO2018090792A1 (zh) * 2016-11-15 2018-05-24 杭州和正医药有限公司 一种选择性布鲁顿酪氨酸激酶抑制剂及其应用
CN108069974A (zh) * 2016-11-15 2018-05-25 杭州和正医药有限公司 一种选择性布鲁顿酪氨酸激酶抑制剂及其应用
US10711006B2 (en) 2016-11-15 2020-07-14 Hangzhou Hertz Pharmaceutical Co., Ltd. Selective Bruton's tyrosine kinase inhibitor and use thereof
CN111212839A (zh) * 2017-09-15 2020-05-29 艾杜罗生物科技公司 吡唑并嘧啶酮化合物及其用途
JP2021501140A (ja) * 2017-10-27 2021-01-14 チョーチアン ディーティーアールエム バイオファーマ コーポレーション リミテッド リンパ球悪性疾患を治療するための方法
JP7266030B2 (ja) 2017-10-27 2023-04-27 チョーチアン ディーティーアールエム バイオファーマ コーポレーション リミテッド リンパ球悪性疾患を治療するための方法
JP2021512059A (ja) * 2018-01-29 2021-05-13 ダナ−ファーバー キャンサー インスティテュート，インコーポレイテッド ブルトン型チロシンキナーゼ（ｂｔｋ）阻害剤のｅ３リガーゼリガンドとのコンジュゲーションによるｂｔｋの分解および使用方法
US11712458B2 (en) 2018-01-29 2023-08-01 Dana-Farber Cancer Institute, Inc. Degradation of Bruton's tyrosine kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligand and methods of use
WO2023197914A1 (zh) * 2022-04-12 2023-10-19 安徽中科拓苒药物科学研究有限公司 一种吡唑并嘧啶类化合物的新用途

Also Published As

Publication number Publication date
AU2020277128A1 (en) 2020-12-24
AU2016232923B2 (en) 2020-08-27
AU2016232923A1 (en) 2017-10-05
EA201792066A1 (ru) 2018-03-30
EA037058B1 (ru) 2021-02-01
IL254435A0 (en) 2017-11-30
JP2018512413A (ja) 2018-05-17
KR20170129733A (ko) 2017-11-27
KR102428387B1 (ko) 2022-08-02
CN111349099A (zh) 2020-06-30
AU2020277128B2 (en) 2022-12-22
CA2980016C (en) 2023-04-11
EA202092671A1 (ru) 2021-03-31
JP2022003103A (ja) 2022-01-11
CN106146508A (zh) 2016-11-23
BR112017019790B1 (pt) 2023-11-07
CN107406454B (zh) 2020-05-19
JP7012534B2 (ja) 2022-02-14
CA3191171A1 (en) 2016-09-22
CN107406454A (zh) 2017-11-28
CN114790209A (zh) 2022-07-26
EP3272752A1 (en) 2018-01-24
EP3272752A4 (en) 2018-10-31
KR20220110872A (ko) 2022-08-09
CA2980016A1 (en) 2016-09-22
IL254435B1 (en) 2024-03-01
MX2017011836A (es) 2017-12-07
BR112017019790A2 (zh) 2018-05-22

Similar Documents

Publication Publication Date Title
WO2016145935A1 (zh) 优化的联合用药及其治疗癌症和自身免疫疾病的用途
US10064866B2 (en) Treatment of B-cell malignancies by a combination JAK and PI3K inhibitors
CN109475566A (zh) 药物组合物及其用于治疗癌症和自身免疫疾病的用途
CN105452239B (zh) 作为jak抑制剂的联吡唑衍生物
JP6404332B2 (ja) 新規な、ＮＩＫ阻害剤としての３−（１Ｈ−ピラゾール−４−イル）−１Ｈ−ピロロ［２，３−ｃ］ピリジン誘導体
JP6616411B2 (ja) 新規な、ｎｉｋ阻害剤としてのピラゾール誘導体
CA2921568A1 (en) Survival benefit in patients with solid tumors with elevated c-reactive protein levels
JP6916796B2 (ja) Ｎｉｋ阻害剤としての新たな６員のヘテロ芳香族置換シアノインドリン誘導体
JP2016517859A (ja) 癌を治療するための、ｎｉｋ阻害剤としての３−（２−アミノピリミジン−４−イル）−５−（３−ヒドロキシプロピニル）−１ｈ−ピロロ［２，３−ｃ］ピリジン誘導体
JP6912460B2 (ja) ＰＩ３Ｋβ阻害剤としてのキノキサリンおよびピリドピラジン誘導体
TW202309022A (zh) 用於治療具egfr突變之癌症之胺基取代雜環
CA3158254C (en) Treatment of b-cell malignancies by a combination jak and pi3k inhibitors
CN117440813A (zh) 治疗脑或cns的癌转移的egfr降解剂
CN116490507A (zh) 用于治疗癌症的杂环包缩合cdc7激酶抑制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16764117

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 254435

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 20177025465

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2017/011836

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2017549326

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2980016

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112017019790

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2016232923

Country of ref document: AU

Date of ref document: 20160318

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201792066

Country of ref document: EA

REEP Request for entry into the european phase

Ref document number: 2016764117

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 112017019790

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20170915