WO2022166468A1 - Bruton's酪氨酸激酶抑制剂及其应用 - Google Patents

Bruton's酪氨酸激酶抑制剂及其应用 Download PDF

Info

Publication number
WO2022166468A1
WO2022166468A1 PCT/CN2021/141767 CN2021141767W WO2022166468A1 WO 2022166468 A1 WO2022166468 A1 WO 2022166468A1 CN 2021141767 W CN2021141767 W CN 2021141767W WO 2022166468 A1 WO2022166468 A1 WO 2022166468A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
membered
cycloalkyl
independently selected
cyano
Prior art date
Application number
PCT/CN2021/141767
Other languages
English (en)
French (fr)
Inventor
梁永宏
许志勇
曾兆森
严文广
熊方均
Original Assignee
药雅科技(上海)有限公司
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 claimed from CN202110152506.4A external-priority patent/CN114853752B/zh
Priority claimed from CN202110203074.5A external-priority patent/CN114957241B/zh
Priority claimed from CN202110203701.5A external-priority patent/CN114957242B/zh
Application filed by 药雅科技(上海)有限公司 filed Critical 药雅科技(上海)有限公司
Publication of WO2022166468A1 publication Critical patent/WO2022166468A1/zh

Links

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
    • A61K31/33—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/435—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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present invention discloses compounds that are BTK inhibitors useful for the treatment of diseases treatable by inhibition of BTK. Also provided are pharmaceutical compositions containing the compounds and methods for preparing the compounds.
  • Bruton's tyrosine kinases are members of the Tec family of non-receptor protein tyrosine kinases.
  • the Tec family is the second largest family of human non-receptor kinases after the Src family, and its main members include Bruton's tyrosine kinase, BMX(etk), ITK, TEC and TXK(PLK).
  • Bruton's tyrosine kinase was identified in 1993 as a defective protein in human X-linked agammaglobulinemia (XLA).
  • This protein is expressed at all stages of B cell development (except for terminally differentiated plasma cells), and Bruton's tyrosine kinase is an essential gene for cell differentiation and proliferation during the transition from pre-B lymphocytes to late-stage B cells, and is It is expressed in B-cell lymphoma, acute lymphoblastic leukemia (ALL) and plasmacytoma. In addition, there is also a small amount of expression in myeloid cells and erythroid progenitor cells.
  • Bruton's tyrosine kinase small molecule inhibitors such as ibrutinib, acalabrutinib and zanubrutinib have been approved by the US FDA for the treatment of mantle cell lymphoma (MCL). ) and CLL.
  • ibrutinib, acaltinib and zanubrutinib have significant therapeutic effects, in addition to some patients with B-cell lymphoma who develop resistance to the drug in the later stage, a considerable number of patients are not sensitive to their treatment. For example, about 1/3 of patients in MCL do not respond to its treatment, and the response rate in DLBCL is not high. In view of the above problems, there is still a need in the art to develop Bruton's tyrosine kinase inhibitors with high activity and specificity.
  • the present invention provides a compound of a novel Bruton's tyrosine kinase inhibitor represented by formula (I) or its stereoisomer, stable isotope derivative, hydrate, solvate, pharmaceutically acceptable of salt:
  • R can be independently selected from H, D,
  • L 1 is independently selected from -C 0-4 alkyl-, -CR 1 R 2 -, -C 1-2 alkyl(R 1 )(OH)-, -C(O)-, -CR 1 R 2 O-, -OCR 1 R 2 -, -SCR 1 R 2 -, -CR 1 R 2 S-, -NR 1 -, -NR 1 C(O)-, -C(O)NR 1 -, -NR 1 C(O)NR 2 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 1 S(O) 2 -, -S(O) 2 NR 1 -;
  • L 2 is independently selected from -C 0-4 alkyl-, -CR 1 R 2 -, -C 1-2 alkyl(R 1 )(OH)-, -C(O)-, -CR 1 R 2 O-, -OCR 1 R 2 -, -SCR 1 R 2 -, -CR 1 R 2 S-, -NR 1 -, -NR 1 C(O)-, -C(O)NR 1 -, -NR 1 C(O)NR 2 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 1 S(O) 2 -, -S(O) 2 NR 1 -;
  • Ar 1 and Ar 2 are independently selected from benzene ring or 5-6 membered heteroaromatic ring, wherein the above-mentioned benzene ring and heteroaromatic ring are optionally substituted by one or more G 1 ;
  • X can be independently selected from N, CR 3 ;
  • n 1 or 2;
  • U is independently selected from bond, -C 1-4 alkyl-, -CR 4 R 5 -, -C 1-2 alkyl(R 4 )(OH)-, -C(O)-, -CR 4 R 5 O-, -OCR 4 R 5 -, -SCR 4 R 5 -, -CR 4 R 5 S-, -NR 4 -, -NR 4 C(O)-, -C(O)NR 4 -, - NR 4 C(O)NR 5 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 4 S(O) 2 -, -S(O) 2 NR 4 - ;
  • Y does not exist or selects C 3-8 cycloalkyl, 3-8-membered heterocycloalkyl, 5-12-membered fused alkyl, 5-12-membered fused heterocyclic, 5-12-membered spiro, 5-12 A membered spiroheterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocycloalkyl, spirocyclyl, fused ring, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is any Option is replaced by one or more G 3 ;
  • Z is independently selected from cyano, -NR 12 CN,
  • Bond a is a double bond or a triple bond
  • R a , R b and R c are each independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycle base. wherein the alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with 1 or more G4 ; R and R or R and R are optionally taken together with the carbon atoms to which they are attached to form an optional 3-6 membered rings containing heteroatoms;
  • R a and R c are absent, and R b is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered hetero cyclyl is substituted with one or more G 5 ;
  • R 12 is independently selected from H, D, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally replaced by 1 replaced by one or more G 6 ;
  • G 1 , G 2 , G 3 , G 4 , G 5 and G 6 are each independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-8 cycloalkyl or 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR 6 , -OC(O)NR 6 R 7 , -C(O )OR 6 , -C(O)NR 6 R 7 , -C(O)R 6 , -NR 6 R 7 , -NR 6 C(O)R 7 , -NR 6 C(O)NR 7 R 8 , -S (O) mR6 or -NR6S ( O ) mR7 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is optionally 1 or
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl group;
  • the compound of the general formula (I), its pharmaceutically acceptable salt or its stereoisomer, the general formula (I) is further shown as the general formula Ia:
  • X1, X2, X3 can be independently selected from N, CR 1 ;
  • Ar 1 and Ar 2 are independently selected from benzene ring or 5-6 membered heteroaromatic ring, wherein the above-mentioned benzene ring and heteroaromatic ring are optionally substituted by one or more G 1 ;
  • R 1 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, COOH, CONH 2 , NHCOH, CONHR 2 , OR 2 or -NHR 2 ;
  • R 2 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -OR 3 , -NR 3 R 4 , - C(O)NR 3 R 4 , wherein said alkyl, cycloalkyl or heterocycloalkyl is optionally cyano, halogen, -OR 5 , -NR 5 R 6 , C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • L 1 , L 2 and U are independently selected from bond, -C 1-4 alkyl-, -CR 7 R 8 -, -C 1-2 alkyl(R 7 )(OH)-, -C(O) -, -CR 7 R 8 O-, -OCR 7 R 8 -, -SCR 7 R 8 -, -CR 7 R 8 S-, -NR 7 -, -NR 7 C(O)-, -C(O )NR 7 -, -NR 7 C(O)NR 8 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 7 S(O) 2 -, -S( O) 2 NR 7 -;
  • Y does not exist or selects C 3-8 cycloalkyl, 3-8-membered heterocycloalkyl, 5-12-membered fused alkyl, 5-12-membered fused heterocyclic, 5-12-membered spiro, 5-12 A membered spiroheterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocycloalkyl, spirocyclyl, fused ring, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is any Option is replaced by one or more G 2 ;
  • Z is independently selected from cyano, -NR9CN ,
  • Bond a is a double bond or a triple bond
  • R a , R b and R c are each independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycle base. wherein the alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with one or more G 3 ; R a and R b or R b and R c are optionally taken together with the carbon atoms to which they are attached to form an optional 3-6 membered rings containing heteroatoms;
  • R a and R c are absent, and R b is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered hetero cyclyl is substituted with one or more G 4 ;
  • R 12 is independently selected from H, D, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally replaced by 1 replaced by one or more G 5s ;
  • G 1 , G 2 , G 3 , G 4 and G 5 are each independently selected from cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane base or 3-8-membered heterocyclic group, C 6-10 -membered aryl, 5-10-membered heteroaryl, -OR 10 , -OC(O)NR 10 R 11 , -C(O)OR 10 , -C( O)NR 10 R 11 , -C(O)R 10 , -NR 10 R 11 , -NR 10 C(O)R 11 , -NR 10 C(O)NR 11 R 12 , -S(O) m R 10 or -NR 10 S(O) m R 11 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are optionally replaced by one or
  • X 1 , X 2 , X 3 , X 4 can be independently selected from N, CR 1 ;
  • Bonds a and b are single or double bonds
  • Ar 1 and Ar 2 are independently selected from benzene ring or 5-6 membered heteroaromatic ring, wherein the above-mentioned benzene ring and heteroaromatic ring are optionally substituted by one or more G 1 ;
  • R 1 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, COOH, CONH 2 , NHCOH, CONHR 2 , OR 2 or -NHR 2 ;
  • R 2 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -OR 3 , -NR 3 R 4 , - C(O)NR 3 R 4 , wherein said alkyl, cycloalkyl or heterocycloalkyl is optionally cyano, halogen, -OR 5 , -NR 5 R 6 , C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • L 1 , L 2 and W are independently selected from -C 0-4 alkyl-, -CR 7 R 8 -, -C 1-2 alkyl(R 7 )(OH)-, -C(O)-, -CR 7 R 8 O-, -OCR 7 R 8 -, -SCR 7 R 8 -, -CR 7 R 8 S-, -NR 7 -, -NR 7 C(O)-, -C(O)NR 7 -, -NR 7 C(O)NR 8 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 7 S(O) 2 -, -S(O) 2NR7- ;
  • Y does not exist or selects C 3-8 cycloalkyl, 3-8-membered heterocycloalkyl, 5-12-membered fused alkyl, 5-12-membered fused heterocyclic, 5-12-membered spiro, 5-12 A membered spiroheterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocycloalkyl, spirocyclyl, fused ring, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is any Option is replaced by one or more G 2 ;
  • Z is independently selected from cyano, -NR 12 CN,
  • the key c is a double bond or a triple bond
  • R a , R b and R c are each independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycle base. wherein the alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with 1 or more G;
  • Ra and Rb or Rb and Rc optionally together with the carbon atoms to which they are attached form a 3-6 membered ring optionally containing heteroatoms; when bond c is a triple bond, Ra and Rc are absent, R b is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl substituted by one or more G 4 ;
  • R 9 is independently selected from H, D, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally replaced by one or more G 5s ;
  • G 1 , G 2 , G 3 , G 4 and G 5 are each independently selected from cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane base or 3-8-membered heterocyclic group, C 6-10 -membered aryl, 5-10-membered heteroaryl, -OR 10 , -OC(O)NR 10 R 11 , -C(O)OR 10 , -C( O)NR 10 R 11 , -C(O)R 10 , -NR 10 R 11 , -NR 10 C(O)R 11 , -NR 10 C(O)NR 11 R 12 , -S(O) m R 10 or -NR 10 S(O) m R 11 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are optionally replaced by one or
  • X 1 , X 2 can be independently selected from N, CR 1 ;
  • X 3 can be independently selected from absent, N, CR 1 ;
  • Bonds a and b are single or double bonds
  • R 1 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, COOH, CONH 2 , NHCOH, CONHR 2 , OR 2 or -NHR 2 ;
  • R 2 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -OR 3 , -NR 3 R 4 , - C(O)NR 3 R 4 , wherein said alkyl, cycloalkyl or heterocycloalkyl is optionally cyano, halogen, -OR 5 , -NR 5 R 6 , C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • W is independently selected from bond, -C 1-4 alkyl-, -CR 7 R 8 -, -C 1-2 alkyl(R 7 )(OH)-, -C(O)-, -CR 7 R 8 O-, -OCR 7 R 8 -, -SCR 7 R 8 -, -CR 7 R 8 S-, -NR 7 -, -NR 7 C(O)-, -C(O)NR 7 -, - NR 7 C(O)NR 8 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 7 S(O) 2 -, -S(O) 2 NR 7 - ;
  • Y does not exist or selects C 3-8 cycloalkyl, 3-8-membered heterocycloalkyl, 5-12-membered fused alkyl, 5-12-membered fused heterocyclic, 5-12-membered spiro, 5-12 A membered spiroheterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocycloalkyl, spirocyclyl, fused ring, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is any Option is replaced by one or more G 1 ;
  • Z is independently selected from cyano, -NR 12 CN,
  • the key c is a double bond or a triple bond
  • R a , R b and R c are each independently selected from H, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl. wherein the alkyl, cycloalkyl and heterocyclyl groups are optionally substituted with 1 or more G;
  • R a and R b or R b and R c optionally together with the carbon atoms to which they are attached form a 3-6 membered ring optionally containing heteroatoms;
  • R a and R c are absent, and R b is independently selected from H, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl replaced by one or more G 3 ;
  • R 9 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally separated by 1 or Replaced by multiple G 4s ;
  • G 1 , G 2 , G 3 and G 4 are each independently selected from cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 -8-membered heterocyclic group, C 6-10 aryl group, 5-10-membered heteroaryl group, -OR 10 , -OC(O)NR 10 R 11 , -C(O)OR 10 , -C(O)NR 10 R 11 , -C(O)R 10 , -NR 10 R 11 , -NR 10 C(O)R 11 , -NR 10 C(O)NR 11 R 12 , -S(O) m R 10 or - NR 10 S(O) m R 11 , wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group are optionally replaced by 1 or
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 and R 15 are each independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 3-8 cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl;
  • the compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds, isomers, solvates thereof or their precursors, or their pharmaceutically acceptable salts:
  • the present invention provides a novel Bruton's tyrosine kinase inhibitor or its isomers, hydrates, solvates, polymorphs, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers in the preparation of novel Use in Bruton's tyrosine kinase inhibitors.
  • the pharmaceutical composition of the present application further comprises one or more pharmaceutical excipients.
  • the pharmaceutical excipients in this application refer to the excipients and additives used in the production of drugs and the formulation of prescriptions, and refer to substances that have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations except for the active ingredients. .
  • pharmaceutical excipients In addition to shaping, acting as a carrier and improving stability, pharmaceutical excipients also have important functions such as solubilization, solubilization, slow and controlled release, and are important components that may affect the quality, safety and effectiveness of drugs.
  • compositions can be divided into natural products, semi-synthetics and total synthetics according to their sources; according to their functions and uses, they can be divided into: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants Agents, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, antiadherents, antioxidants, chelating agents Mixtures, Penetration Enhancers, pH Adjusters, Buffers, Plasticizers, Surfactants, Foaming Agents, Defoamers, Thickeners, Inclusion Agents, Moisturizers, Absorbents, Diluents, Flocculants and Deflocculants According to the route of administration, it can be divided into oral, injection, mucosal, transdermal or topical administration, nasal or oral inhalation administration and ocular administration
  • the pharmaceutical composition of the present application can be prepared into various suitable dosage forms according to the route of administration.
  • the pharmaceutical composition can be formulated into any orally acceptable formulation, including but not limited to tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions and oral emulsions Wait.
  • the carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added.
  • Diluents for capsules typically include lactose and dried cornstarch.
  • Oral suspensions usually incorporate the active ingredient in admixture with suitable emulsifying and suspending agents.
  • suitable emulsifying and suspending agents may also be added to the above oral formulations.
  • the pharmaceutical compositions When applied transdermally or topically, the pharmaceutical compositions may be formulated in a suitable ointment, lotion or liniment in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or liniments include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition can also be administered in the form of injections, including injection solutions, sterile powders for injections and concentrated solutions for injections.
  • useful vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils can also be employed as a solvent or suspending medium, such as mono- or diglycerides.
  • a compound of the present application, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug thereof may be administered in combination with a second therapeutic agent.
  • the pharmaceutical compositions of the present application further comprise one or more second therapeutic agents.
  • the second therapeutic agent is a chemotherapeutic drug, a targeted anticancer drug, or an immunotherapy drug.
  • the second therapeutic agent is selected from the group consisting of rituximab, lenalidomide, fludarabine, cyclophosphamide, doxorubicin, vincristine, prednisone.
  • One aspect of the present application pertains to the use of a compound of the present application, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug thereof for the manufacture of a medicament for the prevention and/or treatment of a Diseases and/or symptoms associated with Bruton's tyrosine kinase overactivity.
  • One aspect of the present application pertains to the use of a compound of the present application, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug thereof for the manufacture of a medicament for the prevention and/or treatment of a Diseases and/or symptoms associated with Bruton's tyrosine kinase overactivity.
  • the disease and/or condition associated with Bruton's tyrosine kinase overactivity is selected from tumors (eg, hematological tumors or solid tumors), inflammatory or autoimmune diseases.
  • the hematological tumor is selected from lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia.
  • the solid tumor is selected from the group consisting of lung cancer, breast cancer, prostate cancer, gastric cancer, liver cancer, pancreatic cancer, ovarian cancer, colon cancer.
  • the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Sjogren's syndrome, and the underlying disease asthma.
  • the subject is a mammal; eg, bovine, equine, ovine, porcine, canine, feline, rodent, primate; For example, people.
  • Another aspect of the present application pertains to the use of a compound of the present application, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug thereof for the manufacture of a formulation for reducing or inhibiting Bruton in a cell Tyrosine kinase activity.
  • the formulation is administered to a subject (eg, mammal; eg, bovine, equine, ovine, porcine, canine, feline, rodent, in a primate; eg, a human) to reduce or inhibit the activity of Bruton's tyrosine kinase in cells in a subject; alternatively, the formulation is administered to cells in vitro (eg, a cell line or from a test cells) to reduce or inhibit Bruton's tyrosine kinase activity in cells in vitro.
  • a subject eg, mammal; eg, bovine, equine, ovine, porcine, canine, feline, rodent, in a primate; eg, a human
  • cells in vitro eg, a cell line or from a test cells
  • the cells are selected from tumor cells (eg, solid tumor cells, eg, lung cancer cells, breast cancer cells, prostate cancer cells, gastric cancer cells, liver cancer cells, pancreatic cancer cells, ovarian cancer cells, colon cancer cells) .
  • tumor cells eg, solid tumor cells, eg, lung cancer cells, breast cancer cells, prostate cancer cells, gastric cancer cells, liver cancer cells, pancreatic cancer cells, ovarian cancer cells, colon cancer cells.
  • the cells are selected from myeloid cells or lymphocytes.
  • the cells are primary cells from a subject or a culture thereof, or an established cell line.
  • Another aspect of the present application pertains to a method of reducing or inhibiting Bruton's tyrosine kinase activity in a cell, comprising administering to the cell an effective amount of a compound of the present application, a pharmaceutically acceptable salt thereof, a steric thereof Isomers or prodrugs thereof.
  • the method is performed in vivo or in vitro; preferably, the method is performed in vivo, eg, applied to a subject (eg, a mammal; eg, a bovine, equine, ovine, porcine, canine, feline, rodent, primate; eg, human) to reduce or inhibit the activity of Bruton's tyrosine kinase in cells of the subject; or, The method is performed in vitro, eg, applied to in vitro cells (eg, cell lines or cells from a subject) to reduce or inhibit Bruton's tyrosine kinase activity in in vitro cells.
  • a subject eg, a mammal; eg, a bovine, equine, ovine, porcine, canine, feline, rodent, primate; eg, human
  • the method is performed in vitro, eg, applied to in vitro cells (eg, cell lines or cells from
  • the cells are selected from tumor cells (eg, solid tumor cells, eg, lung cancer cells, breast cancer cells, prostate cancer cells, gastric cancer cells, liver cancer cells, pancreatic cancer cells, ovarian cancer cells, colon cancer cells) .
  • tumor cells eg, solid tumor cells, eg, lung cancer cells, breast cancer cells, prostate cancer cells, gastric cancer cells, liver cancer cells, pancreatic cancer cells, ovarian cancer cells, colon cancer cells.
  • the cells are selected from myeloid cells or lymphocytes.
  • the cells are primary cells from a subject or a culture thereof, or an established cell line.
  • kits comprising a compound of the present application, a pharmaceutically acceptable salt thereof, a stereoisomer or prodrug thereof, and optionally further instructions for use.
  • kits are used to reduce or inhibit Bruton's tyrosine kinase activity in a cell.
  • the cells are selected from tumor cells (eg, solid tumor cells, eg, lung cancer cells, breast cancer cells, prostate cancer cells, gastric cancer cells, liver cancer cells, pancreatic cancer cells, ovarian cancer cells, colon cancer cells) .
  • tumor cells eg, solid tumor cells, eg, lung cancer cells, breast cancer cells, prostate cancer cells, gastric cancer cells, liver cancer cells, pancreatic cancer cells, ovarian cancer cells, colon cancer cells.
  • the cells are selected from myeloid cells or lymphocytes.
  • the cells are primary cells from a subject or a culture thereof, or an established cell line.
  • Cxy used herein means a range of carbon atoms, where x and y are both integers, eg C3-8cycloalkyl means a cycloalkyl group having 3-8 carbon atoms , ie a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that “ C3-8 " also includes any subrange therein, eg, C3-7 , C3-6 , C4-7 , C4-6 , C5-6 , and the like.
  • Alkyl refers to a straight chain containing 1 to 20 carbon atoms, eg, 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms Chain or branched hydrocarbyl group.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl and 2-ethylbutyl.
  • the alkyl group may be substituted or unsubstituted.
  • alkenyl refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon double bond and usually 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms group.
  • alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-butenyl , 4-pentadienyl and 1,4-butadienyl.
  • the alkenyl group may be substituted or unsubstituted.
  • Alkynyl refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond and usually 2 to 20 carbon atoms, eg, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms group.
  • Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
  • the alkynyl group may be substituted or unsubstituted.
  • Cycloalkyl refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocarbocyclic rings, usually containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may optionally be bi- or tricyclic rings fused together, such as decalinyl, which may be substituted or unsubstituted.
  • Heterocyclyl refers to a stable 3-18-membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1-6 atoms selected from nitrogen, oxygen and sulfur heteroatoms.
  • a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, with nitrogen, carbon or sulfur selectivity on the heterocyclyl group is oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclic group can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule by a single bond through a carbon atom or a heteroatom in the ring.
  • a heterocyclyl group containing a fused ring may contain one or more aromatic or heteroaromatic rings, so long as the attachment to the remainder of the molecule is an atom on a non-aromatic ring.
  • the heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indoline, dioxolane, 1,1- Dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piper oxazinyl, piperidinyl, 4-piperidinyl, pyranyl, pyrazolidine, pyrrolidinyl, quinazinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.
  • Spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated electron system preferably 6 to 14 membered, more preferably 7 to 10 membered.
  • Spirocycloalkyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl according to the number of spiro atoms shared between rings, preferably mono-spirocycloalkyl and bis-spirocycloalkyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocyclic group.
  • Non-limiting examples of spiroheterocyclyl include:
  • “Fused heterocyclic group” refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more bicyclic bond, but none of the rings have a fully conjugated pi electron system, where one or more ring atoms are selected from nitrogen, oxygen, or a heteroatom of S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclyl groups include:
  • Aryl or “aryl” refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
  • Heteroaryl refers to a 5-16 membered ring system comprising 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 selected from nitrogen, oxygen and sulfur heteroatoms, at least one aromatic ring.
  • a heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the Nitrogen, carbon and sulfur atoms can be selectively oxidized, and nitrogen atoms can be selectively quaternized.
  • the heteroaryl group is preferably a stable 4-11 membered monoaromatic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-8 membered monoaromatic ring , which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxinyl, benzofuranonyl, benzoyl furanyl, benzonaphthofuryl, benzopyranone, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, Imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinine base, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, tri
  • the heteroaryl group is preferably a 5-8 membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl and thiazolyl.
  • the heteroaryl group can be substituted or unsubstituted.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Haldroxy refers to -OH
  • amino refers to -NH2
  • amino refers to -NHCO-
  • cyano refers to -CN
  • nitro refers to -CN
  • isocyano refers to -NC
  • Trifluoromethyl refers to -CF3 .
  • heteroatom refers to atoms other than carbon and hydrogen, the heteroatoms being independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, Without being limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different. .
  • fused or "fused ring” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
  • spiro or "spirocycle” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
  • heterocyclyl optionally substituted with alkyl means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with the alkyl group and the case where the heterocyclic group is not substituted with the alkyl group.
  • Substituted means that one or more atoms in a group, preferably 5, more preferably 1 to 3 atoms, are independently of each other substituted with the corresponding number of substituents. It goes without saying that the substituents are in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, carbon atoms with free amine or hydroxyl groups bound to carbon atoms with unsaturated (eg, olefinic) bonds may be unstable.
  • the substituents include but are not limited to hydroxyl, amine, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 8 cycloalkyl, etc.
  • “Pharmaceutical composition” refers to a composition comprising one or more of the compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • Stereoisomers include optical isomers, geometric isomers and conformational isomers.
  • the compounds of the present invention may exist in the form of optical isomers. These optical isomers are of the "R” or “S” configuration, depending on the configuration of the substituents around the chiral carbon atom.
  • Optical isomers include enantiomers and diastereomers, and methods of making and separating optical isomers are known in the art.
  • the compounds of the present invention may also exist as geometric isomers.
  • the present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around a carbon-carbon double bond or carbon-nitrogen bond are designated as the Z or E configuration, and substituents around a cycloalkyl or heterocycle are designated as the cis or trans configuration.
  • the compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.
  • the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming of the compounds or chemical formulae.
  • isotopes are all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms with the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen , carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H, 3H , 13C , 14C , 15N , 18O, 31 , respectively. P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples, using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent.
  • Such compounds have various potential uses, eg, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
  • Prodrug means that a compound of the present invention can be administered in the form of a prodrug.
  • Prodrugs refer to derivatives that are converted into biologically active compounds of the present invention under physiological conditions in vivo, eg, by oxidation, reduction, hydrolysis, etc., each with or without enzymes.
  • prodrugs are compounds in which the amine group in the compounds of the present invention is acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamineamido, pivaloyloxymethylamine , or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted to a boronate salt such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy Oxygen groups, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms disulfide bridges with carrier molecules such as peptides that selectively deliver drugs to the target and/or to the cytosol of cells, these compounds may be used by the present invention
  • the compounds are prepared according to known methods.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable” means prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention which contain acidic groups can exist in salt form and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts.
  • salts include sodium, potassium, calcium, magnesium salts or with amines or organic amines such as primary, secondary, tertiary, cyclic, etc., such as ammonia, isopropylamine, trimethylamine, dimethine
  • Particularly preferred organic bases such as ethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline and caffeine are isopropylamine, Salts of ethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • the compounds of the invention which contain basic groups can exist in salt form and can be used according to the invention in the form of their additions to inorganic or organic acids.
  • suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propylene acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid , adipic acid and other acids known to those skilled in the art.
  • the present invention includes, in addition to the salt forms mentioned, inner or betaine salts.
  • the respective salts are obtained by conventional methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.
  • a compound when referring to "a compound”, “a compound of the present invention” or “a compound of the present invention” in this application, it includes all such compound forms, such as prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, Isomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof.
  • tumor includes benign tumors and malignant tumors (eg, cancer).
  • cancer includes various malignancies in which Bruton's tyrosine kinases are involved, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, cell carcinoma, multiple myeloma, Breast ovarian cancer, uterine lining cancer, cervical cancer, stomach cancer, node cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (eg hepatocellular carcinoma), more particularly liver cancer, stomach cancer and bladder cancer.
  • non-small cell lung cancer esophageal cancer
  • melanoma melanoma
  • rhabdomyosarcoma cell carcinoma
  • multiple myeloma breast ovarian cancer
  • uterine lining cancer cervical cancer, stomach cancer, node cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (eg hepatocellular carcinoma), more particularly liver cancer, stomach cancer and bladder cancer.
  • an "effective amount” for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition.
  • An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.
  • polymorph or “polymorph (phenomenon)" means that the compounds of the present invention have multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form. The present invention covers All polymorphs or mixtures thereof.
  • solvate refers to a complex consisting of one or more molecules of the compound of the present invention in combination with one or more molecules of a solvent.
  • the solvent may be water, in which case the solvate is a hydrate.
  • an organic solvent may be used.
  • the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may only accidentally retain water or a mixture of water and some other solvent.
  • the compounds of the present invention may be reacted in a solvent or in a solvent Precipitation or crystallization. Solvates of the compounds of the present invention are also included within the scope of the present invention.
  • the term "pharmaceutically acceptable” refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, Dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.
  • subject refers to an individual suffering from a disease, disorder or condition, etc., including mammals and non-mammals
  • mammals include, but are not limited to, the class of mammals Any member of: humans, non-human primates (eg chimpanzees and other apes and monkeys); domestic animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals , including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • treatment refers to the treatment of related disease conditions in mammals, particularly humans, including
  • disease and “disorder” can be used interchangeably or have different meanings, because some specific diseases or conditions have no known causative agent (so the cause of the disease is not clear), so they cannot be considered as A disease can only be seen as an unwanted condition or syndrome which has more or less specific symptoms that have been confirmed by clinical researchers.
  • administering refers to methods that enable the delivery of a compound or composition to the desired site of biological action. These include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
  • the present invention also provides methods for preparing the compounds.
  • the preparation of the compounds of the general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be construed as limiting the scope of the present invention in any way.
  • the compounds of the present invention can also be synthesized using synthetic techniques known to those skilled in the art, or a combination of methods known in the art and methods described in the present invention.
  • the products obtained in each step are obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, and the like.
  • the starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (reaxys).
  • temperatures are in degrees Celsius.
  • Reagents were purchased from commercial suppliers such as Chemblocks Inc or Phase Pharma, and these reagents were used directly without further purification unless otherwise stated.
  • column chromatography used 200-300 mesh silica gel from Qingdao Ocean Chemical Factory;
  • preparative thin-layer chromatography used thin-layer chromatography silica gel plate (HSGF254) produced by Yantai Chemical Industry Research Institute; MS was measured with Therno LCD Fleet type (ESI) liquid chromatography-mass spectrometer.
  • the nuclear magnetic data (1H NMR) used Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instrument, the solvents used for nuclear magnetic data were CDCl 3 , CD 3 OD, D 2 O, DMS-d 6 , etc., with tetramethylsilane (0.000ppm) ) or residual solvent (CDCl 3 : 7.26 ppm; CD 3 OD: 3.31 ppm; D 2 O: 4.79 ppm; d6-DMSO: 2.50 ppm) When the peak shape diversity is indicated, the following abbreviations denote different peaks Shape: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet doublet), dt (doublet triplet) peak). If a coupling constant is given, it is in Hertz (Hz).
  • N-bromosuccinimide (5.2 g, 29.6 mmol) was added to 4,6-dichloro-2oxo-imidazo[4,5-c]]pyridine (5.6 g, 27 mmol) in acetic acid (100 mL) ) in the solution. After stirring at 60°C for 2 hours, the acetic acid was removed under reduced pressure. The residue was suspended in water (60 mL), and saturated sodium bicarbonate solution (40 mL) was added. The solid was filtered and stirred in water (200 mL) at 80°C for 30 minutes.
  • N,N,N',N'-tetramethylethylenediamine (9 g, 50.1 mmol) was added to the product from the previous step, 4,6-dichloro-6-bromo-2oxo-imidazo[4,5- c]]Pyridine (5.64 g, 20 mmol) was in a solution of dry tetrahydrofuran (100 mL) and the solution was stirred at -60°C for 1 min under nitrogen.
  • n-Butyllithium (20.4 mL, 50.1 mmol, 2.5M in hexanes) was added slowly, and the mixture was stirred for 2 hours. Dry carbon dioxide gas was bubbled into the solution, and the mixture was stirred at -60°C for 1 hour.
  • 4,6-Dichloro-2oxo-imidazo[4,5-c]]pyridine-7-carboxylic acid (2.49 g, 10 mmol) was dissolved in thionyl chloride (40 ml), and the mixture was heated at 75 °C Stir for 2 hours. Excess thionyl chloride was removed under vacuum and the residue was dissolved in dry tetrahydrofuran (40 mL). Aqueous ammonia (6.0 mL) was added at 0°C, and the mixture was stirred at ambient temperature for 10 hours.
  • N,N,N',N'-tetramethylethylenediamine (9 g, 50.1 mmol) was added to the product from the previous step, 4,6-dichloro-6-bromopyrazole[4,5-c]] and Pyridine (5.64 g, 20 mmol) was in a solution of dry tetrahydrofuran (100 mL), and the solution was stirred at -60 °C for 1 min under nitrogen.
  • n-Butyllithium (20.4 mL, 50.1 mmol, 2.5M in hexanes) was added slowly, and the mixture was stirred for 2 hours. Dry carbon dioxide gas was bubbled into the solution, and the mixture was stirred at -60°C for 1 hour.
  • 4,6-Dichloropyrazoloimidazo[4,5-c]]pyridine-7-carboxylic acid (2.49 g, 10 mmol) was dissolved in thionyl chloride (40 ml), and the mixture was stirred at 75°C for 2 hours . Excess thionyl chloride was removed under vacuum and the residue was dissolved in dry tetrahydrofuran (40 mL). Aqueous ammonia (6.0 mL) was added at 0°C, and the mixture was stirred at ambient temperature for 10 hours.
  • n-Butyllithium (27.8 mL, 2.5M solution in hexane, 69.6 mmol) was added to a solution of diisopropylamine (7.5 g, 74.3 mmol) in tetrahydrofuran (50 mL) at -78°C, The mixture was stirred at -78°C for 30 minutes and a solution of 2,6-dichloro-nitropyridine (19.0 g, 67.6 mmol) in tetrahydrofuran (50 mL) was added during 40 minutes. The mixture was stirred at -78°C for 3 hours. Dry carbon dioxide was bubbled into the reaction mixture, and the mixture was stirred at ambient temperature overnight.
  • 2,6-Dichloro-4-nitronicotinic acid 49 g, 154 mmol was dissolved in dry THF (1000 mL), cooled to between -40 °C and -50 °C and stirred for about 5 mm. Then vinyl bromide was added dropwise Magnesium (in THF, 692 mL, 692 mmol). The mixture was stirred between about -40°C and -50°C for about 4 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL).
  • the product 10b (18.59g, 0.05mol) obtained in the previous step, 4-phenoxyphenylboronic acid (10.7g, 0.05mol), tris(dibenzylideneacetone)dipalladium (4g, 4.4mmol), cesium carbonate, After mixing 1,4-dioxane (500 mL) and water (100 mL), the mixture was heated to 120° C. under reflux, and the reaction was stirred for 16 hours. The reaction was cooled to room temperature and stirred overnight to give a pale yellow precipitate. The reaction mixture was diluted with water (10 mL) and the solid was collected by filtration.
  • Step 1 Synthesis of compound 6-(4-phenoxyphenyl-2-oxo-imidazo[4,5-c]pyridine-8-carboxamide 20b
  • the compound is obtained by reacting the intermediate (S)-5-(3-aminopiperidine)-2,3-dioxo-pyrido[3,4-b]opyrazine-8-carboxamide with acrylic acid from Example 28 30 (250 mg, 65% yield) was a pale yellow solid.
  • Example 28 The method of Example 28 was used for procurement, and the intermediate (S)-2-(3-tert-butoxycarbonylaminopiperidine)-3,4-diamino-5 cyano-pyridine was reacted with urea, and the subsequent 2 steps were the same as those in Example 1.
  • Compound 38 (238 mg, 62% yield) was similarly obtained as a yellow solid.
  • Racemate (R,S)-4-(1-acrylamidopiperidin-3-yl)-2-oximidazo[4,5-c]pyridine-7-carboxamide was separated by chiral column to obtain the compound 41 and 42.
  • the MS (ESI) of both were consistent with the racemate.
  • Table 1 lists the activities of representative compounds of the present invention in the BTK assay. In these assays, the following scales are used: for IC50 , where "A” means IC50 ⁇ 10nM; “B” means 10 ⁇ IC50 ⁇ 100nM ;”C” means 100 ⁇ IC50 ⁇ 500nM ;"D" Indicates that 500 ⁇ IC 50 ⁇ 2000nM.
  • Sample serial number BTKIC 50 (nM) Sample serial number BTKIC 50 (nM) 1 A twenty two A 2 A twenty three A 3 A twenty four A 4 A 25 A 5 A 26 A 6 A 27 A 7 A 28 A 8 A 36 A 9 A 38 A 18 A 40 A 19 A 41 A 20 A 42 A twenty one A A
  • Cell viability was assessed by measuring adenosine triphosphate (ATP) content using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, #G7572, Madison, WI).
  • Diffuse large B-cell lymphoma cell line TMD-8 was purchased from the American Type Culture Collection (ATCC).
  • ATCC American Type Culture Collection
  • Cell density was determined by counting with a Scepter automated cell counter (Millipore, #PHCC00000) after cells were trypsinized from the cell culture dishes and resuspended in DPBS medium. Cells were diluted to a solution containing 44,000 cells per milliliter. The density-adjusted cell solution was added to the cell assay plate at 90 ⁇ l per well.
  • the plate was placed in a 37°C, 5% CO2 incubator for 24 hours and then different concentrations of the compounds to be tested were added. Cells were incubated with compounds in the presence of 10% fetal bovine serum for 72 hours. use The Luminescent Cell Viability Assay kit (see manufacturer's instructions) measures ATP levels to assess cell growth inhibition. Briefly, 30 [mu]l of [image] reagent was added to each well, the plate was shaken for 10 minutes, cell lysis was induced, and the fluorescent signal was recorded by detection with a Fluoroskan Ascent FL (ThermoScientific Fluoroskan Ascent FL), a fluorescence/chemiluminescence analyzer.
  • Fluoroskan Ascent FL ThermoScientific Fluoroskan Ascent FL
  • Table 2 lists the anti-cellular proliferative activity of the compounds of the present application in cell-based assays. In these assays, the following scales are used: for IC50 , where "A” means IC50 ⁇ 10nM; “B” means 10 ⁇ IC50 ⁇ 100nM ;”C” means 100 ⁇ IC50 ⁇ 500nM ;"D” Indicates that 500 ⁇ IC 50 ⁇ 2000nM.
  • the compounds of the present application have strong anti-proliferative activity against tumor cells such as TMD-8.
  • Sample serial number TMD-8 IC 50 (nM) Sample serial number TMD-8 IC 50 (nM) twenty three A 38 A 25 A 40 A 26 A 41 A 27 A 42 A

Abstract

作为BTK抑制剂的杂环类化合物、其制备方法及其医药学上的应用。具体而言，本发明涉及一种通式(I)的所示的化合物及其可药用的盐，含有所述化合和或其药用的盐的药物组合物、应用所述化合物或可药用的盐治疗或者预防BTK相关性病症、特别是肿瘤的药物中的用途，这是一类杂环类化合物，同时公开了该类化合物的或其可药用的盐的药物组合物的制备方法。其中通式(I)的各取代基与说明书中的定义相同。

Description

Bruton’s酪氨酸激酶抑制剂及其应用
相关申请的交叉
本申请要求申请日为申请日为2021年2月3日的中国专利申请PCT/CN2021101525064的优先权、申请日为2021年2月23日的中国专利申请PCT/CN2021102030745的优先权、申请日为2021年2月23日的中国专利申请PCT/CN2021102037015的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明公开了作为BTK抑制剂的化合物，对于通过抑制BTK可治疗的疾病的治疗是有用的。还提供了含有该化合物的药物组合物和用于制备该化合物的方法。
技术背景
Bruton's酪氨酸激酶是非受体蛋白酪氨酸激酶Tec家族的成员。Tec家族是人类非受体激酶中仅次于Src家族的第2大家族，其主要成员包括Bruton's酪氨酸激酶、BMX(etk)、ITK、TEC和TXK(PLK)。Bruton's酪氨酸激酶在1993年被确定为人X-连锁无丙种球蛋白血症(X-linked agammaglobulinemia，XLA)中的缺陷蛋白。这种蛋白在B细胞各个发展阶段均有表达(除了最终分化的浆细胞)，在前B淋巴细胞过渡为后期B细胞过程中，Bruton's酪氨酸激酶为细胞分化和增值所必需基因，且在B细胞淋巴瘤、急性淋巴细胞白血病(ALL)和浆细胞瘤中均有表达。此外，在骨髓细胞和红系祖细胞中也有少量表达。
目前，依鲁替尼(ibrutinib)、阿卡替尼(acalabrutinib)和泽布替尼(Zanubrutinib)等Bruton's酪氨酸激酶小分子抑制剂被美国FDA批准上市，用于治疗套细胞淋巴瘤(MCL)和CLL。
虽然依鲁替尼、阿卡替尼和泽布替尼治疗效果显著，但是临床上的B细胞淋巴瘤患者除了一部分患者在后期产生抗药耐受外，还有相当一部分患者对其治疗不敏感，比如在MCL中约有1/3患者对其治疗无应答，DLBCL中的应答率也不高。鉴于以上问题，本领域仍然需要开发活性高、特异性强的Bruton's酪氨酸激酶抑制剂。
发明内容
为解决上述问题，本发明提供了式(I)所示的一种新型Bruton's酪氨酸激酶抑制剂的化合物或其立体异构体、稳定同位素衍生物、水合物、溶剂化物、药学上可接受的盐：
Figure PCTCN2021141767-appb-000001
R可以独立地选自H，D，
Figure PCTCN2021141767-appb-000002
L 1独立地选自-C 0-4烷基-、-CR 1R 2-、-C 1-2烷基(R 1)(OH)-、-C(O)-、-CR 1R 2O-、-OCR 1R 2-、-SCR 1R 2-、-CR 1R 2S-、-NR 1-、-NR 1C(O)-、-C(O)NR 1-、-NR 1C(O)NR 2-、-CF 2-、-O-、-S-、-S(O) m-、-NR 1S(O) 2-、-S(O) 2NR 1-；
L 2独立地选自-C 0-4烷基-、-CR 1R 2-、-C 1-2烷基(R 1)(OH)-、-C(O)-、-CR 1R 2O-、-OCR 1R 2-、-SCR 1R 2-、-CR 1R 2S-、-NR 1-、-NR 1C(O)-、-C(O)NR 1-、-NR 1C(O)NR 2-、-CF 2-、-O-、-S-、-S(O) m-、-NR 1S(O) 2-、-S(O) 2NR 1-；
Ar 1和Ar 2独立地选苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G 1所取代；
X可以独立地选自N、CR 3；
Figure PCTCN2021141767-appb-000003
独立地选自为如下结构：
Figure PCTCN2021141767-appb-000004
其中n为1或者2；
U独立地选自键、-C 1-4烷基-、-CR 4R 5-、-C 1-2烷基(R 4)(OH)-、-C(O)-、-CR 4R 5O-、-OCR 4R 5-、-SCR 4R 5-、-CR 4R 5S-、-NR 4-、-NR 4C(O)-、-C(O)NR 4-、-NR 4C(O)NR 5-、-CF 2-、-O-、-S-、-S(O) m-、-NR 4S(O) 2-、-S(O) 2NR 4-；
Y不存在或选C 3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G 3所取代；
Z独立地选自氰基、-NR 12CN、
Figure PCTCN2021141767-appb-000005
键a为双键或者三键；
当a为双键时，R a 、R b和R c各自独立地选自H、D、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G 4所取代；R a和R b或R b和R c任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
当键a为三键时，R a和R c不存在，R b独立选自H、D、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基被一个或多个G 5所取代；
R 12独立地选自H、D、C 1-6烷基、C 3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G 6所取代；
G 1、G 2、G 3、G 4、G 5和G 6各自独立选自H、D、氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 6、-OC(O)NR 6R 7、-C(O)OR 6、-C(O)NR 6R 7、-C(O)R 6、-NR 6R 7、-NR 6C(O)R 7、-NR 6C(O)NR 7R 8、-S(O) mR 6或-NR 6S(O) mR 7，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 9、-OC(O)NR 9R 10、-C(O)OR 9、-C(O)NR 9R 10、-C(O)R 9、-NR 9R 10、-NR 9C(O)R 10、-NR 9C(O)NR 10R 11、-S(O) mR 9或-NR 9S(O) iR 10的取代基所取代；
R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立选自H、D、氰基、卤素、C 1-6烷基、C 3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；
且m为1或2。
在一些实施方式中，所述的通式(I)的化合物、其药学上可接受的盐或其立体异构体，通式(I)进一步如通式Ia所示：
Figure PCTCN2021141767-appb-000006
X1，X2，X3可以独立地选自N、CR 1；
Ar 1和Ar 2独立地选苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G 1所取代；
R 1独立地选自H、D、氰基、卤素、C 1-6烷基、COOH、CONH 2、NHCOH、CONHR2、OR 2或-NHR 2；
R 2独立地选自H、D、氰基、卤素、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-OR 3、-NR 3R 4、-C(O)NR 3R 4，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 5、-NR 5R 6、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
L 1，L 2和U独立地选自键、-C 1-4烷基-、-CR 7R 8-、-C 1-2烷基(R 7)(OH)-、-C(O)-、-CR 7R 8O-、-OCR 7R 8-、-SCR 7R 8-、-CR 7R 8S-、-NR 7-、-NR 7C(O)-、-C(O)NR 7-、-NR 7C(O)NR 8-、-CF 2-、-O-、-S-、-S(O) m-、-NR 7S(O) 2-、-S(O) 2NR 7-；
Y不存在或选C 3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G 2所取代；
Z独立地选自氰基、-NR 9CN、
Figure PCTCN2021141767-appb-000007
键a为双键或者三键；
当a为双键时，R a 、R b和R c各自独立地选自H、D、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G 3所取代；R a和R b或R b和R c任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
当键a为三键时，R a和R c不存在，R b独立选自H、D、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基被一个或多个G 4所取代；
R 12独立地选自H、D、C 1-6烷基、C 3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G 5所取代；
G 1、G 2、G 3、G 4和G 5各自独立选自氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 10、-OC(O)NR 10R 11、-C(O)OR 10、-C(O)NR 10R 11、-C(O)R 10、-NR 10R 11、-NR 10C(O)R 11、-NR 10C(O)NR 11R 12、-S(O) mR 10或-NR 10S(O) mR 11，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 13、-OC(O)NR 13R 14、-C(O)OR 13、-C(O)NR 13R 14、-C(O)R 13、-NR 13R 14、 -NR 13C(O)R 14、-NR 13C(O)NR 14R 15、-S(O) mR 13或-NR 13S(O) iR 14的取代基所取代；R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 13、R 14和R 15各自独立选自氢、氰基、卤素、C 1-6烷基、C 3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；
且m为1或2。
在一些实施方式中，所述的通式(I)的化合物、其药学上可接受的盐或其立体异构体，通式(I)进一步如通式Ib所示：
Figure PCTCN2021141767-appb-000008
X 1，X 2，X 3，X 4可以独立地选自N、CR 1；
键a、b为单键或者双键；
Ar 1和Ar 2独立地选苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G 1所取代；
R 1独立地选自H、D、氰基、卤素、C 1-6烷基、COOH、CONH 2、NHCOH、CONHR 2、OR 2或-NHR 2；
R 2独立地选自H、D、氰基、卤素、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-OR 3、-NR 3R 4、-C(O)NR 3R 4，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 5、-NR 5R 6、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
L 1，L 2和W独立地选自-C 0-4烷基-、-CR 7R 8-、-C 1-2烷基(R 7)(OH)-、-C(O)-、-CR 7R 8O-、-OCR 7R 8-、-SCR 7R 8-、-CR 7R 8S-、-NR 7-、-NR 7C(O)-、-C(O)NR 7-、-NR 7C(O)NR 8-、-CF 2-、-O-、-S-、-S(O) m-、-NR 7S(O) 2-、-S(O) 2NR 7-；
Y不存在或选C 3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G 2所取代；
Z独立地选自氰基、-NR 12CN、
Figure PCTCN2021141767-appb-000009
键c为双键或者三键；
当c为双键时，R a、R b和R c各自独立地选自H、D、氰基，卤素、C 1-6烷基、C 3-6环烷 基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G 3所取代；
R a和R b或R b和R c任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；当键c为三键时，R a和R c不存在，R b独立选自H、D、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基被一个或多个G 4所取代；
R 9独立地选自H、D、C 1-6烷基、C 3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G 5所取代；
G 1、G 2、G 3、G 4和G 5各自独立选自氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 10、-OC(O)NR 10R 11、-C(O)OR 10、-C(O)NR 10R 11、-C(O)R 10、-NR 10R 11、-NR 10C(O)R 11、-NR 10C(O)NR 11R 12、-S(O) mR 10或-NR 10S(O) mR 11，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 13、-OC(O)NR 13R 14、-C(O)OR 13、-C(O)NR 13R 14、-C(O)R 13、-NR 13R 14、-NR 13C(O)R 14、-NR 13C(O)NR 14R 15、-S(O) mR 13或-NR 13S(O) iR 14的取代基所取代；R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 13、R 14和R 15各自独立选自氢、氰基、卤素、C 1-6烷基、C 3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；
且m为1或2。
在一些实施方式中，所述的通式(I)的化合物、其药学上可接受的盐或其立体异构体，通式(I)进一步如通式Ic所示：
Figure PCTCN2021141767-appb-000010
X 1，X 2可以独立地选自N、CR 1；
X 3可以独立地选自不存在、N、CR 1；
键a、b为单键或者双键；
R 1独立地选自H、D、氰基、卤素、C 1-6烷基、COOH、CONH 2、NHCOH、CONHR 2、OR 2或-NHR 2；
R 2独立地选自H、D、氰基、卤素、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-OR 3、-NR 3R 4、-C(O)NR 3R 4，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 5、-NR 5R 6、C 1-6 烷基、C 3-6环烷基或3-6元杂环烷基；
W独立地选自键、-C 1-4烷基-、-CR 7R 8-、-C 1-2烷基(R 7)(OH)-、-C(O)-、-CR 7R 8O-、-OCR 7R 8-、-SCR 7R 8-、-CR 7R 8S-、-NR 7-、-NR 7C(O)-、-C(O)NR 7-、-NR 7C(O)NR 8-、-CF 2-、-O-、-S-、-S(O) m-、-NR 7S(O) 2-、-S(O) 2NR 7-；
Y不存在或选C 3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G 1所取代；
Z独立地选自氰基、-NR 12CN、
Figure PCTCN2021141767-appb-000011
键c为双键或者三键；
当c为双键时，R a 、R b和R c各自独立地选自H、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G 2所取代；
R a和R b或R b和R c任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
当键c为三键时，R a和R c不存在，R b独立选自H、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基被一个或多个G 3所取代；
R 9独立地选自H、C 1-6烷基、C 3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G 4所取代；
G 1、G 2、G 3和G 4各自独立选自氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 10、-OC(O)NR 10R 11、-C(O)OR 10、-C(O)NR 10R 11、-C(O)R 10、-NR 10R 11、-NR 10C(O)R 11、-NR 10C(O)NR 11R 12、-S(O) mR 10或-NR 10S(O) mR 11，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 13、-OC(O)NR 13R 14、-C(O)OR 13、-C(O)NR 13R 14、-C(O)R 13、-NR 13R 14、-NR 13C(O)R 14、-NR 13C(O)NR 14R 15、-S(O) mR 13或-NR 13S(O) iR 14的取代基所取代；
R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 13、R 14和R 15各自独立选自氢、氰基、卤素、C 1-6烷基、C 3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；
且m为1或2。
在一些实施方式中，式(I)所述的化合物或者其异构体、溶剂合物或其前体，或它们的药学上可接受的盐选自以下化合物、其异构体、溶剂合物或其前体，或它们的药学上可接受的盐：
Figure PCTCN2021141767-appb-000012
Figure PCTCN2021141767-appb-000013
本发明提供了所述的一种新型Bruton's酪氨酸激酶抑制剂或其异构体、水合物、溶剂化 物、多晶型物、药学上可接受的盐，以及药学上可接受载体在制备新型Bruton's酪氨酸激酶抑制剂中的用途。
任选地，本申请的药物组合物还包含一种或多种药用辅料。
本申请的药用辅料是指生产药品和调配处方时，使用的赋形剂和附加剂，是指除活性成分外，在安全性方面已进行了合理的评估，并且包含在药物制剂中的物质。药用辅料除了赋型、充当载体、提高稳定性外，还具有增溶、助溶、缓控释等重要功能，是可能会影响到药品的质量、安全性和有效性的重要成分。药用辅料根据来源可分为天然物、半合成物和全合成物；根据其作用与用途可分为：溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、湿润剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等；根据其给药途径可分为口服、注射、黏膜、经皮或局部给药、经鼻或口腔吸入给药和眼部给药等。同一药用辅料可用于不同给药途径的药物制剂，且有不同的作用和用途。
本申请的药物组合物可根据给药途径制成各种适宜的剂型。
当口服用药时，所述药物组合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊剂、颗粒剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂等。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。口服混悬剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当经皮或局部施用时，所述药物组合物可制成适当的软膏、洗剂或搽剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或搽剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
所述药物组合物还可以注射剂形式用药，包括注射液、注射用无菌粉末与注射用浓溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
任选地，本申请的化合物、其药学上可接受的盐、其立体异构体或其前药可与第二治疗剂联合施用。因此，任选地，本申请的药物组合物还包含一种或多种第二治疗剂。在某些实 施方案中，所述第二治疗剂为化疗药物、靶向抗癌药或免疫治疗药。在某些实施方案中，所述第二治疗剂选自利妥昔单抗、来那度胺、氟达拉滨、环磷酰胺、阿霉素、长春新碱、强的松。
本申请的一个方面涉及本申请的化合物、其药学上可接受的盐、其立体异构体或其前药用于制备药物的用途，所述药物用于预防和/或治疗受试者的与布鲁顿酪氨酸激酶过度活性相关的疾病和/或症状。
本申请的一个方面涉及本申请的化合物、其药学上可接受的盐、其立体异构体或其前药用于制备药物的用途，所述药物用于预防和/或治疗受试者的与布鲁顿酪氨酸激酶过度活性相关的疾病和/或症状。
在某些实施方案中，所述与布鲁顿酪氨酸激酶过度活性相关的疾病和/或症状选自肿瘤(例如血液肿瘤或实体瘤)、炎症或自身免疫性疾病。
在某些实施方案中，所述血液肿瘤选自淋巴瘤、骨髓瘤、淋巴细胞白血病、急性髓系白血病。
在某些实施方案中，所述实体瘤选自肺癌、乳腺癌、前列腺癌、胃癌、肝癌、胰腺癌、卵巢癌、结肠癌。
在某些实施方案中，所述炎症或自身免疫性疾病选自类风湿关节炎、红斑狼疮、狼疮性肾炎、多发性硬化症、肖格伦综合征及潜在疾病哮喘。
在某些实施方案中，所述受试者为哺乳动物；例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；例如，人。
本申请的另一个方面涉及本申请的化合物、其药学上可接受的盐、其立体异构体或其前药用于制备制剂的用途，所述制剂用于降低或抑制细胞中的布鲁顿酪氨酸激酶活性。
在某些实施方案中，所述制剂被施用至受试者(例如哺乳动物；例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；例如，人)体内，以降低或抑制受试者体内细胞中的布鲁顿酪氨酸激酶的活性；或者，所述制剂被施用至体外细胞(例如细胞系或者来自受试者的细胞)，以降低或抑制体外细胞中的布鲁顿酪氨酸激酶活性。
在某些实施方案中，所述细胞选自肿瘤细胞(例如实体瘤细胞，例如肺癌细胞、乳腺癌细胞、前列腺癌细胞、胃癌细胞、肝癌细胞、胰腺癌细胞、卵巢癌细胞、结肠癌细胞)。
在某些实施方案中，所述细胞选自髓系细胞或淋巴细胞。
在某些实施方案中，所述细胞为来自受试者的原代细胞或其培养物，或已建立的细胞系。
本申请的另一个方面涉及一种降低或抑制细胞中的布鲁顿酪氨酸激酶活性的方法，包括给所述细胞使用有效量的本申请的化合物、其药学上可接受的盐、其立体异构体或其前药。
在某些实施方案中，所述方法在体内或者体外进行；优选地，所述方法在体内进行，例如应用于受试者(例如哺乳动物；例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；例如，人)体内，以降低或抑制受试者体内细胞中的布鲁顿酪氨酸激酶的活性；或者，所述方法在体外进行，例如应用于体外细胞(例如细胞系或者来自受试者的细胞)，以降低或抑制体外细胞中的布鲁顿酪氨酸激酶的活性。
在某些实施方案中，所述细胞选自肿瘤细胞(例如实体瘤细胞，例如肺癌细胞、乳腺癌细胞、前列腺癌细胞、胃癌细胞、肝癌细胞、胰腺癌细胞、卵巢癌细胞、结肠癌细胞)。
在某些实施方案中，所述细胞选自髓系细胞或淋巴细胞。
在某些实施方案中，所述细胞为来自受试者的原代细胞或其培养物，或已建立的细胞系。
本申请的另一个方面涉及一种试剂盒，所述试剂盒包括本申请的化合物、其药学上可接受的盐、其立体异构体或其前药，且任选地还包括使用说明。
在某些实施方案中，所述试剂盒用于降低或抑制细胞中的布鲁顿酪氨酸激酶活性。
在某些实施方案中，所述细胞选自肿瘤细胞(例如实体瘤细胞，例如肺癌细胞、乳腺癌细胞、前列腺癌细胞、胃癌细胞、肝癌细胞、胰腺癌细胞、卵巢癌细胞、结肠癌细胞)。
在某些实施方案中，所述细胞选自髓系细胞或淋巴细胞。
在某些实施方案中，所述细胞为来自受试者的原代细胞或其培养物，或已建立的细胞系。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改，替换或变更。
以下通过实施形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅于以下的实例。凡基于上述内容所实现的技术均属于本发明的范围。
某些化学术语
除非有相反陈述，否则下列用在说明书和权利要求书中的术语。
具有下述含义在本文中使用的表示方式“C x-y”表示碳原子数的范围、其中x和y均为整数，例如C 3-8环烷基表示具有3-8个碳原子的环烷基，即具有3、4、5、6、7或8个碳原子的环烷基。还应理解，“C 3-8”还包含其中的任意亚范围、例如C 3-7、C 3-6、C 4-7、C 4-6、C 5-6等。
“烷基”指含有1至20个碳原子，例如1至18个碳原子、1至12个碳原子、1至8 个碳原子、1至6个碳原子或1至4个碳原子的直链或支链的烃基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基和2-乙基丁基。所述烷基可以是取代的或未取代的。
“烯基”指含有至少一个碳碳双键和通常2至20个碳原子例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。烯基的非限制性实例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-2-丙烯基、1，4-戊二烯基和1，4-丁二烯基。所述烯基可以是取代的或未取代的。
“炔基”指含有至少一个碳碳三键和通常2至20个碳原子，例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。炔基的非限制性实例包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基。所述炔基可以是取代的或未取代的。
“环烷基”指含有3至14个碳环原子的饱和环形烃基取代基。环烷基可以是单碳环，通常含有3至7个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基和环庚基。环烷基可选择地可以是稠合到一起的双或三环、如十氢萘基、所述环烷基可以是取代的或未取代的。
“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。为了本申请，杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢吡喃基等。
“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。 这些可以含有一个或多个双键，但没有一个环具有完全共扼的电子系统优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环基。螺杂环基的非限制性实施例包含：
Figure PCTCN2021141767-appb-000014
“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实施例包含：
Figure PCTCN2021141767-appb-000015
“芳基”或“芳香基”指含有6至14个碳原子的芳香族单环或稠合多环基团，优选为6至10元，例如苯基和萘基，更优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上、其中与母体结构连接在一起的环为芳基环。
“杂芳基”或“杂芳香基”是指5-16元环状系统，其包含1-15个碳原子，优选的1-10个碳原子，1-4个选自氮，氧和硫的杂原子，至少一个芳香环。除非另作说明，杂芳基可以是单环、双环、三环或四环系统，其可能包含稠环或桥环系统，只要与分子其它部分的连接点为芳环原子，杂芳环上的氮原子、碳原子和硫原子可以透择性的被氧化，氮原子可选择性的被季铵化。为了本发明，杂芳基优选的为稳定的4-11元单芳香环，其包含1-3个选自氮、氧和硫的杂原子，更优选的为稳定的5-8元单芳香环，其包含1-3个选自选自氮、氧和硫的杂原子。杂芳基的非限定性实例包括吖啶基、氮杂卓基、苯并咪唑基、苯并吲哚基、苯并二氧芑基、苯并二恶茂基、苯并呋喃酮基、苯并呋喃基、苯并萘并呋喃基、苯并吡喃酮基、苯并吡喃基、苯并吡唑基、苯并噻二唑基、苯并噻唑基、苯并三唑基、呋喃基、咪唑基、吲唑基、吲哚基、恶唑基、嘌呤基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、奎宁基、四唑基，噻二唑基、噻唑基、噻吩基、三嗪基，三唑基等。本申请 中，杂芳基优选为5-8元杂芳基，其包含1-3选自选自氮、氧和硫的杂原子，更优选为吡啶基、嘧啶基、噻唑基。所述杂芳基可以是取代的或未取代的。
“卤素”指氟、氯、溴或碘。
“羟基”指-OH，“氨基”指-NH 2，“酰胺基”指-NHCO-，“氰基”指-CN，“硝基”指-CN，“异氰基”指-NC，“三氟甲基”指-CF 3。
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子，杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子，在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部此不同。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个原子，较佳为5个、更佳为1～3个原子彼此独立地被相应数目的取代基取代。不言而喻，取代基处在它们的可能的化学位置本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离的胺基或羟基与具有不饱和(如烯烃)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于羟基、胺基、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基等。
“药物组合物”指含有一种或多种本文所述的化合物或其可药用的盐或前药以及其他分例如可药用的载体和赋形剂的组合物。药物组合物的目的是促对生物体的给药、利于活性成分的吸收进而发挥生物活性。
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物称为“异构体”、其原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。本发明的化合物可以以光学异构体形式存在。根据手性碳原子周围取代基的构型，这些光学异构体是“R”或“S”构型。光学异构体包括对映异构体和非对映异构体、制备和分离光学异构体的方法是本领域中已知的。
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团周的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型、环烷基或杂环周围的取代基指定为顺式或反式构型。
本发明的化合物还可能显示互变异构现象，例如酮-烯醇互变异构。
应该理解，本发明包括任何互变异构或立体异构形式和其混合物、并且不仅限于化合物的命名或化学结式中所使用的任何一个互变异构或立体异构形式。
“同位素”是在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯，分别例如但不限于 2H、 3H、 13C、 14C、 15N、 18O、 31P、 32P、 35S、 18F和 36Cl。本发明的同位素标记化合物通常可通过本域技术人员已知的传统技术或通过与所附实施例中描的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的剂制。这样的化合物具有各种潜在用途、例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下，这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。
“前药”是指本发明的化合物可以以前药的形式给予。前药是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例是下述化合物：其中本发明的化合物中的胺基被酰化、烷基化或磷酸化，例如二十烷酰基胺基、丙胺酰胺基、新戊酰氧基甲基胺基、或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙胺酰氧基、或其中羧基被酯化或酰胺化，或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子，例如肽形成二硫桥键、这些化合物可以由本发明的化合物根据公知方法制备。
“可药用的盐”或者“药学上可接受的”是指由可药用的碱或酸，包括无机碱或酸和有机碱或酸制成的。在本发明的化合物含有一个或多个酸性或碱性基团的情况下，本发明还包含它们相应的可药用盐。因此，含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用，例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与胺或有机胺，例如伯胺、仲胺、叔胺、环胺等，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二环己胺、乙二胺、嘌呤、哌嗪、哌啶、胆碱和咖啡因等特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因的盐。含有碱性基团的本发明的化合物可以盐形式存在并可根据本发明以它们与无机或有机酸的加成的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、 磷酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、胺基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团，本发明除所提到的盐形式外还包括内盐或内铵盐。各盐通过本领域技术人员已知的常规方法获得，例如通过在溶剂或分散剂中使这些与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。
因此，在本申请中当提及“化合物”、“本发明化合物”或“本发明所化合物”时，包括所有所述化合物形式、例如其前药、稳定同位素衍生物、可药用的盐、异构体、内消旋体、外消旋体、对映异构体、非对映异体及其混合物。
在本文中、术语“肿瘤”包括良性肿瘤和恶性肿瘤(例如癌症)。
在本文中，术语“癌症”包括Bruton's酪氨酸激酶参与其发生的各种恶性肿瘤、包括但不限于非小细胞肺癌、食管癌、黑色素瘤、横纹肌肉榴、细胞癌、多发性骨髓瘤、乳腺癌卵巢癌、子宫膜癌、宫颈癌、胃癌、结癌、膀胱癌、胰腺癌、肺癌、乳腺癌、前列腺癌和肝癌(例如肝细胞癌)，更具体为肝癌、胃癌和膀胱癌。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶型格形态，本发明的一些化合物可能有一个以上的晶体形式，本发明涵盖所有的多品型态或其混合物。
本发明化合物的中间体化合物及其多品形物也在本发明的范围内。
结晶经常产生本发明化合物的溶剂化物，本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合成的合体。
溶剂可以是水，这种情况下，溶剂化物是水合物。另外还可以是有机溶剂。因此，本发明化合物可作为水合物存在，包括一水合物、二水合物、半水合物、三水合物、四水合物等，以及相应的溶剂化形态。本发明化合物可以是真溶剂化物，但在其它一些情况下，本发明化合物也可能只是偶然保留了水或水跟一些其它溶剂的混合物本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。
本文所用的跟制剂，组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂等渗剂、溶剂、或乳化剂。
文所用术语“主体”、“患者”、“对象”或“个体”是指患有疾病、紊乱或病症等的个体，包括哺乳动物和非哺乳动物，哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛，马、绵羊，山羊，猪；家养动物，例如兔，狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病病症的治疗，包括
(i)预防哺乳动物，特别是之前已经暴露在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物，产生相应的疾病或病症；
(ii)抑制疾病或病症，即，控制其发展；
(iii)缓解疾病或病症，即，使疾病或病症消退缓；
(iv)缓解疾病或病症引起的症状。
本文所用术语“疾病”和“病症”可以互相替代，也可以是不同意思，因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚)，所以还不能被认作疾病而只能被看做不想要的状况或综合症，所述综合症或多或少有一些具体症状已经被临床研究人员证实。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法这些方法。包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
合成方法
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备，可通过以 下示例性方法和实施例完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可地本领域技术人员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知方法和本发明所述的方法。每步应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需要的起始原料和化学试剂可以根据文献(reaxys)常规合成或购买。
本发明的化合物可通过以下方案制得：
方案A：
Figure PCTCN2021141767-appb-000016
方案B：
Figure PCTCN2021141767-appb-000017
方案C：
Figure PCTCN2021141767-appb-000018
方案D：
Figure PCTCN2021141767-appb-000019
方案E：
Figure PCTCN2021141767-appb-000020
方案F：
Figure PCTCN2021141767-appb-000021
除非另有说明，温度是摄氏温度。试剂购自Chemblocks Inc或相辉医药等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。
除非另有说明，下列反应在室温、无水溶剂中、氮气或气的正压下或使用干燥管进行；玻璃器皿烘干和/或加热干燥。
除非另有说明，柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用Therno LCD  Fleet型(ESI)液相色谱-质谱联用仪。
核磁数据(1H NMR)使用Bruker Avance-400MHz或Varian Oxford-400Hz核磁仪，核磁数据使用的溶剂有CDCl 3、CD 3OD、D 2O、DMS-d 6等，以四甲基硅烷(0.000ppm)为基准或以残留溶剂为基准(CDCl 3:7.26ppm；CD 3OD:3.31ppm；D 2O:4.79ppm；d6-DMSO:2.50ppm)当标明峰形多样性时，以下简写表示不同峰形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数，则以Hertz(Hz)为单位。
关键中间体4,6-二氯-2氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺的制备
将N-溴代琥珀酰亚胺(5.2g，29.6mmol)加到4,6-二氯-2氧代-咪唑[4,5-c]]并吡啶(5.6g，27mmol)在乙酸(100mL)中的溶液中。在60℃搅拌2小时后，在减压下去除乙酸。将残余物悬浮在水中(60mL)，并添加饱和碳酸氢钠溶液(40mL)。过滤固体并在80℃的水中(200mL)搅拌30分钟。冷却至环境温度后，过滤固体并在真空下干燥，得到粗品4,6-二氯-6-溴-2氧代-咪唑[4,5-c]]并吡啶7..11g，收率93％。LC/MS(ESI):m/z＝283[M+H] +.
将Ν，Ν，Ν'，Ν'-四甲基乙二胺(9g，50.1mmol)添加到上一步的产物4,6-二氯-6-溴-2氧代-咪唑[4,5-c]]并吡啶(5.64g，20mmol)存于无水四氢呋喃(100mL)中的溶液中，并且该溶液在氮气下于-60℃搅拌1分钟。缓慢添加正丁基锂(20.4mL，50.1mmol，己烷中2.5M)，并将混合物搅拌2小时。将干二氧化碳气体鼓泡到溶液中，并且在-60℃下将混合物搅拌1小时。加热至环境温度后，加入水(100mL)。减压除去四氢呋喃，残渣在乙酸乙酯和水之间分配。用1M盐酸将水层酸化至pH＝1，并过滤固体以得到粗品4,6-二氯-2氧代-咪唑[4,5-c]]并吡啶-7-甲酸3.77g，收率76％。LC/MS(ESI):m/z＝249[M+H] +.
将4,6-二氯-2氧代-咪唑[4,5-c]]并吡啶-7-甲酸(2.49g，10mmol)溶解于亚硫酰氯(40ml)中，并且将混合物在75℃下搅拌2小时。在真空下去除多余的亚硫酰氯，并将残余物溶解在无水四氢呋喃(40mL)中。在0℃下添加氨水(6.0mL)，并在环境温度下搅拌混合物10小时。过滤固体并从乙醇(20mL)中重结晶得到4,6-二氯2-氧代-咪唑并|4,5-c]吡啶-7-甲酰胺2.08g，收率84％。LC/MS(ESI):m/z＝248[M+H] +.
关键中间体4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酰胺的制备
将N-溴代琥珀酰亚胺(5.2g，29.6mmol)加到2,6-二氯-3-甲基-4-氨基吡啶(17.7g，0.1mol)在乙酸(300mL)中的溶液中。在60℃搅拌2小时后，在减压下去除乙酸。将残余物悬浮在水中(180mL)，并添加饱和碳酸氢钠溶液(120mL)。过滤固体并在80℃的水中(600mL)搅拌30分钟。冷却至环境温度后，过滤固体并在真空下干燥，得到粗品2,6- 二氯-3-甲基-4-氨基-5-甲基吡啶23.8g，收率93％。LC/MS(ESI):m/z＝256[M+H] +.
将上一步得到产物二氯-3-甲基-4-氨基-5-甲基吡啶(12.8g,0.05mol)溶于乙酸模酐(50mL)和无水甲苯(500mL)，加热到100℃，搅拌14小时，冷却到室温，减压脱溶，得到中间体粗品2,6-二氯-3-甲基-4-乙酰胺基-5-甲基吡啶，不经过纯化直接用于下一步反应。LC/MS(ESI):m/z＝256[M+H] +.
将上一步粗品2,6-二氯-3-甲基-4-乙酰胺基-5-甲基吡啶、乙酸酐、乙酸钾和甲苯加热到78℃，趁热加入亚硝酸异戊酯，搅拌18小时，冷却到室温，减压脱溶，得到中间体粗品
将Ν，Ν，Ν'，Ν'-四甲基乙二胺(9g，50.1mmol)添加到上一步的产物4,6-二氯-6-溴吡唑[4,5-c]]并吡啶(5.64g，20mmol)存于无水四氢呋喃(100mL)中的溶液中，并且该溶液在氮气下于-60℃搅拌1分钟。缓慢添加正丁基锂(20.4mL，50.1mmol，己烷中2.5M)，并将混合物搅拌2小时。将干二氧化碳气体鼓泡到溶液中，并且在-60℃下将混合物搅拌1小时。加热至环境温度后，加入水(100mL)。减压除去四氢呋喃，残渣在乙酸乙酯和水之间分配。用1M盐酸将水层酸化至pH＝1，并过滤固体以得到粗品4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酸3.77g，收率76％。LC/MS(ESI):m/z＝249[M+H] +.
将4,6-二氯吡唑咪唑[4,5-c]]并吡啶-7-甲酸(2.49g，10mmol)溶解于亚硫酰氯(40ml)中，并且将混合物在75℃下搅拌2小时。在真空下去除多余的亚硫酰氯，并将残余物溶解在无水四氢呋喃(40mL)中。在0℃下添加氨水(6.0mL)，并在环境温度下搅拌混合物10小时。过滤固体并从乙醇(20mL)中重结晶得到4,6-二氯2-氧代-咪唑并|4,5-c]吡啶-7-甲酰胺2.08g，收率84％。LC/MS(ESI):m/z＝248[M+H] +.
关键中间体4,6-二氯-吡咯[3,2-c]]并吡啶-7-甲酰胺的制备
在-78℃下，将正丁基锂(27.8mL，存于己烷中之2.5M溶液，69.6mmol)加入到二异丙胺(7.5g，74.3mmol)溶于四氢呋喃(50mL)的溶液中，将混合物在-78℃下搅拌30分钟，并在40分钟期间添加2,6-二氯-硝基吡啶(19.0g，67.6mmol)存于四氢呋喃(50mL)中的溶液。将混合物在-78℃搅拌3小时。将干燥的二氧化碳鼓泡到反应混合物中，并且在环境温度下将混合物搅拌过夜。在减压下去除溶剂，并将残余物溶解在乙酸乙酯(50mL)和10％氢氧化钠水溶液(100mL)的混合物中。用浓盐酸使水相呈酸性，并用乙酸乙酯(3x 150mL)萃取。有机层在硫酸钠上干燥，过滤并浓缩以得到中间体2,6-二氯-4-硝基烟酸，无需进一步纯化。LC/MS(ESI):m/z＝326[M+H] +。
2,6-二氯-4-硝基烟酸(49g，154mmol溶于无水THF(1000mL)中，冷却至-40℃与-50℃之间搅拌约5mm。然后逐滴添加乙烯基溴化镁(在THF中，692mL，692mmol)。将混 合物在约-40℃和-50℃之间搅拌约4h。用饱和NH 4C1水溶液(20mL)淬火反应物。在减压下去除溶剂以获得残余物，其通过制备HPLC纯化得到4,6-二溴-1H-吡咯并[3,2-c]吡啶-7-羧酸(5.4g)，收率11％。LC/MS(ESI):m/z＝321[M+H] +。
向4,6-二氯-1H-吡咯并[3,2-c]吡啶-7-羧酸(3.2g，1.mmol)存于DMF(50mL)中之溶液中添加HOBt(2.29g，15mmol)及EDCl(2.88g，15mmol)。将反应混合物在室温下搅拌约1小时后，添加NH 3/THF(200mL)，并将所得混合物在室温下搅拌过夜。然后过滤悬浮液，减压浓缩滤液。加水，用乙酸乙酯萃取。用盐水洗涤合并的有机相，在Na 2SO 4上干燥，过滤并减压浓缩以提供4,6-二溴-1H-吡咯并[3,2-c]吡啶-7-甲酰胺(1.53g，48％)。LC/MS(ESI):m/z＝320[M+H] +。
关键中间体4-氯-2-氧代咪唑[4,5-c]并吡啶-7-甲腈的合成
采用文献(Chemistry ofHeterocyclic Compounds,1994,vol.30,#8,p.923-927)方法，在冰水冷却下，将7-溴-2-氧代咪唑[4,5-c]并吡啶(5.35g,25mmol)溶于15mL浓硫酸的溶液滴加到硝酸钾(7g,69mmol)溶于15mL浓硫酸的溶液中，然后加热到100℃，搅拌反应2h，冷却至室温，倒入冰水中，用氢氧化钠水溶液中和至pH＝6，过滤固体并在真空下干燥，然用DMF结晶得到棕黄色固体4-硝基-7-溴-2-氧代咪唑[4,5-c]并吡啶(4.92g,产率76％)。LC/MS(ESI):m/z＝260[M+H] +.
将4-硝基-7-溴-2-氧代咪唑[4,5-c]并吡啶(2.6g,10mmol)与50mL浓盐酸放入封管中，加热至150-160℃，搅拌反应12h，冷却至室温，减压除去水，然后加10mL水，用碳酸氢钠水溶液中和至pH＝6，搅拌反应半小时，过滤固体并在真空下干燥得到棕色固体4-氯-7-溴-2-氧代咪唑[4,5-c]并吡啶(2.0g,产率81％)。LC/MS(ESI):m/z＝249[M+H] +.
往反应瓶中加入化合物4-氯-7-溴-2-氧代咪唑[4,5-c]并吡啶(1.98g,8.0mmol)，氰化锌(0.56g,4.8mmol)，10wt％Pd/C(0.36g,0.16mmol)，1,1'-双(二苯基膦)二茂铁(0.18g,0.32mmol)和N,N-二甲基乙酰胺15ml。氮气置换3次，加入甲酸锌二水合物(0.15g,0.8mmol)，再次氮气置换3次搅拌下100℃反应过夜。冷却至室温，反应液用乙酸乙酯和水稀释，乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物4-氯-2-氧代咪唑[4,5-c]并吡啶-7-甲腈(1.21g，产率78％)为棕色固体。LC/MS(ESI):m/z＝195[M+H] +.
实施例1：(S)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基哌啶-1-基)-2-氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺(化合物1)的制备
Figure PCTCN2021141767-appb-000022
步骤1：化合物1b的合成
将原料4,6-二氯-2氧代-咪唑[4,5-c]]并吡啶-7-甲酸1a(0,744g，3mmol)、4-苯氧基苯硼酸(1.32g，6mmol)和磷酸三钾一水合物(10.56g，9mmol)溶解于二氧六环(10mL)和水(4mL)中。用多次充氮气后，添加四(三苯基膦)钯(0.53g，0.45mmol)。用氮气将混合物再喷洒5分钟，然后回流加热24小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(10mL)稀释反应混合物，并通过过滤收集固体。粗产物用甲醇(50mL)打浆，然后得到米黄色固体1b(0.66g,58％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝382[M+H] +。
步骤2：化合物1c的合成
将上一步得到的产物1b(0.38g，1mmol)、(S)-3-Boc-氨基哌啶(0.22g，1.1mmol)、碳酸钾(0.22g，2mmol)催化量碘化钾和DMF(30mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，残余物用硅胶快速柱得到黄色固体1c(0.315g,58％)，LC/MS(ESI):m/z＝545.2[M+H] +。
步骤3：化合物1d的合成
于反应瓶中加入上一步中间体1c(0.27g,0.5mmol)，2ml乙酸乙酯，1N HCl的1,4-二氧六环溶液4ml。室温下搅拌2小时，反应液用1N氢氧化钠溶液中和，乙酸乙酯萃取。所得有机相再用饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。得到化合物1d(0.193g，产率87％)，直接用于下一步，LC/MS(ESI):m/z＝445.2[M+H] +。
步骤4：化合物1的合成
于反应瓶中加入化合物1d(133mg,0.3mmol)，三乙胺(51mg,0.5mmol)，4ml四氢呋喃，冰水浴冷却后缓慢滴加丁-2-炔酰氯(45mg,0.5mmol)的0.5ml四氢呋喃溶液。加完 后继续搅拌4小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化，得到化合物1(49mg，产率32％)为黄色固体。 1H NMR(400MHz,CD3OD)δ:7.41-7.04(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝511.2[M+H] +.
实施例2：(S)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基哌啶-1-基)吡唑[4,5-c]]并吡啶-7-甲酰胺(化合物2)的制备
Figure PCTCN2021141767-appb-000023
用与实施例1相似的方法(中间体换为4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酰胺)得到化合物2(53mg，产率36％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.56-7.04(m,9H),3.98-3.84(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.98(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.36(s,1H)；LC/MS(ESI):m/z＝495[M+H] +.
实施例3(S)-6-(4-苯氧基苯基)-4-(3-丙烯酰胺基哌啶-1-基)-2-氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺(化合物3)的制备
Figure PCTCN2021141767-appb-000024
用与实施例1相似的方法(中间体换为4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酰胺)得到化合物2(48mg，产率32％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.41-7.04(m,9H),6.27-6.17(m,1H),6.13-6.03(m,1H),5.59(dd,1H),4.01(br s,1H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.68(m,3H),1.35(s,1H)；LC/MS(ESI):m/z＝499.2[M+H] +.
实施例4：(S)-6-(4-苯氧基苯基)-4-(3-丙烯酰胺基吡咯烷-1-基)-2-氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺(化合物4)的制备
用与实施例1相似的方法(中间体换为4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酰胺)得到化合物2(55mg，产率38％，此为最后一步产率，下同)为淡黄色固体。 1H NMR(400MHz,CD3OD)δ:7.42-7.04(m,9H),6.71-6.54(d,1H),6.32-6.22(m,1H),5.74(m,1H),4.40-4.23(m,2H),3.91(dd,1H),3.86-3.58(m,3H),2.24-2.02(s,2H)；LC/MS(ESI):m/z＝495.2[M+H] +.
实施例5：(S)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基吡咯烷-1-基)-2-氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺(化合物5)的制备
用与实施例1相似的方法(中间体换为4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酰胺)得到化合物5(52mg，产率35％，此为最后一步产率，下同)为淡黄色固体，LC/MS(ESI):m/z＝497[M+H] +.
实施例6：(R)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基哌啶-1-基)-2-氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺(化合物6)的制备
化合物6(60mg，产率39％)为黄色固体。 1H NMR(400MHz,CD3OD)δ:7.42-7.04(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝511.2[M+H] +.
实施例7：(R)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基哌啶-1-基)吡唑[4,5-c]]并吡啶-7-甲酰胺(化合物7)的制备
用与实施例1相似的方法(中间体换为4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酰胺)得到化合物7(54mg，产率36％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.41-7.04(m,9H),6.27-6.17(m,1H),6.13-6.03(m,1H),5.59(dd,1H),4.01(br s,1H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.68(m,3H),1.35(s,1H)；LC/MS(ESI):m/z＝499[M+H] +.
实施例8：(R)-6-(4-苯氧基苯基)-4-(3-丙烯酰胺基哌啶-1-基)-2-氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺(化合物8)的制备
用与实施例1相似的方法(中间体换为4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酰胺)得到化合物2(45mg，产率31％，此为最后一步产率，下同)为淡黄色固体。 1H NMR(400MHz,CD3OD)δ:7.56-7.04(m,9H),6.71-6.54(d,1H),6.32-6.22(m,1H),5.74(m,1H),4.40-4.23(m,2H),3.91(dd,1H),3.86-3.58(m,3H),2.24-2.02(s,2H)；LC/MS(ESI):m/z＝485[M+H] +.
实施例9：(R)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基吡咯烷-1-基)-2-氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺(化合物9)的制备
用与实施例1相似的方法(中间体换为4,6-二氯吡唑[4,5-c]]并吡啶-7-甲酰胺)得到化合物2(55mg，产率37％，此为最后一步产率，下同)为淡黄色固体，LC/MS(ESI):m/z＝497[M+H] +.
实施例10：(S)-7-(4-苯氧基苯基)-5-(3-丁-2-炔酰胺基哌啶-1-基)-2,3-二氧代-吡啶[3,4-b]]并吡嗪-8-甲酰胺(化合物10)的制备
Figure PCTCN2021141767-appb-000025
步骤1：化合物10b的合成
将原料2,6-二氯-3-硝基-4-氨基吡啶10a(20.8g，0.1mol)、(S)-3-Boc-氨基哌啶(22g，0.11mol)、碳酸钾(22g，0.2mmol)催化量碘化钾和DMF(2000mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体10c(20.8g,56％)，LC/MS(ESI):m/z＝373[M+H] +。
步骤2：化合物10c的合成
将上一步得到的产物10b(18.59g，0.05mol)、4-苯氧基苯硼酸(10.7g，0.05mol)、三(二亚苄基丙酮)二钯(4g，4.4mmol)、碳酸铯、1,4-二氧六环(500mL)和水(100mL)混合后，然后回流加热到120℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(10mL)稀释反应混合物，并通过过滤收集固体。粗产物用甲醇(50mL)打浆，然后得到米黄色固体10b(12.9g,51％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝506[M+H] +。
步骤3：化合物10d的合成
将N-溴代琥珀酰亚胺(5.2g，29.6mmol)加到10c(12.1g，24mmol)在乙酸(100mL)中的溶液中。在60℃搅拌2小时后，在减压下去除乙酸。将残余物悬浮在水中(60mL)，并添加饱和碳酸氢钠溶液(40mL)。过滤固体并在80℃的水中(200mL)搅拌30分钟。冷却至环境温度后，过滤固体并在真空下干燥，得到粗品黄褐色固体10d(12.2g,87％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝585[M+H] +。
步骤4：化合物10e的合成
在氮气保护下，将10d(7.8g，13.35mmol)、Zn(CN) 2(940mg，8mmol)、三(二亚苄基丙酮)二钯(0.61g，0.65mmol)和1,1'-双(二苯基膦)二茂铁(0.74g，1.35mmol)的混合物加到DMF/H2O(99:1，50mL)中，搅拌30分钟，然后加热到120℃，搅拌反应24小时。将所得混合物冷却至室温，和饱和NH 4Cl溶液:浓氨水:H 2O(4:1:4，10mL)沉淀。将反应物冷却至0℃并过滤。滤饼用饱和NH 4Cl溶液:浓氨水:H 2O(4:1:4，2mL)洗涤，在真空下干燥得到深褐色固体(5.38g，76％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝531[M+H] +。
步骤5：化合物10f的合成
将10e(5.31g，10mmol)溶于50mL乙醇中，在室温下在1.0atm H2气氛下在雷尼镍催化剂(2.0g)上氢化4h。反应完毕后，向溶液加入1.6g硅藻土后，剧烈搅拌混合物并在硅藻土垫上过滤。滤液用硅胶柱层析法纯化，得到深褐色固体10f(4.70g，94％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝501[M+H] +。
步骤6：化合物10g的合成
向10f(2.5g，5mmol)与20ml甲醇的溶液中添加甲醇钠(0.63g，)，并在室温下将混合物搅拌30分钟。将草酸二乙酯(0.76g,5.1mmol)溶于8ml甲醇的溶液逐滴添加到混合物中30分钟，并将所得混合物加热至回流7h。在减压下浓缩混合物，用30mL水稀释，然后在冰浴中冷却。用10％的盐酸将反应混合物调节到pH为6.5。通过过滤收集沉淀的固体，用水洗涤并干燥，得到黄色固体化合物10g(2.6g，94％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝555[M+H] +。
步骤7：化合物10h的合成
将上一步化合物10g(1.66g，3mmol)分批加入80％硫酸(11mL)，在60℃下搅拌反应2.5小时。冷却至室温后，将反应混合物加入冰中并加热至室温搅拌温度。用KOH将pH值调至8，用乙酸乙酯萃取(2×)。用无水硫酸钠干燥，浓缩减压得到棕色固体中间体 10h(1.40g，97％)无需再纯化进行下一反应，LC/MS(ESI):m/z＝473[M+H] +。
步骤8：化合物10的合成
向25mL三颈烧瓶中添加中间体10h(237mg，0.5mmol)在N，N-二甲基甲酰胺(8mL)和-2-丁炔酸(46.2mg,0.55mmol)、HATU(379mg、164mmol)和N-乙基二异丙基胺(275μL)(温度升至35℃)。最终的解决方案是在室温下搅拌2小时。用稀释液稀释混合物乙酸乙酯(10毫升)和水洗(5毫升)。有机的相分离，水层用乙酸乙酯萃取(2×10ml)。合并的有机提取物用洗涤液洗涤水(含少量氯化钠)(4×10ml)，用盐水冲洗(10毫升)，用无水硫酸钠干燥。集中在减压下得到粗产物，通过柱层析纯化，得到黄色固体化合物10(140mg，产率52％)。 1HNMR(400MHz,CD3OD)δ:7.41-7.04(m,11H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝539.2[M+H] +.
实施例11：(R)-7-(4-苯氧基苯基)-5-(3-丁-2-炔酰胺基哌啶-1-基)-2,3-二氧代-吡啶[3,4-b]]并吡嗪-8-甲酰胺(化合物11)的制备
Figure PCTCN2021141767-appb-000026
用与实施例10相似的方法(中间体换为(R)-3-Boc-氨基哌啶)得到化合物11(129mg，产率48％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.41-7.04(m,9H),3.98-3.84(m,1H),3.19-3.06(m,1H),3.06-2.89(m,1H),3.08-2.90(m,1H),2.81(br s,1H),1.97(s,3H),1.91-1.81(m,1H),1.73(s,2H),and 1.36(s,1H)；LC/MS(ESI):m/z＝539.2[M+H] +.
实施例12：(S)-7-(4-苯氧基苯基)-5-(3-丙烯酰胺基哌啶-1-基)-2,3-二氧代-吡啶[3,4-b]]并 吡嗪-8-甲酰胺化合物12)的制备
Figure PCTCN2021141767-appb-000027
用与实施例10相似的方法(中间体换为丙烯酸)得到化合物12(100mg，产率38％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.43-7.04(m,9H),6.27-6.17(m,1H),6.13-6.03(m,1H),5.59(dd,1H),4.01(br s,1H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.68(m,3H),1.35(s,1H)；LC/MS(ESI):m/z＝527.2[M+H] +.
实施例13：(R)-7-(4-苯氧基苯基)-5-(3-丙烯酰胺基哌啶-1-基)-2,3-二氧代-吡啶[3,4-b]]并吡嗪-8-甲酰胺化合物13)的制备
Figure PCTCN2021141767-appb-000028
用与实施例10相似的方法(中间体换为丙烯酸)得到化合物13(84mg，产率32％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.43-7.04(m,9H),6.27-6.17(m,1H),6.13-6.03(m,1H),5.59(dd,1H),4.01(br s,1H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.68(m,3H),1.35(s,1H)；LC/MS(ESI):m/z＝511.2[M+H] +.
实施例14：(S)-7-(4-苯氧基苯基)-5-(3-丁-2-炔酰胺基吡咯烷-1-基)-2,3-二氧代-吡啶[3,4-b]]并吡嗪-8-甲酰胺(化合物14)的制备
Figure PCTCN2021141767-appb-000029
用与实施例10相似的方法(中间体换为(S)-3-Boc-氨基吡咯烷)得到化合物14(147mg，产率56％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.42-7.06(m,9H),4.34(m,1H),3.26-3.13(m,2H),3.11-2.97(m,2H),2.24(m,1H),1.94(s,3H),1.85(m,1H)；LC/MS(ESI):m/z＝525.2[M+H] +.
实施例15：(R)-7-(4-苯氧基苯基)-5-(3-丁-2-炔酰胺基吡咯烷-1-基)-2,3-二氧代-吡啶[3,4-b]]并吡嗪-8-甲酰胺(化合物15)的制备
Figure PCTCN2021141767-appb-000030
用与实施例10相似的方法(中间体换为(R)-3-Boc-氨基吡咯烷)得到化合物15(160mg，产率61％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.42-7.06(m,9H),4.34(m,1H),3.26-3.13(m,2H),3.11-2.97(m,2H),2.24(m,1H),1.94(s,3H),1.85(m,1H)；LC/MS(ESI):m/z＝525.2[M+H] +.
实施例16：(S)-7-(4-苯氧基苯基)-5-(3-丙烯酰胺基吡咯烷-1-基)-2,3-二氧代-吡啶[3,4-b]]并吡嗪-8-甲酰胺(化合物16)的制备
Figure PCTCN2021141767-appb-000031
用与实施例10相似的方法(中间体换为(S)-3-Boc-氨基吡咯烷)得到化合物16(97mg，产率38％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.42-7.06(m,9H),6.71-6.55(d,1H),6.32-6.22(m,1H),5.74(m,1H),4.40-4.23(m,2H),3.91(dd,1H),3.86-3.58(m,3H),2.24-2.02(s,2H)；LC/MS(ESI):m/z＝513.2[M+H] +.
实施例17：(R)-7-(4-苯氧基苯基)-5-(3-丙烯酰胺基吡咯烷-1-基)-2,3-二氧代-吡啶[3,4-b]]并吡嗪-8-甲酰胺(化合物17)的制备
Figure PCTCN2021141767-appb-000032
用与实施例10相似的方法(中间体换为(R)-3-Boc-氨基吡咯烷)得到化合物17(92mg，产率36％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.42-7.06(m,9H),6.71-6.55(d,1H),6.32-6.22(m,1H),5.74(m,1H),4.40-4.23(m,2H),3.91(dd,1H),3.86-3.58(m,3H),2.24-2.02(s,2H)；LC/MS(ESI):m/z＝513.2[M+H] +.
实施例18：(S)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基哌啶-1-基)-咪唑[4,5-c]并吡啶-7-甲酰胺(化合物18)的制备
Figure PCTCN2021141767-appb-000033
用与实施例10相似的方法(中间体换为原甲酸三乙酯)得到化合物18(123mg，产率52％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:8.13(s,1H), 7.41-7.06(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝495.2[M+H] +.
实施例19：(S)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基哌啶-1-基)-2-甲基咪唑[4,5-c]并吡啶-7-甲酰胺(化合物19)的制备
Figure PCTCN2021141767-appb-000034
用与实施例1相似的方法(中间体换为乙酸酐)得到化合物19(124mg，产率49％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.43-7.08(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),2.54(s,3H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝509.2[M+H] +.
实施例20：6-(4-苯氧基苯基)-5-(1-丙烯酰胺基哌啶-4-基)-2-氧代-咪唑[4,5-c]并吡啶-8-甲酰胺(化合物20)的制备
Figure PCTCN2021141767-appb-000035
步骤1：化合物6-(4-苯氧基苯基-2-氧代-咪唑[4,5-c]并吡啶-8-甲酰胺20b的合成
将原料4,6-二氯-2氧代-咪唑[4,5-c]]并吡啶-7-甲酰胺20a(3.7g，15mmol)、4-苯氧基 苯硼酸(6.42g，30mmol)和磷酸三钾一水合物(10.35g，45mmol)溶解于二氧六环(200mL)和水(20mL)中。用多次充氮气后，添加四(三苯基膦)钯(2.31g，2mmol)。用氮气将混合物再喷洒5分钟，然后回流加热24小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(10mL)稀释反应混合物，并通过过滤收集固体。粗产物用甲醇(150mL)打浆，然后得到米黄色固体20b(2.91g,52％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝382[M+H] +。
步骤2：化合物20c的合成
将上一步中间体6-(4-苯氧基苯基-2-氧代-咪唑[4,5-c]并吡啶-8-甲酰胺20b(1.9g，5mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(2.31g，7.5mmol)、碳酸钾(2.07g，15mmol)、四(三苯基膦)钯、1,4-二氧六环(100mL)和水(25mL)混合后，在氮气保护加热回流，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，反应液减压蒸溶，通过柱层析纯化得到米黄色固体20c(1.0g,38％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝528[M+H] +。
步骤3：化合物20d的合成
将上一步化合物20c(528mg，1mmol)存于乙酸乙酯(10mL)和甲醇(10mL)中的溶液中添加10％Pd/C(0.1g)，并且用氢气将反应物脱气6次，然后在氢气氛下在室温下搅拌12h。过滤溶液，将滤液蒸发成棕色固体的粗产物20d(507mg,96％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝530[M+H] +。
步骤4：化合物20e的合成
于反应瓶中加入上一步中间体20d(0.265g,0.5mmol)，2ml乙酸乙酯，1N HCl的1,4-二氧六环溶液4ml。室温下搅拌2小时，反应液用1N氢氧化钠溶液中和，乙酸乙酯萃取。所得有机相再用饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。得到化合物20e(0.170g，产率79％)，直接用于下一步，LC/MS(ESI):m/z＝430.2[M+H] +。
步骤5：化合物20的合成
于反应瓶中加入化合物20e(129mg,0.3mmol)，三乙胺(51mg,0.5mmol)，4ml四氢呋喃，冰水浴冷却后缓慢滴加丁-2-炔酰氯(45mg,0.5mmol)的0.5ml四氢呋喃溶液。加完后继续搅拌4小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化，得到化合物20(52mg，产率36％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:7.43-7.08(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),2.54(s,3H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝484.2[M+H] +.
实施例21和22：(S)-6-(4-苯氧基苯基)-5-(3-丙烯酰胺基哌啶-4-基)-2-氧代-咪唑[4,5-c]并吡啶-8-甲酰胺(化合物21)和(R)-6-(4-苯氧基苯基)-5-(3-丙烯酰胺基哌啶-4-基)-咪唑[4,5-c]并吡啶-8-甲酰胺(化合物22)的制备
Figure PCTCN2021141767-appb-000036
用与实施例11相似的方法(中间体换为1-叔丁氧羰基-3,6-二氢-2H-吡啶-5-硼酸频哪醇酯)得到化合物21和22(124mg，产率49％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:7.43-7.08(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),2.54(s,3H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝509.2[M+H] +.
实施例23：(S)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基哌啶-1-基)-吡咯[3,2-c]]并吡啶-7-甲酰胺(化合物23)的制备
Figure PCTCN2021141767-appb-000037
Figure PCTCN2021141767-appb-000038
步骤1：化合物23b的合成
将原料4,6-二氯-1H-吡咯并[3,2-c]吡啶-7-甲酰胺23a(0.64g，2mmol)、(S)-3-Boc-氨基哌啶(0.44g，2.2mmol)、碳酸钾(0.44g，4mmol)催化量碘化钾和DMF(40mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体23c(0.61g,78％)，LC/MS(ESI):m/z 394[M+H] +。
步骤2：化合物23c的合成
将中间体23b(0.394g，1mmol)、4-苯氧基苯硼酸(0.86g，4mmol)和磷酸三钾一水合物(1.38g，6mmol)溶解于二氧六环(15mL)和水(8mL)中。用多次充氮气后，添加四(三苯基膦)钯(0.35g，0.3mmol)。用氮气将混合物再喷洒5分钟，然后回流加热24小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(10mL)稀释反应混合物，并通过过滤收集固体。粗产物用甲醇(50mL)打浆，然后得到米黄色固体23b(0.30g,56％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝529[M+H] +。
步骤3：化合物23d的合成
于反应瓶中加入上一步中间体23c(0.27g,0.5mmol)，2ml乙酸乙酯，1N HCl的1,4-二氧六环溶液4ml。室温下搅拌2小时，反应液用1N氢氧化钠溶液中和，乙酸乙酯萃取。所得有机相再用饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。得到化合物23d(0.187g，产率87％)，直接用于下一步，LC/MS(ESI):m/z＝428.2[M+H] +。
步骤4：化合物23的合成
于反应瓶中加入化合物23d(128mg,0.3mmol)，三乙胺(51mg,0.5mmol)，4ml四氢呋喃，冰水浴冷却后缓慢滴加丁-2-炔酰氯(45mg,0.5mmol)的0.5ml四氢呋喃溶液。加完后继续搅拌4小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化，得到化合物23(53mg，产率36％)为黄色固体。LC/MS(ESI):m/z＝494.2[M+H] +。
实施例24：(R)-6-(4-苯氧基苯基)-4-(3-丁-2-炔酰胺基哌啶-1-基)-吡咯[3,2-c]]并吡啶-7-甲酰胺(化合物24)的制备
Figure PCTCN2021141767-appb-000039
用与实施例23相似的方法(中间体换为(R)-3-Boc-氨基哌啶)得到化合物24(68mg，产率46％，此为最后一步产率，下同)为淡黄色固体，LC/MS(ESI):m/z＝494.2[M+H] +.
实施例25：6-(4-苯氧基苯基)-4-(1-丙烯酰基哌啶-4-基)-吡咯[3,2-c]]并吡啶-7-甲酰胺(化合物25)的制备
Figure PCTCN2021141767-appb-000040
用与实施例11相似的方法(中间体换为N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯)得到化合物25(59mg，产率42％，此为最后一步产率，下同)为淡黄色固体，LC/MS(ESI):m/z＝467.2[M+H] +.
实施例26和27：(S)-6-(4-苯氧基苯基)-4-(1-丙烯酰基哌啶-3-基)-吡咯[3,2-c]]并吡啶-7-甲酰胺(化合物26)和(R)-6-(4-苯氧基苯基)-4-(1-丙烯酰基哌啶-3-基)-吡咯[3,2-c]]并吡啶-7-甲酰胺(化合物27)的制备
Figure PCTCN2021141767-appb-000041
用与实施例16相似的方法(中间体换为1-叔丁氧羰基-3,6-二氢-2H-吡啶-5-硼酸频哪醇酯)得到消旋体化合物(R,S)-6-(4-苯氧基苯基)-4-(1-丙烯酰基哌啶-3-基)-吡咯[3,2-c]]并吡啶-7-甲酰胺(67mg，产率49％，此为最后一步产率，下同)为淡黄色固体，LC/MS(ESI):m/z＝467.2[M+H] +.
实施例28：(S)-5-(3-丁-2-炔酰胺基哌啶-1-基)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺(化合物28)的制备
Figure PCTCN2021141767-appb-000042
步骤1：化合物28b的合成
于反应瓶中加入化合物28a(3.47g,20.0mmol)，(S)-3-叔丁氧羰基氨基哌啶(4.81g,24.0mmol)，碳酸铯(7.82g,24.0mmol)和N,N-二甲基甲酰胺50ml。搅拌下100℃反应过夜。冷却至室温，反应液用乙酸乙酯和水稀释，乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物28b(5.46g，产率81％)为黄色固体。LC/MS(ESI):m/z＝238.1[M+H] +
步骤2：化合物28c的合成
于反应瓶中加入化合物28b(4.05g,12.0mmol)，N,N-二甲基甲酰胺30ml，分批次加入NBS(3.20g,18.0mmol)，搅拌下50℃反应24小时。冷却至室温，反应液倒入150ml水中，用乙酸乙酯萃取。所得有机相再用饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物28c(3.45g，产率69％)为黄色固体。LC/MS(ESI):m/z＝316.0[M+H] +
步骤4：化合物28d的合成
于反应瓶中加入化合物28c(3.33g,8.0mmol)，氰化锌(0.56g,4.8mmol)，10wt％Pd/C(0.36g,0.16mmol)，1,1'-双(二苯基膦)二茂铁(0.18g,0.32mmol)和N,N-二甲基乙酰胺15ml。氮气置换3次，加入甲酸锌二水合物(0.15g,0.8mmol)，再次氮气置换3次搅拌下100℃反应过夜。冷却至室温，反应液用乙酸乙酯和水稀释，乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物28d(2.20g，产率76％)为棕色固体。LC/MS(ESI):m/z＝263.1[M+H] +.
步骤5：化合物28e的合成
于微波反应管中加入化合物28d(3.33g,6.0mmol)，三乙酰丙酮铁(11mg,0.03mmol)，水合肼(0.36g,7.2mmol)和甲醇8ml。搅拌下140℃微波反应6小时。冷却至室温，反应液减压蒸干，残余物通过柱层析纯化，得到化合物28e(1.85g，产率93％)为黄色固体。LC/MS(ESI):m/z＝233.2[M+H] +.
步骤6：化合物28f的合成
于反应瓶中加入化合物28e(1.16g,3.0mmol)，4N盐酸2ml，草酸二甲酯(0.39g,3.3mmol)。搅拌下80℃反应2小时。冷却至室温，反应液减压蒸干，残余物通过柱层析纯化，得到化合物28f(0.95g，产率82％)为黄色固体。LC/MS(ESI):m/z＝287.1[M+H] +.
步骤7：化合物28g的合成
于反应瓶中加入化合物28f(0.77g,2.0mmol)，硫酸2ml，搅拌下60℃反应1小时。冷却至室温，反应液倒入10ml冰水中，用1N氢氧化钠溶液中和，乙酸乙酯萃取。所得有 机相再用饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物28g(0.44g，产率73％)为黄色固体。LC/MS(ESI):m/z＝305.1[M+H] +.
步骤8：化合物28的合成
于反应瓶中加入化合物28g(304mg,1.0mmol)，N,N-二甲基甲酰胺2ml，2-丁炔酸(101mg,1.2mmol)，HATU(570mg,1.5mmol)和N,N-二异丙基乙胺(258mg,2.0mmol)。搅拌下室温反应2小时。反应液用乙酸乙酯和水稀释，乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物28(230mg，产率62％)为黄色固体。 1H NMR(400MHz,CD3OD)δ:8.5(s,1H),3.99-3.84(m,1H),3.19-3.06(m,1H),3.06-2.89(m,1H),3.08-2.89(m,1H),2.81(br s,1H),1.97(s,3H),1.91-1.81(m,1H),1.73(s,2H),and 1.37(s,1H)；LC/MS(ESI):m/z＝371.1[M+H] +.
实施例29：(R)-5-(3-丁-2-炔酰胺基哌啶-1-基)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺(化合物29)的制备
Figure PCTCN2021141767-appb-000043
用与实施例28相似的方法(中间体换为(R)-3-叔丁氧羰基氨基哌啶)得到化合物20(215mg，产率58％，此为最后一步产率，下同)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:8.5(s,1H),3.99-3.84(m,1H),3.19-3.06(m,1H),3.06-2.89(m,1H),3.08-2.89(m,1H),2.81(br s,1H),1.97(s,3H),1.91-1.81(m,1H),1.73(s,2H),and 1.37(s,1H)；LC/MS(ESI):m/z＝371.1[M+H] +。
实施例30：(S)-5-(3-丙烯酰胺基哌啶-1-基)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺化合物30)的制备
Figure PCTCN2021141767-appb-000044
用实施例28中间体(S)-5-(3-胺基哌啶)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺和丙烯酸反应得到化合物30(250mg，产率65％)为淡黄色固体。 1H NMR(400MHz,CD3OD)δ:8.4(s,1H),6.27-6.16(m,1H),6.13-6.02(m,1H),5.59(dd,1H),4.01(br s,1H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.67(m,3H),1.35(s,1H)；LC/MS(ESI):m/z＝359.1[M+H] +.
实施例31：(R)-5-(3-丙烯酰胺基哌啶-1-基)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺化合物31)的制备
Figure PCTCN2021141767-appb-000045
用实施例2中间体(R)-5-(3-胺基哌啶)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺和丙烯酸反应得到化合物31(235mg，产率61％)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:8.4(s,1H),6.27-6.16(m,1H),6.13-6.02(m,1H),5.59(dd,1H),4.01(br s,1H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.67(m,3H),1.35(s,1H)；LC/MS(ESI):m/z＝359.1[M+H] +.
实施例32：(S)-5-(3-丁-2-炔酰胺基吡咯烷-1-基)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺(化合物32)的制备
Figure PCTCN2021141767-appb-000046
用与实施例1相似的方法(中间体换为(S)-3-叔丁氧羰基氨基吡咯烷)得到化合物32(224mg，产率58％)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:8.4(s,1H),4.34(m,1H),3.26-3.1w(m,2H),3.11-2.98(m,2H),2.24(m,1H),1.94(s,3H),1.85(m,1H)；LC/MS(ESI):m/z＝357.1[M+H] +.
实施例33：(R)-5-(3-丁-2-炔酰胺基吡咯烷-1-基)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺(化合物33)的制备
Figure PCTCN2021141767-appb-000047
用与实施例1相似的方法(中间体换为(R)-3-叔丁氧羰基氨基吡咯烷)得到化合物33(259mg，产率67％)为淡黄色固体。 1H NMR(400MHz,CD3OD)δ:8.4(s,1H),4.34(m,1H),3.26-3.1w(m,2H),3.11-2.98(m,2H),2.24(m,1H),1.94(s,3H),1.85(m,1H)；LC/MS(ESI):m/z＝357.1[M+H] +.
实施例34：(S)-5-(3-丙烯酰胺基吡咯烷-1-基)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺(化合物34)的制备
Figure PCTCN2021141767-appb-000048
用实施例32中间体(S)-5-(3-胺基吡咯烷)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺和丙烯酸反应得到化合物34(221mg，产率59％)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:8.5(s,1H),6.71-6.55(d,1H),6.32-6.22(m,1H),5.74(m,1H),4.40-4.23(m,2H),3.91(dd,1H),3.86-3.58(m,3H),2.24-2.02(s,2H)；LC/MS(ESI):m/z＝345.1[M+H] +.
实施例35：(R)-5-(3-丙烯酰胺基吡咯烷-1-基)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺(化合物35)的制备
Figure PCTCN2021141767-appb-000049
用实施例32中间体(R)-5-(3-胺基吡咯烷)-2,3-二氧代-吡啶[3,4-b]并吡嗪-8-甲酰胺和丙烯酸反应得到化合物35(221mg，产率59％)为淡黄色固体， 1H NMR(400MHz,CD3OD)δ:8.5(s,1H),6.71-6.55(d,1H),6.32-6.22(m,1H),5.74(m,1H),4.40-4.23(m,2H),3.91(dd,1H),3.86-3.58(m,3H),2.24-2.02(s,2H)；LC/MS(ESI):m/z＝345.1[M+H] +.
实施例36：(S)-4-(3-丁-2-炔酰胺基哌啶-1-基)-咪唑[4,5-c]并吡啶-7-甲酰胺(化合物36)的制备
Figure PCTCN2021141767-appb-000050
用实施例28中间体(S)-2-(3-叔丁氧羰基氨基哌啶)-3,4-二氨基-5氰基-吡啶和原甲酸三乙酯反应，后续2步与实施例1相似得到化合物36(241mg，产率68％)为黄色固体。8,6(s,1H),8.13(s,1H),3.98-3.84(m,1H),3.19-3.08(m,1H),3.06-2.89(m,1H),3.06-2.92(m,1H),2.80(br s,1H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝327.1[M+H] +.
实施例37：(S)-4-(3-丁-2-炔酰胺基哌啶-1-基)-2-甲基咪唑[4,5-c]并吡啶-7-甲酰胺(化合物37)的制备
Figure PCTCN2021141767-appb-000051
用实施例28中间体(S)-2-(3-叔丁氧羰基氨基哌啶)-3,4-二氨基-5氰基-吡啶和原乙酸三乙酯反应，后续2步与实施例1相似得到化合物37(223mg，产率61％)为黄色固体。 1H NMR(400MHz,CD3OD)δ:8.7(s,1H),3.98-3.84(m,1H),3.20-3.07(m,1H),3.07-2.89(m,1H),3.05-2.91(m,1H),2.80(br s,1H),2.54(s,3H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝509.2[M+H] +.
实施例38：(S)-4-(3-丁-2-炔酰胺基哌啶-1-基)-2-氧代咪唑[4,5-c]并吡啶-7-甲酰胺(化合物38)的制备
Figure PCTCN2021141767-appb-000052
采购用实施例28方法，中间体(S)-2-(3-叔丁氧羰基氨基哌啶)-3,4-二氨基-5氰基-吡啶和脲反应，后续2步与实施例1相似得到化合物38(238mg，产率62％)为黄色固体。 1H NMR(400MHz,CD3OD)δ:8.6(s,1H),3.97-3.84(m,1H),3.19-3.06(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.98(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.36(s,1H)；LC/MS(ESI):m/z＝343.1[M+H] +.
实施例39：(R)-4-(3-丁-2-炔酰胺基哌啶-1-基)-2-氧代咪唑[4,5-c]并吡啶-7-甲酰胺(化合物39)的制备
Figure PCTCN2021141767-appb-000053
用实施例29中间体(R)-2-(3-叔丁氧羰基氨基哌啶)-3,4-二氨基-5氰基-吡啶和脲反应，后续2步与实施例1相似得到化合物39(253mg，产率66％)为黄色固体， 1H NMR(400MHz,CD3OD)δ:8.6(s,1H),3.97-3.84(m,1H),3.19-3.06(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.98(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.36(s,1H)；LC/MS(ESI):m/z＝343.1[M+H] +.
实施例40：4-(1-丙烯酰胺基哌啶-4-基)-2-氧代咪唑[4,5-c]并吡啶-7-甲酰胺(化合物40)的制备
Figure PCTCN2021141767-appb-000054
Figure PCTCN2021141767-appb-000055
步骤1：化合物40b的合成
将上一步中间体4-氯-2-氧代咪唑[4,5-c]并吡啶-7-甲腈40b(0.975g,5mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(2.31g，7.5mmol)、碳酸钾(2.07g，15mmol)、四(三苯基膦)钯、1,4-二氧六环(100mL)和水(25mL)混合后，在氮气保护加热回流，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，反应液减压蒸溶，通过柱层析纯化得到米黄色固体40b(0.58g,35％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝342[M+H] +。
步骤3：化合物40c的合成
将上一步化合物40b(342mg，1mmol)存于乙酸乙酯(10mL)和甲醇(10mL)中的溶液中添加10％Pd/C(0.1g)，并且用氢气将反应物脱气6次，然后在氢气氛下在室温下搅拌12h。过滤溶液，将滤液蒸发成棕色固体的粗产物40d(322mg,94％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝344[M+H] +。
步骤4：化合物40d的合成
将上一步化合物40c(172mg，0.5mmol)分批加入80％硫酸(6mL)，在60℃下搅拌反应2.5小时。冷却至室温后，将反应混合物加入冰中并加热至室温搅拌温度。用KOH将pH值调至8，用乙酸乙酯萃取(2×15mL)。用无水硫酸钠干燥，浓缩减压得到棕色固体中间体40h(1.19g，91％)无需再纯化进行下一反应，LC/MS(ESI):m/z＝262[M+H] +。
步骤5：化合物40的合成
于反应瓶中加入化合物40d(79mg,0.3mmol)，三乙胺(51mg,0.5mmol)，4ml四氢呋喃，冰水浴冷却后缓慢滴加丙烯酰氯(45mg,0.5mmol)的0.5ml四氢呋喃溶液。加完后继续搅拌4小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化，得到化合物40(36mg，产率38％)为黄色固体。LC/MS(ESI):m/z＝316.2[M+H] +。
实施例41和42：(S)-4-(1-丙烯酰胺基哌啶-3-基)-2-氧代咪唑[4,5-c]并吡啶-7-甲酰胺(化合物41)和(R)-4-(1-丙烯酰胺基哌啶-3-基)-2-氧代咪唑[4,5-c]并吡啶-7-甲酰胺(化合物42)的制备
Figure PCTCN2021141767-appb-000056
用与实施例40相似的方法(中间体换为1-叔丁氧羰基-3,6-二氢-2H-吡啶-5-硼酸频哪醇酯)得到消旋体(R,S)-4-(1-丙烯酰胺基哌啶-3-基)-2-氧代咪唑[4,5-c]并吡啶-7-甲酰胺(46mg，产率48％，此为最后一步产率，下同)为淡黄色固体，LC/MS(ESI):m/z＝316.1[M+H] +.
消旋体(R,S)-4-(1-丙烯酰胺基哌啶-3-基)-2-氧代咪唑[4,5-c]并吡啶-7-甲酰胺经手性柱分离得到化合物41和42。两者的MS(ESI)与消旋体一致。
实施例43：生物活性测试
以下结合测试试例进一步描述解释本发明，但这些实施并非意味着限制本发明的范围。
测试例1、BTK抑制活性筛选
1、实验方法
用激酶缓冲液(50mM HEPES、10mM MgCl 2、2mM DTT、1mM EGTA、0.01％Tween 20)将350ng/uL的BTK母液进行稀释，按每孔加入6μL 1.67×的0.134ng/μL的工作液(终浓度为0.08ng/μL)，用纳升加样仪将DMSO溶解的不同化合物加入到孔中，使化合物终浓度为1000nM-0.244nM，阳性药终浓度为50nM-0.0122nM，4倍梯度，共7个浓度，同时设空白对照孔(不含酶)与阴性对照孔(含酶，加溶媒DMSO)，设2个复孔。酶与化合物或溶媒反应30min后，将用激酶缓冲液配制好的5×的250μM ATP(终浓度为50uM)与5×的0.5μM底物(终浓度为0.1μM，ULight-poly GT)，按1:1混合，按每孔4μL加入孔中；封板膜封板以后，室温反应2小时后，每孔加入5μL 4×的8nM检测试剂(终浓度为2nM，Ab)，室温孵育1小时；PE仪器读板(激发620nm，发射665nm)。计算抑制 率，并计算IC 50值。
2、实验结果
本申请的化合物能强有力地抑制BTK活性。表1中列出本发明中的代表性化合物在BTK检测中所具有的活性。在这些检测中，使用下述级别：对于IC50而言，其中“A”表示IC 50≤10nM；“B”表示10<IC 50≤100nM；“C”表示100<IC 50≤500nM；“D”表示500<IC 50≤2000nM。
表1酶活性抑制结果
样品编号 BTKIC 50(nM) 样品编号 BTKIC 50(nM)
1 A 22 A
2 A 23 A
3 A 24 A
4 A 25 A
5 A 26 A
6 A 27 A
7 A 28 A
8 A 36 A
9 A 38 A
18 A 40 A
19 A 41 A
20 A 42 A
21 A   A
测试例2、肿瘤细胞增殖抑制实验
1、实验方法
采用CellTiter-Glo发光细胞活力检测试剂盒法(Promega，#G7572，Madison，WI)测定三磷酸腺苷(ATP)的含量来评估细胞活力。弥漫性大B细胞淋巴瘤细胞株TMD-8购买自美国菌种保藏中心(ATCC)。用胰酶将细胞从细胞培养皿上消化以及DPBS培养基重悬后，用Scepter自动细胞计数仪(Millipore，#PHCC00000)计数测定细胞密度。将细胞稀释成每毫升含44,000个细胞的溶液。调整密度后的细胞溶液以每孔90μl加入细胞实验板中。孔板置于37℃、5％CO2培养箱培养24小时后加入不同浓度的待测化合物。细胞在10％胎牛血清存 在下与化合物一起培养72小时。使用
Figure PCTCN2021141767-appb-000057
Luminescent Cell Viability Assay kit(见厂家说明书)测定ATP的含量来评估细胞生长抑制。简要来讲，每个孔中加入30μl[image]试剂，摇板10分钟，诱导细胞裂解，用荧光/化学发光分析仪Fluoroskan Ascent FL(ThermoScientific Fluoroskan AscentFL)检测记录荧光信号。从二甲基亚砜(DMSO)处理72或120小时的细胞得到最大的信号值。从单独的培养基(细胞数为零)得到最小信号值定义为0。抑制率％＝(最大信号值-化合物信号值)/(最大信号值-最小信号值)×100％。使用GraphPad PrismV5.0(GraphPad Software,San Diego,CA)软件处理数据。通过S形剂量-反应曲线拟合计算IC50值。
2、实验结果
表2中列出本申请的化合物在基于细胞的检测中所具有的抗细胞增殖的活性。在这些检测中，使用下述级别：对于IC50而言，其中“A”表示IC 50≤10nM；“B”表示10<IC 50≤100nM；“C”表示100<IC 50≤500nM；“D”表示500<IC 50≤2000nM。本申请的化合物对肿瘤细胞如TMD-8有很强的抗细胞增殖的活性。
表2肿瘤细胞增殖抑制结果
样品编号 TMD-8 IC 50(nM) 样品编号 TMD-8 IC 50(nM)
23 A 38 A
25 A 40 A
26 A 41 A
27 A 42 A
尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。

Claims (9)

  1. 一种具有通式(I)所示的化合物、其立体异构体、可药用的盐、多晶型物或异构体，其中通式(I)所示的化合物结构如下：
    Figure PCTCN2021141767-appb-100001
    R可以独立地选自H，D，
    Figure PCTCN2021141767-appb-100002
    L 1独立地选自-C 0-4烷基-、-CR 1R 2-、-C 1-2烷基(R 1)(OH)-、-C(O)-、-CR 1R 2O-、-OCR 1R 2-、-SCR 1R 2-、-CR 1R 2S-、-NR 1-、-NR 1C(O)-、-C(O)NR 1-、-NR 1C(O)NR 2-、-CF 2-、-O-、-S-、-S(O) m-、-NR 1S(O) 2-、-S(O) 2NR 1-；
    L 2独立地选自-C 0-4烷基-、-CR 1R 2-、-C 1-2烷基(R 1)(OH)-、-C(O)-、-CR 1R 2O-、-OCR 1R 2-、-SCR 1R 2-、-CR 1R 2S-、-NR 1-、-NR 1C(O)-、-C(O)NR 1-、-NR 1C(O)NR 2-、-CF 2-、-O-、-S-、-S(O) m-、-NR 1S(O) 2-、-S(O) 2NR 1-；
    Ar 1和Ar 2独立地选苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G 1所取代；
    X可以独立地选自N、CR 3；
    Figure PCTCN2021141767-appb-100003
    独立地选自如下结构：
    Figure PCTCN2021141767-appb-100004
    其中n为1或者2；
    U独立地选自键、-C 1-4烷基-、-CR 4R 5-、-C 1-2烷基(R 4)(OH)-、-C(O)-、-CR 4R 5O-、-OCR 4R 5-、-SCR 4R 5-、-CR 4R 5S-、-NR 4-、-NR 4C(O)-、-C(O)NR 4-、-NR 4C(O)NR 5-、-CF 2-、-O-、-S-、-S(O) m-、-NR 4S(O) 2-、-S(O) 2NR 4-；
    Y不存在或选C 3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G 3所取代；
    Z独立地选自氰基、-NR 12CN、
    Figure PCTCN2021141767-appb-100005
    键a为双键或者三键；
    当a为双键时，R a 、R b和R c各自独立地选自H、D、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G 4所取代；
    R a和R b或R b和R c任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
    当键a为三键时，R a和R c不存在，R b独立选自H、D、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基被一个或多个G 5所取代；
    R 12独立地选自H、D、C 1-6烷基、C 3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G 6所取代；
    G 1、G 2、G 3、G 4、G 5和G 6各自独立选自H、D、氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 6、-OC(O)NR 6R 7、-C(O)OR 6、-C(O)NR 6R 7、-C(O)R 6、-NR 6R 7、-NR 6C(O)R 7、-NR 6C(O)NR 7R 8、-S(O) mR 6或-NR 6S(O) mR 7，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 9、-OC(O)NR 9R 10、-C(O)OR 9、-C(O)NR 9R 10、-C(O)R 9、-NR 9R 10、-NR 9C(O)R 10、-NR 9C(O)NR 10R 11、-S(O) mR 9或-NR 9S(O) iR 10的取代基所取代；
    R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立选自H、D、氰基、卤素、C 1-6烷基、C 3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；
    且m为1或2。
  2. 根据权利要求1所述的通式(I)的化合物、其药学上可接受的盐或其立体异构体，通式(I)进一步如通式Ia所示：
    Figure PCTCN2021141767-appb-100006
    X1，X2，X3可以独立地选自N、CR 1；
    Ar 1和Ar 2独立地选苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G 1所取代；
    R 1独立地选自H、D、氰基、卤素、C 1-6烷基、COOH、CONH 2、NHCOH、CONHR 2、OR 2或-NHR 2；
    R 2独立地选自H、D、氰基、卤素、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-OR 3、-NR 3R 4、-C(O)NR 3R 4，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 5、-NR 5R 6、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
    W独立地选自键、-C 1-4烷基-、-CR 7R 8-、-C 1-2烷基(R 7)(OH)-、-C(O)-、-CR 7R 8O-、-OCR 7R 8-、-SCR 7R 8-、-CR 7R 8S-、-NR 7-、-NR 7C(O)-、-C(O)NR 7-、-NR 7C(O)NR 8-、-CF 2-、-O-、-S-、-S(O) m-、-NR 7S(O) 2-、-S(O) 2NR 7-；
    Y不存在或选C 3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G 2所取代；
    Z独立地选自氰基、-NR 12CN、
    Figure PCTCN2021141767-appb-100007
    键c为双键或者三键；
    当c为双键时，R a 、R b和R c各自独立地选自H、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G 3所取代；
    R a和R b或R b和R c任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
    当键c为三键时，R a和R c不存在，R b独立选自H、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基被一个或多个G 4所取代；
    R 9独立地选自H、C 1-6烷基、C 3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G 5所取代；
    G 1、G 2、G 3、G 4和G 5各自独立选自氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 10、-OC(O)NR 10R 11、-C(O)OR 10、-C(O)NR 10R 11、-C(O)R 10、-NR 10R 11、-NR 10C(O)R 11、-NR 10C(O)NR 11R 12、-S(O) mR 10或-NR 10S(O) mR 11，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 13、-OC(O)NR 13R 14、-C(O)OR 13、-C(O)NR 13R 14、-C(O)R 13、-NR 13R 14、-NR 13C(O)R 14、-NR 13C(O)NR 14R 15、-S(O) mR 13或-NR 13S(O) iR 14的取代基所取代；
    R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 13、R 14和R 15各自独立选自氢、氰基、卤素、C 1-6烷基、C 3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；
    且m为1或2。
  3. 根据权利要求1所述的通式(I)的化合物、其药学上可接受的盐或其立体异构体，通式(I)进一步如通式Ib所示：
    Figure PCTCN2021141767-appb-100008
    X 1，X 2，X 3，X 4可以独立地选自N、CR 1；
    键a、b为单键或者双键；
    Ar 1和Ar 2独立地选苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G 1所取代；
    R 1独立地选自H、D、氰基、卤素、C 1-6烷基、COOH、CONH 2、NHCOH、CONHR 2、OR 2或-NHR 2；
    R 2独立地选自H、D、氰基、卤素、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-OR 3、-NR 3R 4、-C(O)NR 3R 4，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 5、-NR 5R 6、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
    W独立地选自键、-C 1-4烷基-、-CR 7R 8-、-C 1-2烷基(R 7)(OH)-、-C(O)-、-CR 7R 8O-、-OCR 7R 8-、-SCR 7R 8-、-CR 7R 8S-、-NR 7-、-NR 7C(O)-、-C(O)NR 7-、-NR 7C(O)NR 8-、-CF 2-、-O-、-S-、-S(O) m-、-NR 7S(O) 2-、-S(O) 2NR 7-；
    Y不存在或选C 3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G 2所取代；
    Z独立地选自氰基、-NR 12CN、
    Figure PCTCN2021141767-appb-100009
    键c为双键或者三键；
    当c为双键时，R a 、R b和R c各自独立地选自H、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G 3所取代；
    R a和R b或R b和R c任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
    当键c为三键时，R a和R c不存在，R b独立选自H、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基被一个或多个G 4所取代；
    R 9独立地选自H、C 1-6烷基、C 3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G 5所取代；
    G 1、G 2、G 3、G 4和G 5各自独立选自氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 10、-OC(O)NR 10R 11、-C(O)OR 10、-C(O)NR 10R 11、-C(O)R 10、-NR 10R 11、-NR 10C(O)R 11、-NR 10C(O)NR 11R 12、-S(O) mR 10或-NR 10S(O) mR 11，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 13、-OC(O)NR 13R 14、-C(O)OR 13、-C(O)NR 13R 14、-C(O)R 13、-NR 13R 14、-NR 13C(O)R 14、-NR 13C(O)NR 14R 15、-S(O) mR 13或-NR 13S(O) iR 14的取代基所取代；
    R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 13、R 14和R 15各自独立选自氢、氰基、卤素、C 1-6烷基、C 3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；
    且m为1或2。
  4. 根据权利要求1所述的通式(I)的化合物、其药学上可接受的盐或其立体异构体，通式(I)进一步如通式Ic所示：
    Figure PCTCN2021141767-appb-100010
    X 1，X 2可以独立地选自N、CR 1；
    X 3可以独立地选自不存在、N、CR 1；
    键a、b为单键或者双键；
    R 1独立地选自H、D、氰基、卤素、C 1-6烷基、COOH、CONH 2、NHCOH、CONHR 2、OR 2或-NHR 2；
    R 2独立地选自H、D、氰基、卤素、C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、-OR 3、-NR 3R 4、-C(O)NR 3R 4，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 5、-NR 5R 6、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
    W独立地选自键、-C 1-4烷基-、-CR 7R 8-、-C 1-2烷基(R 7)(OH)-、-C(O)-、-CR 7R 8O-、-OCR 7R 8-、-SCR 7R 8-、-CR 7R 8S-、-NR 7-、-NR 7C(O)-、-C(O)NR 7-、-NR 7C(O)NR 8-、-CF 2-、-O-、-S-、-S(O) m-、 -NR 7S(O) 2-、-S(O) 2NR 7-；
    Y不存在或选C 3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G 1所取代；
    Z独立地选自氰基、-NR 12CN、
    Figure PCTCN2021141767-appb-100011
    键c为双键或者三键；
    当c为双键时，R a 、R b和R c各自独立地选自H、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G 2所取代；
    R a和R b或R b和R c任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
    当键c为三键时，R a和R c不存在，R b独立选自H、氰基，卤素、C 1-6烷基、C 3-6环烷基或3-6元杂环基被一个或多个G 3所取代；
    R 9独立地选自H、C 1-6烷基、C 3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G 4所取代；
    G 1、G 2、G 3和G 4各自独立选自氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 10、-OC(O)NR 10R 11、-C(O)OR 10、-C(O)NR 10R 11、-C(O)R 10、-NR 10R 11、-NR 10C(O)R 11、-NR 10C(O)NR 11R 12、-S(O) mR 10或-NR 10S(O) mR 11，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基、C 6-10芳基、5-10元杂芳香基、-OR 13、-OC(O)NR 13R 14、-C(O)OR 13、-C(O)NR 13R 14、-C(O)R 13、-NR 13R 14、-NR 13C(O)R 14、-NR 13C(O)NR 14R 15、-S(O) mR 13或-NR 13S(O) iR 14的取代基所取代；
    R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 13、R 14和R 15各自独立选自氢、氰基、卤素、C 1-6烷基、C 3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；
    且m为1或2。
  5. 根据权利要求1-4所述的化合物、其药学上可接受的盐或其立体异构体，所述的化合物选自：
    Figure PCTCN2021141767-appb-100012
    Figure PCTCN2021141767-appb-100013
    Figure PCTCN2021141767-appb-100014
    或其前药、稳定同位素衍生物、可药用的盐、异构体及其混合和形式。
  6. 一种药物组合物，包含权利要求1-5任一项的化合物、其药学上可接受的盐、其立体异构体或其前药，任选地，本申请的药物组合物还包含一种或多种药用辅料；
    任选地，所述药物组合物还包含一种或多种第二治疗剂；
    优选地，所述第二治疗剂为化疗药物、靶向抗癌药或免疫治疗药；
    优选地，所述第二治疗剂选自利妥昔单抗、来那度胺、氟达拉滨、环磷酰胺、阿霉素、长春新碱、强的松。
  7. 权利要求1-5任一项的化合物、其药学上可接受的盐、其立体异构体或其前药用于制备药物的用途，所述药物用于预防和/或治疗受试者的与布鲁顿酪氨酸激酶过度活性相关的疾病和/或症状；
    优选地，所述与布鲁顿酪氨酸激酶过度活性相关的疾病和/或症状选自肿瘤(例如血液肿瘤或实体瘤)、炎症或自身免疫性疾病；
    优选地，所述血液肿瘤选自淋巴瘤、骨髓瘤、淋巴细胞白血病、急性髓系白血病；
    优选地，所述实体瘤选自肺癌、乳腺癌、前列腺癌、胃癌、肝癌、胰腺癌、卵巢癌、结肠癌；
    优选地，所述炎症或自身免疫性疾病选自类风湿关节炎、红斑狼疮、狼疮性肾炎、多发性硬化症、肖格伦综合征及潜在疾病哮喘；
    优选地，所述受试者为哺乳动物；例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；例如，人；
    优选地，所述药物还包含一种或多种第二治疗剂；
    优选地，所述第二治疗剂为化疗药物、靶向抗癌药或免疫治疗药；
    优选地，所述第二治疗剂选自利妥昔单抗、来那度胺、氟达拉滨、环磷酰胺、阿霉素、长春新碱、强的松。
  8. 权利要求1-5任一项的化合物、其药学上可接受的盐、其立体异构体或其前药用于制备制剂的用途，所述制剂用于降低或抑制细胞中的布鲁顿酪氨酸激酶活性；
    优选地，所述制剂被施用至受试者(例如哺乳动物；例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；例如，人)体内，以降低或抑制受试者体内细胞中的布鲁顿酪氨酸激酶的活性；或者，所述制剂被施用至体外细胞(例如细胞系或者来自受试者的细胞)，以降低或抑制体外细胞中的布鲁顿酪氨酸激酶活性；
    优选地，所述细胞选自肿瘤细胞(例如实体瘤细胞，例如肺癌细胞、乳腺癌细胞、前列腺癌细胞、胃癌细胞、肝癌细胞、胰腺癌细胞、卵巢癌细胞、结肠癌细胞)；
    优选地，所述细胞选自髓系细胞或淋巴细胞；
    优选地，所述细胞为来自受试者的原代细胞或其培养物，或已建立的细胞系。
  9. 一种试剂盒，所述试剂盒包括权利要求1-5任一项的化合物、其药学上可接受的盐、其立体异构体或其前药，且任选地还包括使用说明；
    优选地，所述试剂盒用于降低或抑制细胞中的布鲁顿酪氨酸激酶活性；
    优选地，所述细胞选自肿瘤细胞(例如实体瘤细胞，例如肺癌细胞、乳腺癌细胞、前列腺癌细胞、胃癌细胞、肝癌细胞、胰腺癌细胞、卵巢癌细胞、结肠癌细胞)；
    优选地，所述细胞选自髓系细胞或淋巴细胞；
    优选地，所述细胞为来自受试者的原代细胞或其培养物，或已建立的细胞系。
PCT/CN2021/141767 2021-02-03 2021-12-27 Bruton's酪氨酸激酶抑制剂及其应用 WO2022166468A1 (zh)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202110152506.4A CN114853752B (zh) 2021-02-03 2021-02-03 Btk抑制剂吡啶并杂环类化合物的制备及其应用
CN202110152506.4 2021-02-03
CN202110203701.5 2021-02-23
CN202110203074.5 2021-02-23
CN202110203074.5A CN114957241B (zh) 2021-02-23 2021-02-23 杂环类化合物作为激酶抑制剂的制备及其应用
CN202110203701.5A CN114957242B (zh) 2021-02-23 2021-02-23 吡啶并杂环类化合物作为激酶抑制剂的制备及其应用

Publications (1)

Publication Number Publication Date
WO2022166468A1 true WO2022166468A1 (zh) 2022-08-11

Family

ID=82740837

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/141767 WO2022166468A1 (zh) 2021-02-03 2021-12-27 Bruton's酪氨酸激酶抑制剂及其应用

Country Status (2)

Country Link
TW (1) TW202231639A (zh)
WO (1) WO2022166468A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014210255A1 (en) * 2013-06-26 2014-12-31 Abbvie Inc. Primary carboxamides as btk inhibitors
WO2015128333A1 (en) * 2014-02-27 2015-09-03 Laboratoire Biodim Heteroaromatic derivatives and their use as pharmaceuticals

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014210255A1 (en) * 2013-06-26 2014-12-31 Abbvie Inc. Primary carboxamides as btk inhibitors
WO2015128333A1 (en) * 2014-02-27 2015-09-03 Laboratoire Biodim Heteroaromatic derivatives and their use as pharmaceuticals

Also Published As

Publication number Publication date
TW202231639A (zh) 2022-08-16

Similar Documents

Publication Publication Date Title
WO2018045957A1 (zh) 一种cdk4/6抑制剂及其制备方法和应用
TWI810803B (zh) 突變蛋白抑制劑的製備及其應用
TWI814234B (zh) 突變蛋白抑制劑的製備及其應用
CN115073469B (zh) 吡咯并嘧啶类化合物作为激酶抑制剂的制备及其应用
WO2022028506A1 (zh) Sos1抑制剂、包含其的药物组合物及其用途
WO2022135590A1 (zh) 一类嘧啶并杂环类化合物、制备方法和用途
CN115073450A (zh) Krasg12c突变蛋白抑制剂的制备及其应用
WO2022237676A1 (zh) Shp2磷酸酶抑制剂的制备及其应用
TW201900644A (zh) Fgfr4抑制劑及其制備與應用
CN114437074A (zh) 一种化合物、含该化合物的药物组合物及其用途
CN115028633B (zh) 吡咯并嘧啶类化合物的制备及其应用
WO2022166468A1 (zh) Bruton&#39;s酪氨酸激酶抑制剂及其应用
CN111377873B (zh) 氨基嘧啶化合物及其制备方法和用途
CN112939982A (zh) 一种炔类杂环btk抑制剂及其制备方法和用途
EP4077297A1 (en) Cd206 modulators their use and methods for preparation
CN115340559A (zh) Shp2磷酸酶杂环类抑制剂的制备及其应用
CN114853723A (zh) 吲哚类化合物btk抑制剂的制备及其应用
CN114957241B (zh) 杂环类化合物作为激酶抑制剂的制备及其应用
CN114957242B (zh) 吡啶并杂环类化合物作为激酶抑制剂的制备及其应用
CN114853752B (zh) Btk抑制剂吡啶并杂环类化合物的制备及其应用
CN115043841B (zh) 一种作为btk抑制剂杂环类化合物的制备及其应用
CN115368381B (zh) 杂环类抑制剂的制备及其应用
CN115073468B (zh) 咪唑并吡嗪类btk抑制剂的制备及用途
WO2024078263A1 (zh) 大环杂环类化合物作为egfr抑制剂的制备及其应用
WO2022166469A1 (zh) Fgfr激酶抑制剂及其应用

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: 21924461

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 18261883

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21924461

Country of ref document: EP

Kind code of ref document: A1