WO2022166469A1 - Fgfr激酶抑制剂及其应用 - Google Patents

Fgfr激酶抑制剂及其应用 Download PDF

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WO2022166469A1
WO2022166469A1 PCT/CN2021/141768 CN2021141768W WO2022166469A1 WO 2022166469 A1 WO2022166469 A1 WO 2022166469A1 CN 2021141768 W CN2021141768 W CN 2021141768W WO 2022166469 A1 WO2022166469 A1 WO 2022166469A1
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membered
alkyl
cycloalkyl
independently selected
cyano
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PCT/CN2021/141768
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English (en)
French (fr)
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梁永宏
许志勇
曾兆森
严文广
熊方均
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药雅科技(上海)有限公司
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Priority claimed from CN202110152502.6A external-priority patent/CN114853740B/zh
Priority claimed from CN202110615730.2A external-priority patent/CN115433190A/zh
Priority claimed from CN202111373638.6A external-priority patent/CN114057749B/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
Priority to US18/261,899 priority Critical patent/US20240109896A1/en
Publication of WO2022166469A1 publication Critical patent/WO2022166469A1/zh

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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention discloses compounds that are fibroblast growth factor receptor inhibitors (FGFR) useful for the treatment of diseases treatable by inhibition of FGFR. Also provided are pharmaceutical compositions containing the compounds and methods for preparing the compounds.
  • FGFR fibroblast growth factor receptor inhibitors
  • Fibroblast Growth Factor Receptor is a class of receptor tyrosine kinases (RTKs).
  • the FGFR family mainly includes four subtypes, FGFR1, FGFR2, FGFR3 and FGFR4.
  • FGFRs are involved in and regulate cell proliferation, migration, apoptosis, angiogenesis and many other processes.
  • FGFRs and RTKs have broad functions and are tightly regulated under normal conditions.
  • tumors such as liver cancer, bladder cancer, lung cancer, breast cancer, and prostate cancer
  • activating mutations or ligand/receptor overexpression of FGFR can lead to its persistent overactivation.
  • FGFR signaling components are frequently altered in human cancers, supported by several preclinical models providing compelling evidence for the oncogenic potential of aberrant FGFR signaling during carcinogenesis, validating the use of FGFR signaling as an attractive Cancer therapy targets.
  • FGFR inhibitors such as erdatinib, infigratinib and pemigatinib, as well as some other small molecule inhibitors have been reported: WO2011071821, WO2011135376, WO2014007951, WO2015008839, WO2015008844, WO2015061572, WO201506152, WO20154898 , WO2020168237, WO2018028438, WO2018049781, WO2019034075, WO2018121650, WO2020231990, WO2021146424.
  • FGFR inhibitors Although some FGFR inhibitors have entered the clinical and preclinical development process, they are usually not selective enough, and also have inhibitory effects on other kinases such as c-kit and PDGFRa, which brings certain concerns. Therefore, the development of selective inhibitors targeting FGFR will be of great interest in the clinical treatment of diseases with elevated FGF or FGFR activity.
  • Each L 1 is independently selected from bond, -C 1-4 alkyl-, -C 2-4 alkenyl-, -C 2-4 alkynyl-;
  • Each R 1 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -OR 2 , -NR 2 R 3 , -C(O)NR 2 R 3 , wherein said alkyl, cycloalkyl or heterocycloalkyl is optionally cyano, halogen, -OR 4 , -NR 4 R 5 , C 1-6 alkyl , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • Each U is independently selected from -C 0-4 alkyl-, -CR 6 R 7 -, -C 1-2 alkyl(R 6 )(OH)-, -C(O)-, -CR 6 R 7 O-, -OCR 6 R 7 -, -SCR 6 R 7 -, -CR 6 R 7 S-, -NR 6 -, -NR 6 C(O)-, -C(O)NR 6 -, - NR 6 C(O)NR 7 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 6 S(O) 2 -, -S(O) 2 NR 6 - ;
  • Each Y does not exist or selects C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5 -12-membered spiro-heterocyclic group, aromatic group or heteroaromatic group, wherein 3-8-membered heterocycloalkyl, 5-12-membered condensed heterocyclic group, 5-12-membered spiro-heterocyclic group or heteroaromatic group appears in each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S, the cycloalkyl, heterocycloalkyl, spirocyclyl, fused ring, fused heterocyclyl, spirohetero A cyclic, aryl or heteroaryl group is optionally substituted with one or more G 2 ;
  • Each Z is independently selected from cyano, -NR8CN ,
  • 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 G;
  • Ra and Rb or Rb and Rc optionally together with the carbon atom 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, 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 ;
  • Each R 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 or more G 5s ;
  • Each of G 1 , G 2 , G 3 , G 4 and G 5 is 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 9 , -OC(O)NR 9 R 10 , -C(O) OR 9 , -C(O)NR 9 R 10 , -C(O)R 9 , -NR 9 R 10 , -NR 9 C(O)R 10 , -NR 9 C(O)NR 10 R 11 , - S(O) m R 9 or -NR 9 S(O) m R 10 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is optionally One or more cyano groups,
  • Each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 and R 14 is independently selected from H, D, cyano, halogen, C 1- 6 alkyl, C 3-8 cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and m is 1 or 2.
  • general formula IIa the compound of general formula (I), its pharmaceutically acceptable salt or its stereoisomer, general formula (I) is further shown as general formula IIa:
  • Each of X1, X2, X3, X4, and X5 is independently CR 1 or N, and at least one of X1, X2, X3, X4, and X5 is N;
  • Each R 1 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -OR 2 , -NR 2 R 3 , -C(O)NR 2 R 3 , wherein said alkyl, cycloalkyl or heterocycloalkyl is optionally cyano, halogen, -OR 4 , -NR 4 R 5 , C 1-6 alkyl , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • Each ring B is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the above-mentioned benzene ring and heteroaromatic ring are optionally substituted by one or more G 1 ;
  • Each U is independently selected from -C 0-4 alkyl-, -CR 6 R 7 -, -C 1-2 alkyl(R 6 )(OH)-, -C(O)-, -CR 6 R 7 O-, -OCR 6 R 7 -, -SCR 6 R 7 -, -CR 6 R 7 S-, -NR 6 -, -NR 6 C(O)-, -C(O)NR 6 -, - NR 6 C(O)NR 7 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 6 S(O) 2 -, -S(O) 2 NR 6 - ;
  • Each Y does not exist or selects C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spirocyclyl -12-membered spiro-heterocyclic group, aromatic group or heteroaromatic group, wherein 3-8-membered heterocycloalkyl, 5-12-membered condensed heterocyclic group, 5-12-membered spiro-heterocyclic group or heteroaromatic group appears in each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S, the cycloalkyl, heterocycloalkyl, spirocyclyl, fused ring, fused heterocyclyl, spirohetero A cyclic, aryl or heteroaryl group is optionally substituted with one or more G 2 ;
  • Each Z is independently selected from cyano, -NR8CN ,
  • Bond a is a double bond or a triple bond
  • each of R a , R b and R c is independently selected from H, D, 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;
  • Ra and Rb or Rb and Rc optionally together with the carbon atom to which they are attached form a 3-6 membered ring optionally containing heteroatoms;
  • R a and R c are absent, and each R b is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 3-6 A membered heterocyclyl is substituted with one or more G4;
  • Each R 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 or more G 5s ;
  • Each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 and R 14 is 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;
  • 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 IId:
  • X 1 , X 2 , X 3 can be independently selected from N, CR 1 ;
  • Each R 1 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -OR 2 , -NR 2 R 3 , -C(O)NR 2 R 3 , wherein said alkyl, cycloalkyl or heterocycloalkyl is optionally cyano, halogen, -OR 4 , -NR 4 R 5 , C 1-6 alkyl , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • Each ring B is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the above-mentioned benzene ring and heteroaromatic ring are optionally substituted by one or more G 1 ;
  • Each U is independently selected from -C 0-4 alkyl-, -CR 6 R 7 -, -C 1-2 alkyl(R 6 )(OH)-, -C(O)-, -CR 6 R 7 O-, -OCR 6 R 7 -, -SCR 6 R 7 -, -CR 6 R 7 S-, -NR 6 -, -NR 6 C(O)-, -C(O)NR 6 -, - NR 6 C(O)NR 7 -, -CF 2 -, -O-, -S-, -S(O) m -, -NR 6 S(O) 2 -, -S(O) 2 NR 6 - ;
  • Each Y does not exist or selects C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spirocyclyl -12-membered spiro-heterocyclic group, aromatic group or heteroaromatic group, wherein 3-8-membered heterocycloalkyl, 5-12-membered condensed heterocyclic group, 5-12-membered spiro-heterocyclic group or heteroaromatic group appears in each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S, the cycloalkyl, heterocycloalkyl, spirocyclyl, fused ring, fused heterocyclyl, spirohetero A cyclic, aryl or heteroaryl group is optionally substituted with one or more G 2 ;
  • Each Z is independently selected from cyano, -NR8CN ,
  • Bond a is a double bond or a triple bond
  • each of R a , R b and R c is independently selected from H, D, 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;
  • Ra and Rb or Rb and Rc optionally together with the carbon atom to which they are attached form a 3-6 membered ring optionally containing heteroatoms;
  • R a and R c are absent, and each R b is independently selected from H, D, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 A membered heterocyclyl is substituted with one or more G4;
  • Each R 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 or more G 5s ;
  • Each of G 1 , G 2 , G 3 , G 4 and G 5 is 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 9 , -OC(O)NR 9 R 10 , -C(O) OR 9 , -C(O)NR 9 R 10 , -C(O)R 9 , -NR 9 R 10 , -NR 9 C(O)R 10 , -NR 9 C(O)NR 10 R 11 , - S(O) m R 9 or -NR 9 S(O) m R 10 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is optionally One or more cyano groups,
  • Each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 and R 14 is 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;
  • general formula IIe the compound of general formula (I), its pharmaceutically acceptable salt or its stereoisomer, general formula (I) is further shown as general formula IIe:
  • Ring Ar is a 5-10-membered heteroaromatic ring, wherein the above-mentioned 5-10-membered heteroaromatic ring is optionally substituted by one or more G 1 ;
  • Ring B is independently selected from 5-14-membered heteroaromatic rings and 5-14-membered aromatic rings containing 1-3 heteroatoms selected from S, O, N and Se, the above-mentioned 5-14-membered heteroaromatic rings and 5-
  • the 14-membered aromatic ring is substituted by one or more G 2 ;
  • U is 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) 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 3 ;
  • 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.
  • 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 A 3-6 membered ring containing heteroatoms; when bond a is a triple bond, 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 heterocyclyl is substituted by one or more G;
  • 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 6 ;
  • G 1 , G 2 , G 3 , G 4 , G 5 and G 6 are each independently selected from 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 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, and heteroaryl groups are optionally or multiple cyano
  • each Ar is independently optionally replaced by one or more G 1 at each occurrence;
  • G 1 are each independently selected from 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 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 more cyano groups, halogen, C 1-6 al
  • 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 compound of the present invention can effectively inhibit the activity of FGFR1, FGFR2, FGFR3 or FGFR4, and its IC50 for inhibiting FGFR1, FGFR2, FGFR3 or FGFR4 is 100 to 1000 nM, the better IC 50 is less than 100 nM, and the best IC 50 is less than 10 nM.
  • the compounds of the present invention can be used for the treatment or prevention of FGFR-related tumors, such as non-small cell lung cancer, esophageal cancer, melanoma rhabdomyosarcoma, cell carcinoma, multiple myeloma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, gastric cancer , colon cancer, bladder cancer, pancreatic cancer, lung cancer, prostate cancer and liver cancer (eg hepatocellular carcinoma), more particularly liver cancer, stomach cancer and bladder cancer.
  • FGFR-related tumors such as non-small cell lung cancer, esophageal cancer, melanoma rhabdomyosarcoma, cell carcinoma, multiple myeloma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, gastric cancer , colon cancer, bladder cancer, pancreatic cancer, lung cancer, prostate cancer and liver cancer (eg hepatocellular carcinoma), more particularly liver cancer, stomach cancer and bladder cancer.
  • the present invention provides a method of treating or preventing FGFR-mediated diseases (eg, tumors), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a prodrug, stable isotope derivative thereof compounds, polymorphs, solvates, pharmaceutically acceptable salts, isomers and mixtures thereof, or pharmaceutical compositions comprising the compounds.
  • FGFR-mediated diseases eg, tumors
  • Another aspect of the present invention relates to compounds of general formula I or their prodrugs, stable isotope derivatives, polymorphs, solvates, pharmaceutically acceptable salts, isomers, and mixtures thereof for use as medicines or for medicinal purposes , its use in the treatment or prevention of FGFR-mediated diseases, such as tumors or inflammatory diseases, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, wild cell carcinoma, multiple myeloma, breast cancer, ovarian cancer , Endometrial cancer, uterine cancer, stomach cancer, lymph node cancer, bladder cancer, pancreatic cancer, lung cancer, prostate cancer.
  • diseases such as tumors or inflammatory diseases, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, wild cell carcinoma, multiple myeloma, breast cancer, ovarian cancer , Endometrial cancer, uterine
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or its prodrugs, stable isotope derivatives, pharmaceutically acceptable salt isomers and mixtures thereof and a pharmaceutically acceptable carrier, Diluents, excipients.
  • Another aspect of the present invention relates to the compound represented by the general formula I or its prodrug stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof, or the use of the pharmaceutical composition in the preparation of medicine, and the use therein Drugs are used to treat or prevent FGFR-mediated diseases such as tumors and inflammatory diseases.
  • the drug can be in any pharmaceutical dosage form including but not limited to tablets, sachets, solutions, lyophilized preparations, and injections.
  • 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 line containing 1 to 20 carbon atoms, such as 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 polycyclic heterocyclic group of 5 to 20 members with one atom shared between the monocyclic rings (called spiro atoms), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein 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-spiroheterocyclyl or poly-spiro-heterocyclyl, 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.
  • spirocycloalkyl 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 ring or condensed polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, preferably phenyl
  • the base ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, non-limiting examples include:
  • 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 -NO2
  • 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 described in the present invention can also be synthesized by 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 can be used.
  • 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).
  • alkynyl heterocyclic compounds described in the general formula (IIa) of the present invention are prepared by the following four routes:
  • Method B The starting material II-1a is subjected to Suzuki coupling reaction to obtain intermediate II-2b, followed by Sonagashira coupling reaction to obtain intermediate II-4a, and then method A is used to obtain the compound of general structural formula (IIa).
  • Method C The starting material II-1a is subjected to Sonagashira coupling reaction to obtain intermediate II-3c, followed by aromatic nucleophilic substitution reaction II-3c, and then the Boc protecting group is removed under acidic conditions to obtain intermediate II-4a, and finally A nucleophilic addition reaction occurs to give compounds of general structural formula (I).
  • alkynyl heterocyclic compounds described in the general formula (IId) of the present invention are prepared by the following four routes:
  • Method I 1. The starting material II-1j is reacted with a hydroxyl-bearing precursor (HO-UYP) through Mitsunobu reaction to obtain II-2j; 2. II-2j is reacted with NBS to obtain II-3j; 3. II-4j is obtained by sonogashira coupling between II-3j and aromatic alkyne; 4. II-4j is obtained by the reaction of II-4j with N 2 H 4 to obtain II-5j; 5. II-6j is obtained by deprotection of the amine group in II-6j; 6.
  • HO-UYP hydroxyl-bearing precursor
  • the amine group in II-6j is derivatized with a chemical reagent (eg, acryloyl chloride, etc.) containing a functional group that reacts with a cysteine residue in the ligand binding domain of the kinase to obtain the compound of formula (IId).
  • a chemical reagent eg, acryloyl chloride, etc.
  • Method J 1. The starting material II-1j was reacted with N 2 H 4 to close the ring to obtain II-1k; 2. II-2k was reacted with NBS to obtain bromine to obtain II-3k; 3. II-3k was coupled with an aromatic alkyne by sonogashira coupling 4, II-4k and a precursor with a hydroxyl group (HO-UYP) to obtain II-5k through the Mitsunobu reaction (mitsunobu reaction); then use the method of the last two steps of method J to obtain the general formula (IId ) of the compound.
  • HO-UYP a precursor with a hydroxyl group
  • Method K The starting material II-1l was reacted with NBS to obtain intermediate II-2l; the intermediate II-2l was cyclized with N 2 H 4 to obtain II-3l; the intermediate II-3l was coupled with an aromatic alkyne by sonogashira coupling Combined to obtain II-5k; then the last two steps of method J were used to obtain the compound of general formula (IId).
  • Method L The starting material II-11 is reacted with N 2 H 4 to close the ring to obtain intermediate II-2m; the intermediate II-2m is reacted with NBS to obtain intermediate II-3lk; The compound of general formula (IId) is obtained.
  • temperatures are in degrees Celsius.
  • Reagents were purchased from commercial suppliers such as Chemblocks Inc, Astatech Inc, or Maclean, and these reagents were used 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 Thermo Fisher LCQ Fleet type (ESI) liquid chromatography-mass spectrometer.
  • Nuclear magnetic data ( 1 H NMR) was performed using Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instrument.
  • the solvents used in nuclear magnetic data were CDCl 3 , CD 3 OD, D 2 O, DMSO-d 6 , etc., and tetramethylsilane (0.000 ppm) or based on residual solvent (CDCl 3 : 7.26 ppm; CD 3 OD: 3.31 ppm; D 2 O: 4.79 ppm; DMSO-d 6 : 2.50 ppm)
  • peak shape diversity the following abbreviations Different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double doublet), dt ( double triplet). If a coupling constant is given, it is in Hertz (Hz).
  • Example 7 2-(2-Acryloyl-2-azaspiro[3,3]heptane-6-amino)-4-(3,5-dimethoxyphenethynyl)-5-amine Preparation of formyl-6-aminopyrimidine (compound 7)
  • Example 8 2-(2-Acryloyl-2-azaspiro[3,4]octane-7-amino)-4-(3,5-dimethoxyphenethynyl)-5-amine Preparation of formyl-6-aminopyrimidine (compound 8)
  • 3-Chloropyrazine-2-methylamine dihydrochloride (2.16 g, 10 mmol) was added to the reaction flask, 50 mL of dichloromethane, and N-Cbz-pyrrolidine-3-carbonyl chloride (3.21 g, 12 mmol) in 10 mL of dichloromethane solution, then warmed to room temperature and stirred for half an hour. The mixture was quenched with 30 mL of saturated aqueous sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and washed with saturated brine.
  • Example 48 1-(1-Acryloylazetidin-3-yl)-4-amino-3-(7-methoxy-5-toluo[b]thiophen-2-yl)-1 Preparation of ,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (Compound 48)
  • Example 50 1-(3-(8-Amino-1-(7-methoxy-5-toluo[b]thiophen-2-yl)imidazo[1,5-a]pyrazin-3-yl ) Preparation of azetidine-1-yl)prop-2-en-1-one (compound 50)
  • Example 51 1-(3-(8-Amino-1-(7-methoxy-5-toluo[b]thiophen-2-yl)imidazo[5,1-f][1,2,4 ] Preparation of triazin-7-yl)azetidin-1-yl)prop-2-en-1-one (compound 51)
  • Example 56 In vitro activity inhibition test on kinases FGFR1, FGFR2, FGFR3 and FGFR4
  • FGFR1, FGFR2, FGFR3 and FGFR4 protein kinases were determined by the Caliper mobility shift assay. 4-fold serial dilutions were made in DMSO from a working concentration of 0.2 mM to 10 dilutions. Add 2 ⁇ L of compound to 78 ⁇ L of 1 ⁇ compound buffer. 10 points each for negative control and positive control. Shake the plate on a plate shaker for 20 minutes. Transfer 2 ⁇ L of kinase to the 384 reaction plate, add 1 ⁇ L of the test compound to the 384 reaction plate, centrifuge at 1000 rpm/min for 1 min, and incubate at 25°C for 10 min.
  • Activity was characterized by IC50 , where "A” means IC50 ⁇ 10 nM; “B” means 10 ⁇ IC50 ⁇ 100nM ;”C” means 100 ⁇ IC50 ⁇ 500nM ;"D” means 500 ⁇ IC50 ⁇ 2000nM.
  • Example 57 Human hepatoma cell Hep3B survival test
  • the human hepatoma Hep3B cell line was derived from ATCC. Cells were plated in McCoy's 5A medium with the addition of fetal bovine serum (10% FBS). Cells were maintained in culture medium at 37°C, 95% humidity and 5% carbon dioxide. During the experiment, Hep3B cells were seeded in a 96-well plate at a density of 3500 cells per well, and the volume of cell suspension was 90 ⁇ L per well, and cultured at 37°C in a cell incubator containing 5% CO 2 .
  • the final concentration of the test compound was 1 ⁇ M (as the starting concentration for IC 50 test), and 9 concentrations were diluted four-fold, the 9 concentrations were: 1 ⁇ M, 2.5 ⁇ M, 0.625 ⁇ M, 0.156 ⁇ M, 0.039 ⁇ M, 0.0098 ⁇ M, 0.0024 ⁇ M, 0.0006 ⁇ M and 0.000015 ⁇ M, mixed and centrifuged, 1PL compound DMSO solution was added to the cell culture medium, and IM DMSO was used as a control, and three parallel sub-wells were set for each compound concentration.
  • Sample serial number IC50 (nM) Sample serial number IC50 (nM) 20 A 34 A twenty two A 36 A twenty four A 38 A 26 A pemigatinib B 28 A infigratinib B 30 A Futibatinib A 32 A
  • CellTiter-Glo ⁇ TM> live cell detection kit was used to determine the proliferation of human gastric cancer cells (SNU-16) with FGFR2 gene amplification and human bladder cancer cells (RT4) with high expression of FGFR3 and FGFR3-TACC3 fusion by test compound A inhibitory effect.
  • the medium of RT4 was added with fetal bovine serum and McCoy's 5A medium with a final concentration of 10%.
  • Test procedure Digest SNU-16 and RT4 cells that have reached 80% cell confluence with trypsin, resuspend and count by centrifugation, prepare SNU-16 and RT4 cell suspensions at 3500 and 6000 cells/mL with medium, respectively, add A 96-well cell culture plate (90 ⁇ L/well) was cultured at 37°C in a cell culture incubator containing 5% CO 2 . After 24 hours of cell culture, the reference compound table and the test compound A were dissolved in DMSO into a stock solution with a concentration of 30 mM. The diluted compound stock solution was further diluted with the medium of SNU-16 and RT4, and the diluted mixture was transferred to the corresponding cell plate respectively.
  • the final concentration of the test compound was 1 ⁇ M (as the initial concentration of IC50 test). ), 9 concentrations in four-fold descending dilution, the 9 concentrations are: 1 ⁇ M, 2.5 ⁇ M, 0.625 ⁇ M, 0.156 ⁇ M, 0.039 ⁇ M, 0.0098 ⁇ M, 0.0024 ⁇ M, 0.0006 ⁇ M and 0.000015 ⁇ M, mix well and centrifuge, place in 5 Incubate for 3 days at 37 °C in a cell incubator with % CO 2 .
  • the compounds have strong inhibitory activity on the proliferation of tested human gastric cancer cells (SNU-16), human bladder cancer cells (RT4) and human liver cancer Hep3B cells, and some compounds have stronger inhibitory activities than the control compounds pemigatinib, infigratinib, Futibatinib and Erdafinib et al.
  • Example 59 Assay for hERG potassium channel blockade
  • the experimental method is outlined as follows:
  • HEK293 cell line stably expressing hERG potassium channel was used.
  • hERG potassium channel cells were purchased from Creacell (Cat. No.: A-0320) and cultured in DMEM medium containing 10% fetal bovine serum and 0.8mg/mL G418 , the culture temperature was 37°C, and the carbon dioxide concentration was 5%. Remove the old medium and wash once with PBS, then add 2 mL of TrypLE TM Express solution and incubate at 37°C for about 1 min. When the cells are detached from the bottom of the dish, add about 5 mL of pre-warmed complete medium at 37°C. The cell suspension was gently pipetted to dissociate the aggregated cells.
  • the cell suspension was transferred to a sterile centrifuge tube, and the cells were collected by centrifugation at 1000 rpm for 5 min.
  • cells were seeded in 10 cm cell culture dishes, and the amount of cells seeded in each cell culture dish was 6105 cells (final volume: 10 mL).
  • the cell density must not exceed 80%.
  • the voltage stimulation protocol for whole-cell patch-clamp recording of whole-cell hERG potassium currents was as follows: when the whole-cell seal was formed, the cell membrane voltage was clamped at -80mV. The clamp voltage was depolarized from -80mV to -50mV for 0.5s (as leakage current detection), then stepped to 30mV for 2.5s, and then quickly returned to -50mV for 4s to excite the tail current of the hERG channel. Data were collected every 10s to observe the effect of drugs on hERG tail current. A -50mV stimulus for 0.5s was used as leakage current detection. Test data is collected by Qpatch and stored in the connected service station.
  • Each drug concentration was set as two doses with a duration of at least 5 minutes.
  • the test compound and the compound-free extrinsic fluid act on the cells sequentially from low concentration to high concentration.
  • the current detected by each cell in the compound-free extrinsic fluid serves as its own control group, and two cells are independently and repeatedly detected. All electrophysiological experiments were performed at 24°C.
  • test results showed that test substance 28 had weak or no inhibitory effect on hERG channel; test substance 38 had moderate inhibitory effect on hERG channel.

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Abstract

作为成纤维细胞生长因子受体(FGFR)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FGFR激酶相关性病症、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

FGFR激酶抑制剂及其应用
相关申请的交叉引用
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CN2021101525026、申请日为2021年6月2日的中国专利申请CN2021106157302的优先权、申请日为2021年11月19日的中国专利申请CN2021113736386的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明公开了作为成纤维细胞生长因子受体抑制剂(FGFR)的化合物，对于通过抑制FGFR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
成纤维细胞生长因子受体(Fibroblast Growth Factor Receptor，FGFR)是一类受体酪胺酸激酶(RTK)，FGFR家族主要包括FGFR1、FGFR2、FGFR3和FGFR4四种亚型。FGFRs参与并调控细胞增殖、迁移、凋亡、血管生成及其他许多过程。FGFRs和RTKs功能广泛，在正常情况下受到严格调控。但在肝癌、膀胱癌、肺癌、乳腺癌、前列腺癌等肿瘤中，FGFR激活突变或配体/受体过表达会导致其持续的过度激活。在FGF结合下，FGFR发生二聚化和转磷酸化，这导致受体活化(参考：Dieci,M.V,et aL,CancerDiscov.2013；3:264-279；Korc,N.,andFriesel,R.E.,Curr.Cancer Drug Targets 2009；5:639-651)。下游信号通路的激活通过细胞内受体底物FGFR底物2(FRS2)和磷脂酶Cγ(PLCγ)发生，导致RAS/丝裂原活化蛋白激酶(MAPK)和磷酸肌醇激酶(PI3K)/AKT信号通路的随后上调。其他的通路也可以被激活，包括STAT依赖信号(参考：Turner,N.,Grose,R.,Nat.Ref.Cancer 2010；10:116-129；Brooks,N.S.,et al.,Clin Cancer Res.2012；18:1855-1862；Dienstmann,R.,et al.,Ann.Oncol.2014；25:552-563)。
FGFR信号成分在人类癌症中经常发生改变，一些临床前模型支持提供了令人信服的证据，证明了异常FGFR信号在癌症发生过程中的致癌潜能，从而验证了将FGFR信号作为一个有吸引力的癌症治疗靶点。
近年来，工业界和学术界对小分子FGFR抑制剂的研究都做出了巨大的努力。一些FGFR 抑制剂，例如厄达替尼，英菲格拉替尼和培米加替尼,以及一些其他小分子抑制剂已报道：WO2011071821，WO2011135376，WO2014007951，WO2015008839，WO2015008844，WO2014011900，WO2015061572，WO2015108992，WO2017215485，WO2020168237，WO2018028438，WO2018049781，WO2019034075，WO2018121650，，WO2020231990，WO2021146424。
虽然已经有一些FGFR抑制剂进入到了临床及临床前的研发过程中，但通常都选择性不够好，对于c-kit和PDGFRa等其他激酶也有抑制作用，从而带来一定担忧。因此，研发靶向于FGFR选择性的抑制剂在临床上治疗具有升高的FGF或者FGFR活性的疾病时会非常有意义。
发明内容
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 PCTCN2021141768-appb-000001
其中：
每个环B为苯环或者5-10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；
每个L 1独立地选自键、-C 1-4烷基-、-C 2-4烯基-、-C 2-4炔基-；
每个芳环Ar为6-10元杂芳环，其中上述的苯环和杂芳环任选被一个或多个R 1所取代；
每个R 1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 2、-NR 2R 3、-C(O)NR 2R 3，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 4、-NR 4R 5、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
每个U独立地选自-C 0-4烷基-、-CR 6R 7-、-C 1-2烷基(R 6)(OH)-、-C(O)-、-CR 6R 7O-、-OCR 6R 7-、-SCR 6R 7-、-CR 6R 7S-、-NR 6-、-NR 6C(O)-、-C(O)NR 6-、-NR 6C(O)NR 7-、-CF 2-、-O-、-S-、-S(O) m-、-NR 6S(O) 2-、-S(O) 2NR 6-；
每个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3-8元杂环烷基、5-12元稠杂环基、5-12元螺杂环基者杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子，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；
每个Z独立地选自氰基、-NR 8CN、
Figure PCTCN2021141768-appb-000002
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；
每个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；
每个R 8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；
每个G 1、G 2、G 3、G 4和G 5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 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) mR 10，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 12、-OC(O)NR 12R 13、-C(O)OR 12、-C(O)NR 12R 13、-C(O)R 12、-NR 12R 13、-NR 12C(O)R 13、-NR 12C(O)NR 13R 14、-S(O) mR 12或-NR 12S(O) mR 13的取代基所取代；
每个R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 11、R 12、R 13和R 14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IIa所示：
Figure PCTCN2021141768-appb-000003
其中：
每个X1、X2、X3、X4、X5各自独立地为CR 1或N，且X1、X2、X3、X4、X5中至少有一个为N；
每个R 1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 2、-NR 2R 3、-C(O)NR 2R 3，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 4、-NR 4R 5、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
每个环B为苯环或者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；
每个U独立地选自-C 0-4烷基-、-CR 6R 7-、-C 1-2烷基(R 6)(OH)-、-C(O)-、-CR 6R 7O-、-OCR 6R 7-、-SCR 6R 7-、-CR 6R 7S-、-NR 6-、-NR 6C(O)-、-C(O)NR 6-、-NR 6C(O)NR 7-、-CF 2-、-O-、-S-、-S(O) m-、-NR 6S(O) 2-、-S(O) 2NR 6-；
每个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3-8元杂环烷基、5-12元稠杂环基、5-12元螺杂环基者杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子，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；
每个Z独立地选自氰基、-NR 8CN、
Figure PCTCN2021141768-appb-000004
键a为双键或者三键；
当a为双键时，每个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；
每个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，每个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；
每个R 8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；
每个G 1、G 2、G 3、G 4和G 5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 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) mR 10，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 12、-OC(O)NR 12R 13、-C(O)OR 12、-C(O)NR 12R 13、-C(O)R 12、-NR 12R 13、-NR 12C(O)R 13、-NR 12C(O)NR 13R 14、-S(O) mR 12或-NR 12S(O) mR 13的取代基所取代；
每个R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 11、R 12、R 13和R 14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IId所示：
Figure PCTCN2021141768-appb-000005
其中：
X 1，X 2，X 3可以独立地选自N、CR 1；
每个R 1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 2、-NR 2R 3、-C(O)NR 2R 3，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 4、-NR 4R 5、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
每个环B为苯环或者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；
每个U独立地选自-C 0-4烷基-、-CR 6R 7-、-C 1-2烷基(R 6)(OH)-、-C(O)-、-CR 6R 7O-、-OCR 6R 7-、 -SCR 6R 7-、-CR 6R 7S-、-NR 6-、-NR 6C(O)-、-C(O)NR 6-、-NR 6C(O)NR 7-、-CF 2-、-O-、-S-、-S(O) m-、-NR 6S(O) 2-、-S(O) 2NR 6-；
每个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3-8元杂环烷基、5-12元稠杂环基、5-12元螺杂环基者杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子，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；
每个Z独立地选自氰基、-NR 8CN、
Figure PCTCN2021141768-appb-000006
键a为双键或者三键；
当a为双键时，每个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；
每个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，每个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；
每个R 8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；
每个G 1、G 2、G 3、G 4和G 5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 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) mR 10，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 12、-OC(O)NR 12R 13、-C(O)OR 12、-C(O)NR 12R 13、-C(O)R 12、-NR 12R 13、-NR 12C(O)R 13、-NR 12C(O)NR 13R 14、-S(O) mR 12或-NR 12S(O) mR 13的取代基所取代；
每个R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 11、R 12、R 13和R 14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IIe所示：
Figure PCTCN2021141768-appb-000007
其中：
环Ar为5-10元杂芳环，其中上述的5-10元杂芳环任选被一个或多个G 1所取代；
环B独立地选自含有1-3个选自S，O，N和Se杂原子的5-14元杂芳环和5-14元芳环，上述的5-14元杂芳环和5-14元芳环被一个或多个G 2所取代；
U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 3所取代；
Z独立地选自氰基、-NR 9CN、
Figure PCTCN2021141768-appb-000008
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 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 6所取代；
G 1、G 2、G 3、G 4、G 5和G 6各自独立选自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 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) mR 14的取代基所取代；R 7、R 8、R 10、R 11、R 12、R 13、R 14和R 15各自独立选自氢、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。
其中，每个Ar选自在每次出现时独立地选自
Figure PCTCN2021141768-appb-000009
每个Ar在每次出现时独立地可选地被一个或多个G 1所取代；
G 1各自独立选自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 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) mR 14的取代基所取代；R 10、R 11、R 12、R 13、R 14和R 15各自独立选自氢、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，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 PCTCN2021141768-appb-000010
Figure PCTCN2021141768-appb-000011
Figure PCTCN2021141768-appb-000012
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。
本发明化合物能够有效抑制FGFR1、FGFR2、FGFR3或FGFR4的活性，其抑制FGFR1、FGFR2、FGFR3或FGFR4的IC 50为100至1000nM，更佳IC 50小于100nM，最佳IC 50小于10nM。
本发明化合物可用于治疗或者预防FGFR相关性肿瘤、例如非小细胞肺癌、食管癌、黑色素瘤横纹肌肉瘤、细胞癌、多发性骨髓瘤、乳腺癌、卵巢癌、子宫内膜癌、宫颈癌、胃癌、结肠癌、膀胱癌、胰腺癌、肺癌、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。因此、再一方面，本发明提供一种治疗或者预防FGFR介导的疾病(例如所肿瘤的)方法、其包括给予有需要的患者治疗有效量的本发明所化合物或其前药、稳定同位素衍生物、多晶型物、溶剂化物、可药用的盐、异构体及其混合物、或包含所化合物的药物组合物。
本发明的另一方面涉及作为药物或者医药用途的通式I所示的化合物或其前药、稳定同位素衍生物、多晶型物、溶剂化物、可药用的盐、异构体及其混合物、其用于治或者预防 FGFR介的疾病、例如肿瘤或炎症性疾病、包括但不限于非小细胞肺癌、食管癌、黑色素、横纹肌肉瘤、野细胞癌、多发性骨髓瘤、乳腺癌、卵巢癌、子宫内膜癌、宫癌、胃癌、结膈癌、膀胱癌、胰腺癌、肺癌、前列腺癌。
本发明进一步涉及一种药物组合物，所述药物组合物包含本发明所述化合物或其前药、稳定同位素衍生物、可药用的盐异构体及其混合物及药学上可接受的载体、稀释剂、赋形剂。
本发明的另一方面涉及通式I所示的化合物或其前药稳定同位素衍生物、可药用的盐、异构体及其混合物、或所药物组合物在制备药物中的用途、其中所用药物用于治疗或者预防FGFR介入的疾病例如肿瘤和炎症性疾病。
根据本发明，所药物可以是任何药物剂型包括但不限于片剂、囊剂、溶液剂、冻干制剂、注射剂。
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。螺环烷基的非限制性实施例包含：
Figure PCTCN2021141768-appb-000013
“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 PCTCN2021141768-appb-000014
“芳基”或“芳香基”指含有6至14个碳原子的芳香族环或稠合多环基团，较佳为6至10元，例如苯基和萘基，最佳苯基所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、非限制性实例包括：
“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-NO 2，“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。也可通过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。
本发明通式(IIa)所述炔代杂环类化合物如下四种路线制备：
方法A、起始原料II-1a通过芳香亲核取代反应II-2a，接着Sonagashira偶联反应得到中间体II-3a，然后在酸性条件下脱除Boc保护基得到中间体II-4a，最后发生亲核加成反应得到结构通式(IIa)的化合物；
Figure PCTCN2021141768-appb-000015
方法B、起始原料II-1a通过Suzuki偶联反应得到中间体II-2b，接着Sonagashira偶联反应得到中间体II-4a，然后用方法A得到结构通式(IIa)的化合物。
Figure PCTCN2021141768-appb-000016
方法C、起始原料II-1a通过Sonagashira偶联反应得到中间体II-3c，接着发生芳香亲核取代反应II-3c，然后在酸性条件下脱除Boc保护基得到中间体II-4a，最后发生亲核加成反应得到结构通式(I)的化合物。
Figure PCTCN2021141768-appb-000017
方法D、中间体II-3c通过Suzuki偶联反应得到中间体II-4a，然后用方法A得到结构通式(IIa)的化合物。
Figure PCTCN2021141768-appb-000018
本发明通式(IId)所述炔代杂环类化合物如下四条路线制备：
Figure PCTCN2021141768-appb-000019
方法I：1、起始物II-1j与一带有羟基的前体(HO-U-Y-P)通过光延反应(mitsunobu反应)得到II-2j；2、II-2j与NBS反应上溴得到II-3j；3、II-3j与芳香炔通过sonogashira偶联得到II-4j；4、II-4j与N 2H 4反应关环得到II-5j；5、II-6j中胺基去保护得到II-6j；6、II-6j中的胺基被含有和激酶配体结合域内半胱胺酸残基志反应的功能团的化学试剂(例如，烯丙酰氯等)衍生得到通式(IId)所述化合物。
Figure PCTCN2021141768-appb-000020
方法J：1、起始物II-1j与N 2H 4反应关环得到II-1k；2、II-2k与NBS反应上溴得到II-3k；3、II-3k与芳香炔通过sonogashira偶联得到II-4k；4、II-4k与一带有羟基的前体(HO-U-Y-P) 通过光延反应(mitsunobu反应)得到II-5k；再用方法J最后二步的方法，得到通式(IId)所述化合物。
Figure PCTCN2021141768-appb-000021
方法K：起始物II-1l与NBS反应上溴得到中间体II-2l；中间体II-2l与N 2H 4反应关环得到II-3l；中间体II-3l与芳香炔通过sonogashira偶联得到II-5k；再用方法J最后二步的方法，得到通式(IId)所述化合物。
Figure PCTCN2021141768-appb-000022
方法L：起始物II-1l与N 2H 4反应关环得到中间体II-2m；中间体II-2m与NBS反应上溴得到中间体II-3lk；再用方法L和J的方法，得到通式(IId)所述化合物。
除非另有说明，温度是摄氏温度。试剂购自Chemblocks Inc、Astatech Inc或麦克林等商业供应商，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、氮气或氩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Thermo Fisher LCQ 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、DMSO-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；DMSO-d 6:2.50ppm)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。
具体实施方式
以下通过具体的实施例进一步说明本发明。
实施例1：(S)-2-(1-丙烯酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)嘧啶(化合物1)的制备
Figure PCTCN2021141768-appb-000023
步骤1：化合物1b的合成
氮气下于反应瓶中加入化合物1a(1.49g，10.0mmol)，3,5-二甲氧基苯乙炔(1.70g，10.5mmol)，双三苯基磷二氯化钯(702mg，1.0mmol)，碘化亚铜(190mg，1.0mmol)，三乙胺(5.06g，50.0mmol)和干燥的N,N-二甲基甲酰胺50ml。抽换氮气3次，搅拌下90℃反应过夜。冷却至室温，反应液用水稀释，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1b(2.14g，产率78％)。LC/MS(ESI):m/z＝275.1[M+H] +.
步骤2：化合物1c的合成
于反应瓶中加入化合物1b(0.82g，3.0mmol)，(S)-1-叔丁氧羰基-3-氨基吡咯烷(0.67g，3.6mmol)，碳酸钾(0.83g，6.0mmol)和N,N-二甲基甲酰胺12ml。搅拌下80℃反应6小时。冷却至室温，反应液用水稀释，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1c(1.04g，产率82％)为黄色固体。LC/MS(ESI):m/z＝325.2[M+H] +.
后续二步反应用与实施例1相似的方法得到化合物1(170mg，产率45％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:8.25(d,1H),6.93(d,1H),6.72(d,2H),6.53-6.48(m,2H),6.21(dd,1H),5.89(s,1H),5.63(dd,1H),4.12-3.98(m,1H),3.81-3.60(m,9H),3.55-3.38(m,1H),2.31-1.89(m,2H)；LC/MS(ESI):m/z＝379.2[M+H] +.
实施例2：(S)-2-(1-丙烯酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-溴嘧啶(化合 物2)的制备
用与实施例1相似的方法得到化合物2(156mg，产率37％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:8.34(s,1H),6.72(d,2H),6.51-6.47(m,2H),6.20(dd,1H),5.78(s,1H),5.59(dd,1H),4.09-3.96(m,1H),3.81-3.58(m,9H),3.53-3.34(m,1H),2.30-1.87(m,2H)；LC/MS(ESI):m/z＝457.1[M+H] +.
实施例3：(S)-2-(1-丙烯酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-氟嘧啶(化合物3)的制备
用与实施例1相似的方法得到化合物3(149mg，产率41％)为淡黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:8.23(s,1H),6.71(d,2H),6.52-6.46(m,2H),6.19(dd,1H),5.81(s,1H),5.60(dd,1H),4.14-4.03(m,1H),3.83-3.62(m,9H),3.55-3.36(m,1H),2.28-1.85(m,2H)；LC/MS(ESI):m/z＝397.2[M+H] +.
实施例4：(S)-2-(1-丙烯酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-三氟甲基嘧啶(化合物4)的制备
用与实施例1相似的方法得到化合物4(124mg，产率30％)为淡黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:8.48(s,1H),6.73(d,2H),6.52-6.48(m,2H),6.22(dd,1H),5.93(s,1H),5.56(dd,1H),4.14-4.01(m,1H),3.81(s,6H),3.79-3.62(m,3H),3.53-3.32(m,1H),2.24-1.81(m,2H)；LC/MS(ESI):m/z＝447.2[M+H] +.
实施例5：(S)-2-(1-丙烯酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-氰基嘧啶(化合物5)的制备
用与实施例1相似的方法得到化合物5(126mg，产率37％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:8.31(s,1H),6.72(d,2H),6.51-6.46(m,2H),6.19(dd,1H),5.81(s,1H),5.60(dd,1H),4.14-4.01(m,1H),3.82-3.60(m,9H),3.56-3.39(m,1H),2.30-1.87(m,2H)；LC/MS(ESI):m/z＝404.2[M+H] +.
实施例6：(S)-2-(1-丙烯酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物6)的制备
用与实施例1相似的方法得到化合物6(147mg，产率43％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.57(t,1H),6.32(dd,1H),5.76(dd,1H),5.02(dd,1H),4.21-4.09(m,1H),3.97-3.71(m,9H),3.61-3.45(m,1H),2.41-1.92(m,2H)；LC/MS(ESI):m/z＝437.2[M+H] +.
实施例7：2-(2-丙烯酰基-2-氮杂螺[3,3]庚烷-6-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰 基-6-氨基嘧啶(化合物7)的制备
Figure PCTCN2021141768-appb-000024
用与实施例6相似的方法得到化合物7(127mg，产率31％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.75(d,2H),6.60(t,1H),6.43-6.32(m,1H),5.78(dd,1H),5.25-5.19(m,1H),3.80(s,6H),3.67-3.59(m,4H),3.11-3.03(m,1H),2.16-1.92(m,4H)；LC/MS(ESI):m/z＝463.2[M+H] +.
实施例8：2-(2-丙烯酰基-2-氮杂螺[3,4]辛烷-7-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物8)的制备
用与实施例6相似的方法得到化合物8(134mg，产率33％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.67-6.58(m,1H),6.32(dd,1H),5.76(dd,1H),5.02-4.93(m,1H),3.80(s,6H),3.35-3.21(m,4H),3.10-3.04(m,1H),2.21-1.92(m,4H),1.62-1.51(m,2H)；LC/MS(ESI):m/z＝477.2[M+H] +.
实施例9：2-(6-丙烯酰基-6-氮杂螺[3,5]壬烷-2-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物9)的制备
用与实施例6相似的方法得到化合物9(141mg，产率36％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.58(t,1H),6.25(dd,1H),5.78(dd,1H),5.15-5.04(m,1H),3.80(s,6H),3.56-3.32(m,4H),3.11-3.06(m,1H),2.17-1.94(m,4H),1.68-1.52(m,4H)；LC/MS(ESI):m/z＝491.2[M+H] +.
实施例10：2-(1-丙烯酰基哌啶-4-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物10)的制备
用与实施例6相似的方法得到化合物10(158mg，产率45％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.57(t,1H),6.24(dd,1H),5.73(dd,1H),4.77(dd,1H),3.80(s,6H),3.65-3.41(m,4H),3.28-3.15(m,1H),2.43-1.91(m,4H)；LC/MS(ESI):m/z＝451.2[M+H] +.
实施例11：(S)-2-(1-丙烯酰基哌啶-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物11)的制备
用与实施例6相似的方法得到化合物11(131mg，产率31％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.57(t,1H),6.24(dd,1H),5.78(dd,1H),4.82(dd,1H),3.88-3.34(m,10H),3.18-3.07(m,1H),2.23-1.64(m,4H)；LC/MS(ESI):m/z＝451.2[M+H] +.
实施例12：(S)-2-(丁-2-炔酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物12)的制备
用与实施例1相似的方法(通过中间体6d和2-丁炔酰氯反应)得到化合物12(124mg，产率28％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.65(d,2H),6.49(t,1H),4.17-4.06(m,1H),3.92-3.70(m,9H),3.58-3.45(m,1H),2.41-2.15(m,2H),1.97(s,3H)；LC/MS(ESI):m/z＝449.2[M+H] +.
实施例13：(S)-2-(丁-2-炔酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-溴嘧啶(化合物13)的制备
用与实施例1相似的方法(通过中间体2d和2-丁炔酰氯反应)得到化合物13(118mg，产率22％)为黄色固体。 1HNMR(400MHz,DMSO-d 6)δ:8.35(s,1H),6.73(d,2H),6.50(t,1H),5.84(s,1H),4.11-3.98(m,1H),3.84-3.62(m,9H),3.53-3.38(m,1H),2.31-1.76(m,5H)；LC/MS(ESI):m/z＝469.1[M+H] +.
实施例14：(S)-2-(丁-2-炔酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-三氟甲基嘧啶(化合物14)的制备
用与实施例1相似的方法(通过中间体3d和2-丁炔酰氯反应)得到化合物14(97mg，产率18％)为黄色固体。 1HNMR(400MHz,DMSO-d 6)δ:8.51(s,1H),6.73(d,2H),6.48(t,1H),5.95(s,1H),4.21-4.08(m,1H),3.91-3.67(m,9H),3.58-3.42(m,1H),2.37-1.84(m,5H)；LC/MS(ESI):m/z＝459.2[M+H] +.
实施例15：(R)-2-(1-丙烯酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物15)的制备
用与实施例1相似的方法得到化合物15(145mg，产率41％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.57(t,1H),6.32(dd,1H),5.76(dd,1H),5.02(dd,1H),4.21-4.09(m,1H),3.97-3.71(m,9H),3.61-3.45(m,1H),2.41-1.92(m,2H)；LC/MS(ESI):m/z＝437.2[M+H] +.
实施例16：(S)-2-(1-丙烯酰基吡咯烷-3-胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基嘧啶(化合物16)的制备
用与实施例1相似的方法得到化合物16(130mg，产率32％)为黄色固体。 1H NMR(400 MHz,DMSO-d 6)δ:8.32(s,1H),7.42(s,2H),6.73(d,2H),6.51-6.46(m,2H),6.21(dd,1H),5.85(s,1H),5.58(dd,1H),4.15-4.02(m,1H),3.83-3.62(m,9H),3.56-3.39(m,1H),2.30-1.85(m,2H)；LC/MS(ESI):m/z＝422.2[M+H] +.
实施例17：(S)-2-(1-丙烯酰胺基-3-吡咯烷基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物17)的制备
用与实施例1相似的方法得到17(168mg，产率47％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.57(t,1H),6.38(dd,1H),6.24(dd,1H),5.62(dd,1H),4.11-3.95(m,1H),3.84-3.68(m,9H),3.58-3.37(m,1H),2.34-1.85(m,2H)；LC/MS(ESI):m/z＝437.2[M+H] +.
实施例18：2-(1-丙烯酰基吡咯烷-3-基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶(化合物18)的制备
Figure PCTCN2021141768-appb-000025
步骤1：化合物18c的合成
于反应瓶中加入中间体2-氯-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基-6-氨基嘧啶7b(3.33g,10.0mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(817mg,1.0mmol)，碘化亚铜(285mg,1.5mmol)，干燥的N,N-二甲基乙酰胺50ml。抽换氮气3次，加入现场制备的1-叔丁氧羰基吡咯烷-3-碘化锌的2-甲基四氢呋喃溶液(15ml,约15mmol)，搅拌下85℃反应36小时。冷却至室温，反应液用水稀释，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18c(0.98g，产率21％)。LC/MS(ESI):m/z＝368.2[M+H] +.
后续二步反应用与实施例1相似的方法得到化合物18(175mg，产率51％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.57(t,1H),6.49(dd,1H),6.25(dd,1H),5.52(dd,1H),3.91-3.75(m,7H),3.72-3.58(m,1H),3.52-3.34(m,3H),2.34-1.95(m,2H)；LC/MS(ESI):m/z＝422.2[M+H] +.
实施例19：2-(1-丙烯酰基吡咯烷-3-甲胺基)-4-(3,5-二甲氧基苯乙炔基)-5-胺甲酰基嘧啶 (化合物19)的制备
用与实施例1相似的方法得到化合物19(155mg，产率43％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:6.73(d,2H),6.57(t,1H),6.38(dd,1H),6.24(dd,1H),5.62(dd,1H),4.11-3.95(m,1H),3.84-3.68(m,9H),3.58-3.37(m,1H),2.34-1.85(m,2H)；LC/MS(ESI):m/z＝437.2[M+H] +.
实施例20：(S)-1-(1-丙烯酰基哌啶-3-基)-3-(3,5-二甲氧基苯乙炔基)-4-氨基-7-羟基-1H-吡咯[2,3-d]哒嗪(化合物20)的制备
Figure PCTCN2021141768-appb-000026
步骤1：化合物20b的合成
于反应瓶中加入化合物3-氰基-1H-吡咯-2-甲酸乙酯20a(1.64g，10.0mmol)，水合肼5mL，乙醇50mL，搅拌下升温至回流反应过夜。冷却至室温，溶剂减压蒸干。残余物通过柱层析纯化，得到化合物20b(0.64g，产率43％)为白色固体。LC/MS(ESI):m/z＝151.1[M+H] +.
步骤2：化合物20c的合成
于反应瓶中加入化合物20b(0.6g，4.0mmol)，N,N-二甲基甲酰胺10mL，分批次加入NBS(1.07g，6.0mmol)，搅拌下50℃反应4小时。冷却至室温，反应液倒入50mL水中，用乙酸乙酯萃取。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1c(0.63g，产率69％)为白色固体。LC/MS(ESI):m/z＝229.0[M+H] +.
步骤3：化合物20d的合成
于反应瓶中加入化合物20c(0.46g，2.0mmol)，3,5-二甲氧基苯乙炔(0.48g，3.0mmol)，双三苯基磷二氯化钯(140mg，0.2mmol)，碘化亚铜(38mg，0.2mmol)，三乙胺(1.01 g，10.0mmol)和N,N-二甲基甲酰胺15mL。氮气置换3次，搅拌下90℃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1d(0.46g，产率74％)为黄色固体。LC/MS(ESI):m/z＝311.1[M+H] +.
步骤4：化合物20e的合成
于反应瓶中加入(R)-1-叔丁氧羰基-3-羟基哌啶(241mg，1.2mmol)，三苯基膦(315mg，1.2mmol)和THF 10mL，然后加入DIAD(243mg，1.2mmol)。将黄色溶液搅拌5-10分钟，然后加入中间体20d(310mg，1.0mmol)，室温搅拌反应12小时。减压蒸去溶剂得到棕色油，残余物通过柱层析纯化，得到化合物20e(345mg，产率70％)为黄色固体。LC/MS(ESI):m/z＝494.2[M+H] +.
步骤5：化合物20f的合成
于反应瓶中加入中间体20e(296mg，0.6mmol)，乙酸乙酯1mL，4N HCl的1,4-二氧六环溶液1mL。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20f(227mg，产率96％)，直接用于下一步，LC/MS(ESI):m/z＝394.2[M+H] +.
步骤6：化合物20的合成
于反应瓶中加入化合物20f(197mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丙烯酰氯(78mg，0.75mmol)的0.5mL二氯甲烷溶液。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(96mg，产率43％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:11.52(s,1H),7.53(s,1H),6.82(d,2H),6.53(t,1H),6.42-6.33(m,1H),6.13-6.05(m,1H),5.73-5.63(m,1H),5.13-5.04(m,1H),3.88-3.57(m,2H),3.79(s,6H),3.18-3.08(m,2H),2.23-1.64(m,4H)；LC/MS(ESI):m/z＝448.2[M+H] +.
实施例21：(S)-1-(1-丁-2-炔酰基哌啶-3-基)-3-(3,5-二甲氧基苯乙炔基)-4-氨基-7-羟基-1H-吡咯[2,3-d]哒嗪(化合物21)的制备
用与实施例20相似的方法(通过和2-丁炔酰氯反应)得到化合物21(80mg，产率35％，此为最后一步产率，下同)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:11.53(s,1H),7.54(s,1H),6.82(d,2H),6.54(t,1H),5.13-5.02(m,1H),3.88-3.56(m,2H),3.79(s,6H),3.18-3.09(m,2H),2.23-1.63(m,4H),1.98(s,3H)；LC/MS(ESI):m/z＝460.2[M+H] +.
实施例22：(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3,5-二甲氧基苯乙炔基)-4-氨基-7-羟基-1H- 吡咯[2,3-d]哒嗪(化合物22)的制备
用与实施例20相似的方法(中间体换为(R)-1-叔丁氧羰基-3-羟基吡咯烷)得到化合物21(95mg，产率44％)为黄色固体。 1H NMR(400MHz,CDCl 3)δ:9.84-9.90(d,1H),7.37-7.41(d,1H),6.71(s,2H),6.53-6.55(m,2H),6.47-6.48(m,1H),6.35-6.45(m,1H),5.77-5.85(m,2H),3.76-4.23(m,11H),2.59-2.2.68(m,1H),2.37-2.39(br,1H)；LC/MS(ESI):m/z＝434.0[M+H] +.
实施例23：(S)-1-(1-丁-2-炔酰基吡咯烷-3-基)-3-(3,5-二甲氧基苯乙炔基)-4-氨基-7-羟基-1H-吡咯[2,3-d]哒嗪(化合物23)的制备
用与实施例20相似的方法(通过2-丁炔酰氯反应)得到化合物23(84mg，产率38％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:11.53(s,1H),7.53(s,1H),6.82(d,2H),6.53(t,1H),5.29-5.20(m,1H),4.04-3.95(m,2H),3.79(s,6H),3.63-3.52(m,2H),2.43-2.30(m,2H),1.98(s,3H)；LC/MS(ESI):m/z＝446.2[M+H] +.
实施例24：(S)-1-(1-丙烯酰基哌啶-3-基)-3-(3,5-二甲氧基苯乙炔基)-4-氨基-7-羟基-1H-吡唑[2,3-d]哒嗪(化合物24)的制备
用与实施例20相似的方法(原料换为3-氰基-1H-吡唑-2-甲酸乙酯)得到化合物24(102mg，产率46％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:11.52(s,1H),6.82(d,2H),6.53(t,1H),6.42-6.33(m,1H),6.13-6.04(m,1H),5.73-5.62(m,1H),5.13-5.02(m,1H),3.88-3.56(m,2H),3.79(s,6H),3.18-3.07(m,2H),2.23-1.64(m,4H)；LC/MS(ESI):m/z＝449.2[M+H] +.
实施例25：(S)-1-(1-丁-2-炔酰基哌啶-3-基)-3-(3,5-二甲氧基苯乙炔基)-4-氨基-7-羟基-1H-吡唑[2,3-d]哒嗪(化合物25)的制备
用与实施例20相似的方法(通过中间体和2-丁炔酰氯反应)得到化合物25(84mg，产率37％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:11.53(s,1H),6.82(d,2H),6.54(t,1H),5.13-5.02(m,1H),3.88-3.56(m,2H),3.79(s,6H),3.18-3.08(m,2H),2.23-1.63(m,4H),1.98(s,3H)；LC/MS(ESI):m/z＝461.2[M+H] +.
实施例26：(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3,5-二甲氧基苯乙炔基)-4-氨基-7-羟基-1H-吡唑[2,3-d]哒嗪(化合物26)的制备
用与实施例20相似的方法(原料换为3-氰基-1H-吡唑-2-甲酸乙酯，中间体换为(R)-1-叔丁氧羰基-3-羟基吡咯烷)得到化合物26(90mg，产率42％)为类白色固体。 1H NMR(400MHz,DMSO-d 6)δ:11.52(s,1H),6.82(d,2H),6.53(t,1H),6.42-6.33(m,1H),6.13-6.04(m,1H),5.73-5.62(m,1H),5.31-5.22(m,1H),4.05-3.97(m,2H),3.78(s,6H),3.63-3.52(m,2H),2.43-2.32(m,2H)；LC/MS(ESI):m/z＝435.2[M+H] +.
实施例27：(S)-1-(1-丁-2-炔酰基吡咯烷-3-基)-3-(3,5-二甲氧基苯乙炔基)-4-氨基-7-羟基-1H-吡唑[2,3-d]哒嗪(化合物27)的制备
用与实施例20相似的方法(通过中间体和2-丁炔酰氯反应)得到化合物27(88mg，产率40％)为类白色固体。 1HNMR(400MHz,DMSO-d 6)δ:11.53(s,1H),6.82(d,2H),6.53(t,1H),5.30-5.21(m,1H),4.05-3.96(m,2H),3.79(s,6H),3.63-3.52(m,2H),2.43-2.31(m,2H),1.98(s,3H)；LC/MS(ESI):m/z＝447.2[M+H] +.
实施例28：(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3,5-二甲氧基-2,6-二氟苯乙炔基)-4-氨基-7-羟基-1H-吡咯[2,3-d]哒嗪(化合物28)的制备
用与实施例20相似的方法(中间体换为3,5-二甲氧基-2,6-二氟苯乙炔)得到化合物28(95mg，产率44％)为类白色固体。 1H NMR(400MHz,DMSO)δ:11.58(s,1H),8.06-8.11(d,1H),7.14-7.10(s,1H),6.69-6.55(m,1H),6.22-6.15(m,1H),6.18-5.97(m,1H),5.99-5.68(m,1H),5.60(br,2H),4,14-4.13(m,1H),3.90(s,6H),3.54-3.99(m,3H),2.47-2.39(m,2H)；LC/MS(ESI):m/z＝470.0[M+H] +.
实施例29：(S)-1-(1-丁-2-炔酰基吡咯烷-3-基)-3-(3,5-二甲氧基-2,6-二氟苯乙炔基)-4-氨基-7-羟基-1H-吡咯[2,3-d]哒嗪(化合物29)的制备
用与实施例20相似的方法(中间体换为3,5-二甲氧基-2,6-二氟苯乙炔)得到化合物20(112mg，产率52％)为黄色固体。LC/MS(ESI):m/z＝482.0[M+H] +.
实施例30：(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3,5-二甲氧基-2,6-二氯苯乙炔基)-4-氨基-7-羟基-1H-吡咯[2,3-d]哒嗪(化合物30)的制备
用与实施例20相似的方法(中间体换为3,5-二甲氧基-2,6-二氯苯乙炔)得到化合物30(95mg，产率41％)为类白色固体。LC/MS(ESI):m/z＝503.0[M+H] +.
实施例31：(S)-1-(1-丁-2-炔酰基吡咯烷-3-基)-3-(3,5-二甲氧基-2,6-二氯苯乙炔基)-4-氨基-7-羟基-1H-吡咯[2,3-d]哒嗪(化合物31)的制备
用与实施例20相似的方法(中间体换为3,5-二甲氧基-2,6-二氯苯乙炔)得到化合物31(134mg，产率57％)为黄色固体。LC/MS(ESI):m/z＝514.0[M+H] +.
实施例32：(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3,5-二甲氧基-2,6-二氟苯乙炔基)-4-氨基-7-羟基-1H-吡咯[2,3-d]哒嗪(化合物32)的制备
用与实施例19相似的方法(中间体换为3,5-二甲氧基-2,6-二氟苯乙炔)得到化合物31(73mg，产率34％)为黄色固体。 1LC/MS(ESI):m/z＝471.0[M+H] +.
实施例33：(S)-1-(1-丁-2-炔酰基吡咯烷-3-基)-3-(3,5-二甲氧基-2,6-二氟苯乙炔基)-4-氨 基-7-羟基-1H-吡唑[2,3-d]哒嗪(化合物33)的制备
用与实施例19相似的方法(中间体换为3,5-二甲氧基-2,6-二氟苯乙炔)得到化合物33(129mg，产率58％)为黄色固体。LC/MS(ESI):m/z＝483.0[M+H] +.
实施例34：(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-(3,5-二甲氧基-2,6-二氟苯乙炔基)-4-氨基-7-羟基-1H-吡唑[2,3-d]哒嗪(化合物34)的制备
用与实施例20相似的方法(中间体换为3,5-二甲氧基-2,6-二氯苯乙炔)得到化合物34(88mg，产率38％)为黄色固体。LC/MS(ESI):m/z＝503.0[M+H] +.
实施例35：(S)-1-(1-丁-2-炔酰基吡咯烷-3-基)-3-(3,5-二甲氧基-2,6-二氯苯乙炔基)-4-氨基-7-羟基-1H-吡唑[2,3-d]哒嗪(化合物35)的制备
用与实施例20相似的方法(中间体换为3,5-二甲氧基-2,6-二氯苯乙炔)得到化合物35(134mg，产率57％)为黄色固体。LC/MS(ESI):m/z＝515.0[M+H] +.
实施例36：(S)-1-(1-丙烯酰基吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(化合物36)的制备
Figure PCTCN2021141768-appb-000027
于反应瓶中加入化合物4-氰基-1H-吡唑-5-甲酸乙酯(10g，4.0mmol)，N,N-二甲基甲酰胺100mL，分批次加入NBS(1.07g，6.0mmol)，搅拌下50℃反应4小时。冷却至室温，反应液倒入50mL水中，用乙酸乙酯萃取。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3-溴-4-氰基-1H-吡唑-5-甲酸乙酯(0.63g，产率69％)为白色固体。LC/MS(ESI):m/z＝245.0[M+H] +.
于反应瓶中加入化合物3-溴-4-氰基-1H-吡唑-5-甲酸乙酯(1.64g，10.0mmol)，水合肼5mL，乙醇50mL，搅拌下升温至回流反应过夜。冷却至室温，溶剂减压蒸干。残余物 通过柱层析纯化，得到化合物3-溴-4-氨基-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(0.64g，产率43％)为白色固体。LC/MS(ESI):m/z＝230[M+H] +。
于反应瓶中加入化合物3-溴-4-氨基-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(0.46g，2.0mmol)，7-甲氧基-5-甲基苯并[b]噻吩-2-硼酸(0.48g，3.0mmol)，双三苯基磷二氯化钯(140mg，0.2mmol)，碘化亚铜(38mg，0.2mmol)，三乙胺(1.01g，10.0mmol)和N,N-二甲基甲酰胺15mL。氮气置换3次，搅拌下90℃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-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(0.46g，产率74％)为黄色固体。LC/MS(ESI):m/z＝328[M+H] +.
于反应瓶中加入(R)-1-叔丁氧羰基-3-羟基吡咯烷(241mg，1.2mmol)，三苯基膦(315mg，1.2mmol)和THF 10mL，然后加入DIAD(243mg，1.2mmol)。将黄色溶液搅拌5-10分钟，然后加入中间体4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(310mg，1.0mmol)，室温搅拌反应12小时。减压蒸去溶剂得到棕色油，残余物通过柱层析纯化，得到化合物(S)-1-(N-boc-吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(345mg，产率70％)为黄色固体。LC/MS(ESI):m/z＝497[M+H] +.
于反应瓶中加入中间体(S)-1-(N-boc-吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(296mg，0.6mmol)，乙酸乙酯1mL，4N HCl的1,4-二氧六环溶液1mL。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(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(227mg，产率96％)，直接用于下一步，LC/MS(ESI):m/z＝397.2[M+H] +.
于反应瓶中加入化合物(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(197mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丙烯酰氯(78mg，0.75mmol)的0.5mL二氯甲烷溶液。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36(96mg，产率43％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:11.52(s,1H),7.53(s,1H),6.82(d,2H),6.53(t,1H),6.42-6.33(m,1H),6.13-6.05(m,1H),5.73-5.63(m,1H),5.13-5.04(m,1H),3.88-3.57(m,2H),3.79(s,6H),3.18-3.08(m,2H),2.23-1.64(m,4H)； LC/MS(ESI):m/z＝451.2[M+H] +.
实施例37：(S)-1-(1-丁-2-炔酰基吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(化合物37)的制备
于反应瓶中加入化合物(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(197mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丁-2-炔酰氯(77mg，0.75mmol)的0.5mL二氯甲烷溶液。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37(86mg，产率37％)为黄色固体。LC/MS(ESI):m/z＝463.2[M+H] +.
实施例38：(S)-1-(1-丙烯酰基吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(化合物38)的制备
Figure PCTCN2021141768-appb-000028
于反应瓶中加入化合物3-氰基-1H-吡咯-2-甲酸乙酯(1.64g，10.0mmol)，水合肼5mL，乙醇50mL，搅拌下升温至回流反应过夜。冷却至室温，溶剂减压蒸干。残余物通过柱层析纯化，得到化合物4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(0.64g，产率43％)为白色固体。LC/MS(ESI):m/z＝151.1[M+H] +。
于反应瓶中加入化合物4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(0.60g，4.0mmol)，N,N-二甲基甲酰胺10mL，分批次加入NBS(1.07g，6.0mmol)，搅拌下50℃反应4小时。冷却至室温，反应液倒入50mL水中，用乙酸乙酯萃取。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3-溴-4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(0.59g，产率65％)为白色固体。LC/MS(ESI):m/z＝229.0[M+H] +.
于反应瓶中加入化合物3-溴-4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(0.46g，2.0mmol)，7-甲氧基-5-甲基苯并[b]噻吩-2-硼酸(0.48g，3.0mmol)，双三苯基磷二氯化钯(140mg，0.2mmol)，碘化亚铜(38mg，0.2mmol)，三乙胺(1.01g，10.0mmol)和N,N-二甲基甲酰胺15mL。氮气置换3次，搅拌下90℃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-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(0.44g，产率71％)为黄色固体。LC/MS(ESI):m/z＝327.1[M+H] +.
于反应瓶中加入(R)-1-叔丁氧羰基-3-羟基吡咯烷(241mg，1.2mmol)，三苯基膦(315mg，1.2mmol)和THF 10mL，然后加入DIAD(243mg，1.2mmol)。将黄色溶液搅拌5-10分钟，然后加入中间体4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(310mg，1.0mmol)，室温搅拌反应12小时。减压蒸去溶剂得到棕色油，残余物通过柱层析纯化，得到化合物(S)-1-(N-boc-吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(320mg，产率65％)为黄色固体。LC/MS(ESI):m/z＝496.2[M+H] +.
于反应瓶中加入中间体(S)-1-(N-boc-吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(296mg，0.6mmol)，乙酸乙酯1mL，4N HCl的1,4-二氧六环溶液1mL。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(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(220mg，产率93％)，直接用于下一步，LC/MS(ESI):m/z＝396.1[M+H] +.
于反应瓶中加入化合物(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(197mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丙烯酰氯(78mg，0.75mmol)的0.5mL二氯甲烷溶液。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38(92mg，产率41％)为黄色固体。 1H NMR(400MHz,MeOD)δ:7.74(d,1H),7.37(s,1H),7.27(s,1H),6.78(s,1H),6.72-6.63(m,1H),6.41-6.30(m,1H),6.24-6.16(m,1H),5.82-5.77(m,1H),4.26-3.67(m,4H),3.99(s,3H),2.67-2.51(m,2H),2.51(s,3H)；LC/MS(ESI):m/z＝450.2[M+H] +.
实施例39：((S)-1-(1-丁-2-炔酰基吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲苯并[b]噻吩-2- 基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(化合物39)的制备
于反应瓶中加入化合物(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(197mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丁-2-炔酰氯(77mg，0.75mmol)的0.5mL二氯甲烷溶液。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39(81mg，产率35％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:11.52(br,1H),7.83(d,1H),7.80(s,1H),7.46(s,1H),7.31(s,1H),6.86(s,1H),6.15-6.08(m,1H),5.09(br,2H),4.21-4.17(m,1H),3.99(s,3H),3.67-3.52(m,2H),2.50(s,3H),2.02-2.07(d,3H)；LC/MS(ESI):m/z＝462.2[M+H] +.
实施例40：(S)-1-(3-(8-氨基-1-(N-甲基吲哚-2-基)咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-基)丙-2-烯-1-酮(化合物40)的制备
Figure PCTCN2021141768-appb-000029
用与实施例29相似的方法(中间体换为3-溴-4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮和1-甲基吲哚-2-硼酸)得到化合物40(86mg，产率43％)为黄色固体。LC/MS(ESI):m/z＝403.2[M+H] +.
实施例41：(S)-1-(3-(8-氨基-1-(苯并呋喃-2-基)咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-基)丙-2-烯-1-酮(化合物41)的制备
Figure PCTCN2021141768-appb-000030
用与实施例29相似的方法(中间体换为3-溴-4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮和苯并呋喃-2-硼酸)得到化合物41(76mg，产率39％)为黄色固体。LC/MS(ESI):m/z＝390.2[M+H] +.
实施例42：(S)-1-(3-(8-氨基-1-(N-甲基吲哚-3-基)咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-基)丙-2-烯-1-酮(化合物42)的制备
Figure PCTCN2021141768-appb-000031
用与实施例28相似的方法(中间体换为3-溴-4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮和1-甲基吲哚-3-硼酸)得到化合物41(93mg，产率46％)为黄色固体。LC/MS(ESI):m/z＝403.2[M+H] +.
实施例43：(S)-1-(3-(8-氨基-1-(萘-2-基)咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-基)丙-2-烯-1-酮(化合物43)的制备
Figure PCTCN2021141768-appb-000032
用与实施例29相似的方法(中间体换为3-溴-4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮和2-萘硼酸)得到化合物43(80mg，产率40％)为黄色固体。LC/MS(ESI):m/z＝400.2[M+H] +.
实施例44：(S)-1-(3-(8-氨基-1-(7-甲氧基-5-甲苯并[b]噻吩-2-基)咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-基)丙-2-烯-1-酮(化合物44)的制备
Figure PCTCN2021141768-appb-000033
于反应瓶中加入3-氯吡嗪-2-甲胺二盐酸盐(2.16g，10mmol)，二氯甲烷50mL，0℃滴加N-Cbz-吡咯烷-3-甲酰氯(3.21g，12mmol)的二氯甲烷溶液10mL，然后升温至室温，搅拌半小时。此混合物用30mL饱和碳酸氢钠水溶液淬灭，分出有机相，水相用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤。将合并的有机相用无水硫酸钠干燥，过滤除去干燥剂，减压除去溶剂得粗品，通过快速柱纯化得到(S)-苄基3-(((3-氯吡嗪-2-基)甲基)氨基甲酰基)吡咯烷-1-羧酸酯(2.74g，产率73％)，LC/MS(ESI):m/z＝375.1[M+H] +.
于反应瓶中加入(S)-苄基3-(((3-氯吡嗪-2-基)甲基)氨基甲酰基)吡咯烷-1-羧酸酯(1.87g，5mmol)，乙腈25mL，室温下滴加三氯氧磷4mL和几滴N,N-二甲基甲酰胺，氮气保护下升温至80℃搅拌反应2小时。冷却至室温，溶剂减压蒸干。残余物倒入冰水中，二氯甲烷萃取，所得有机相再用饱和碳酸氢钠溶液和饱和食盐水洗涤，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(S)-苄基3-(8-氯咪唑[1,5-a]吡嗪-3-基)吡咯烷-1- 羧酸酯(0.73g，产率41％)，LC/MS(ESI):m/z＝357.1[M+H] +.
于反应瓶中加入化合物(S)-苄基3-(8-氯咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-羧酸酯(0.71g，2.0mmol)，N,N-二甲基甲酰胺6mL，分批次加入NBS(0.54g，4.0mmol)，搅拌下室温反应3小时。反应液倒入50mL水中，用乙酸乙酯萃取。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(S)-苄基3-(1-溴-8-氯咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-羧酸酯(0.65g，产率75％)为白色固体。LC/MS(ESI):m/z＝435.0[M+H] +.
于反应瓶中加入化合物(S)-苄基3-(1-溴-8-氯咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-羧酸酯(0.65g，1.5mmol)，异丙醇10mL，氨水(30％，2mL)，搅拌下回流反应5小时。冷却至室温，反应液用水稀释，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(S)-苄基3-(8-氨基-1-溴咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-羧酸酯(0.54g，产率87％)为白色固体。LC/MS(ESI):m/z＝416.3[M+H] +.
于反应瓶中加入化合物(S)-苄基3-(8-氨基-1-溴咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-羧酸酯(0.50g，1.2mmol)，7-甲氧基-5-甲基苯并[b]噻吩-2-硼酸(0.29g，1.8mmol)，双三苯基磷二氯化钯(140mg，0.2mmol)，碘化亚铜(38mg，0.2mmol)，三乙胺(0.5g，5.0mmol)和N,N-二甲基甲酰胺10mL。氮气置换3次，搅拌下90℃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(S)-苄基3-(8-氨基-1-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)[1,5-a]吡嗪-3-基)吡咯烷-1-羧酸酯(0.52g，产率85％)为黄色固体。LC/MS(ESI):m/z＝514.2[M+H] +.
于反应瓶中加入化合物(S)-苄基3-(8-氨基-1-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)[1,5-a]吡嗪-3-基)吡咯烷-1-羧酸酯(0.52g，1.0mmol)，浓盐酸4mL，室温反应24h。反应液倒入冰水中，1N氢氧化钠溶液调节PH至弱碱性，二氯甲烷萃取，所得有机相再用饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，有机相减压蒸干。得到化合物(S)-1-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-3-(吡咯烷-3-基)咪唑[1,5-a]吡嗪-8-胺(0.38g，产率85％)，LC/MS(ESI):m/z＝451.2[M+H] +.
于反应瓶中加入化合物(S)-1-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-3-(吡咯烷-3-基)咪唑[1,5-a]吡嗪-8-胺(225mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丙烯酰氯(78mg，0.75mmol)的0.5mL二氯甲烷溶液。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44(70mg，产率32％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:7.64(s,1H),7.26-7.14(m,3H),6.79(s,1H),6.42-6.33(m,1H),6.13-6.04(m,1H),5.91-5.78(br s,2H),5.73-5.62(m,1H),4.18-3.95(m,3H),3.91(s,3H),3.64-3.53(m,2H),2.49-2.30(m,5H)；LC/MS(ESI):m/z＝434.2[M+H] +.
实施例45：(S)-1-(3-(8-氨基-1-(7-甲氧基-5-甲苯并[b]噻吩-2-基)咪唑[1,5-a]吡嗪-3-基)吡咯烷-1-基)丁-2-炔-1-酮(化合物45)的制备
于反应瓶中加入化合物(S)-8-氨基1-(7-甲氧基-5-甲苯并[b]噻吩-2-基)-3-(吡咯烷-3-基)咪唑[1,5-a]吡嗪(190mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丁-2-炔酰氯(78mg，0.75mmol)的0.5mL二氯甲烷溶液。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45(82mg，产率37％)为黄色固体。LC/MS(ESI):m/z＝446.2[M+H] +.
实施例46：(S)-1-(3-(8-氨基-1-(7-甲氧基-5-甲苯并[b]噻吩-2-基)咪唑[5,1-f][1,2,4]三嗪-7-基)吡咯烷-1-基)丙-2-烯-1-酮(化合物46)的制备
Figure PCTCN2021141768-appb-000034
用与实施例43前三步相似的方法(原料换为3-氨基-6-(氨甲基)-1,2,4-三嗪-5(4H)-酮双盐酸盐)得到中间体(S)-苄基3-(2-氨基-5-溴-4-羟基咪唑[5,1-f][1,2,4]三嗪-7-yl)吡咯烷-1-羧酸酯(2.25g，产率67％)。LC/MS(ESI):m/z＝433.1[M+H] +.
于反应瓶中加入化合物亚硝酸叔丁酯(0.77g，7.5mmol)，四氢呋喃10mL，几滴N,N-二甲基甲酰胺，滴加(S)-苄基3-(2-氨基-5-溴-4-羟基咪唑[5,1-f][1,2,4]三嗪-7-yl)吡咯烷-1-羧 酸酯(2.17g，5mmol)的四氢呋喃溶液5mL，室温搅拌反应12小时。反应液减压蒸干。残余物通过柱层析纯化，得到中间体(S)-苄基3-(5-溴-4-羟基咪唑[5,1-f][1,2,4]三嗪-7-yl)吡咯烷-1-羧酸酯(1.30g，产率62％)为黄色固体。LC/MS(ESI):m/z＝418.0[M+H] +.
将化合物(S)-苄基3-(5-溴-4-羟基咪唑[5,1-f][1,2,4]三嗪-7-yl)吡咯烷-1-羧酸酯(1.25g，3mmol)溶于甲苯15mL中，加入三氯氧磷(3.1mL，33mmol)升温至回流搅拌反应24小时。冷却至室温，残余物倒入冰水中，二氯甲烷萃取，所得有机相再用饱和碳酸氢钠溶液和饱和食盐水洗涤，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(S)-苄基3-(5-溴-4-氯咪唑[5,1-f][1,2,4]三嗪-7-yl)吡咯烷-1-羧酸酯(1.02g，产率78％)。LC/MS(ESI):m/z＝436.0[M+H] +.
后续步骤用与实施例185后四步相似的方法得到化合物46(80mg，产率37％)为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ:8.73(s,1H),7.26-7.14(m,2H),6.81(s,1H),6.42-6.33(m,1H),6.15-6.05(m,1H),5.96-5.82(br s,2H),5.71-5.63(m,1H),4.18-3.95(m,3H),3.91(s,3H),3.64-3.53(m,2H),2.49-2.30(m,5H)；LC/MS(ESI):m/z＝435.2[M+H] +.
实施例47：(S)-1-(3-(8-氨基-1-(7-甲氧基-5-甲苯并[b]噻吩-2-基)咪唑[5,1-f][1,2,4]三嗪-7-基)咯烷-1-基)丁-2-炔-1-酮(化合物47)的制备
于反应瓶中加入化合物(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)咪唑[5,1-f][1,2,4]三嗪(190mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丁-2-炔酰氯(78mg，0.75mmol)的0.5mL二氯甲烷溶液。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47(100mg，产率45％)为黄色固体。LC/MS(ESI):m/z＝447.2[M+H] +.
实施例48：1-(1-丙烯酰基氮杂环丁烷-3-基)-4-氨基-3-(7-甲氧基-5-甲苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(化合物48)的制备
Figure PCTCN2021141768-appb-000035
于反应瓶中加入(R)-1-叔丁氧羰基-3-羟基吡咯烷(241mg，1.2mmol)，三苯基膦(315mg，1.2mmol)和THF 10mL，然后加入DIAD(243mg，1.2mmol)。将黄色溶液搅拌5-10分钟，然后加入中间体4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d] 哒嗪-7-酮(310mg，1.0mmol)，室温搅拌反应12小时。减压蒸去溶剂得到棕色油，残余物通过柱层析纯化，得到化合物(S)-1-(N-boc-吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(338mg，产率70％)为黄色固体。LC/MS(ESI):m/z＝483.2[M+H] +.
于反应瓶中加入中间体(S)-1-(N-boc-吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(296mg，0.6mmol)，乙酸乙酯1mL，4N HCl的1,4-二氧六环溶液1mL。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(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡唑[3,4-d]哒嗪-7-酮(220mg，产率96％)，直接用于下一步，LC/MS(ESI):m/z＝383.1[M+H] +.
于反应瓶中加入化合物(S)-1-(吡咯烷-3-基)-4-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(191mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丙烯酰氯(78mg，0.75mmol)的0.5mL二氯甲烷溶液。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48(94mg，产率43％)为黄色固体。LC/MS(ESI):m/z＝437.1[M+H] +.
实施例49：1-(1-丙烯酰基氮杂环丁烷-3-基)-4-氨基-3-(7-甲氧基-5-甲苯并[b]噻吩-2-基)-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮(化合物49)的制备
Figure PCTCN2021141768-appb-000036
用与实施例136相似的方法(中间体换为3-溴-4-氨基-1,6-二氢-7H-吡咯[3,4-d]哒嗪-7-酮和(7-甲氧基-5-甲基苯并[B]噻吩-2-基)硼酸)得到化合物49(92mg，产率42％)为黄色固体。LC/MS(ESI):m/z＝436.1[M+H] +.
实施例50：1-(3-(8-氨基-1-(7-甲氧基-5-甲苯并[b]噻吩-2-基)咪唑[1,5-a]吡嗪-3-基)氮杂环丁烷-1-基)丙-2-烯-1-酮(化合物50)的制备
Figure PCTCN2021141768-appb-000037
用与实施例46相似的方法(中间体换为1-((苄氧羰基)氮杂环丁烷-3-羧酸)得到化合物50(67mg，产率32％)为黄色固体。LC/MS(ESI):m/z＝420.1[M+H] +.
实施例51：1-(3-(8-氨基-1-(7-甲氧基-5-甲苯并[b]噻吩-2-基)咪唑[5,1-f][1,2,4]三嗪-7-基)氮杂环丁烷-1-基)丙-2-烯-1-酮(化合物51)的制备
Figure PCTCN2021141768-appb-000038
用与实施例46相似的方法(中间体换为1-((苄氧羰基)氮杂环丁烷-3-羧酸)得到化合物51(74mg，产率35％)为黄色固体。LC/MS(ESI):m/z＝421.1[M+H] +.
实施例52：2-(1-丙烯酰基氮杂环丁烷-3-基)-4-氨基-6-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1H-嘧啶-6-甲酰胺(化合物52)的制备
Figure PCTCN2021141768-appb-000039
于反应瓶中加入化合物叔丁基3-胍亚氨基氮杂环丁烷-1-羧酸酯盐酸盐(2.35g，10mmol)，甲醇钠(2.16g，40mmol)，甲醇40mL，冰水浴冷却后缓慢滴加丙二酸酯(1.92g，12mmol)的5mL甲醇溶液。加完后自然回到室温搅拌反应12小时。反应液用水淬灭，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，得到化合物叔丁基3-(4,6-羟基嘧啶-2-基)氮杂环丁烷-1-羧酸酯(2.22g，产率83％)为白色固体。LC/MS(ESI):m/z＝268.1[M+H] +.
于反应瓶中加入N,N-二甲基甲酰胺2mL，三氯氧磷6mL，冰水浴下搅拌1小时，加入化合物叔丁基3-(4,6-羟基嘧啶-2-基)氮杂环丁烷-1-羧酸酯(2.14g，8mmol)，升温至回流搅拌反应4小时。冷却至室温，残余物倒入冰水中，二氯甲烷萃取，所得有机相再用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物叔丁基3-(4,6-二氯-5-甲酰基嘧啶-2-基)氮杂环丁烷-1-羧酸酯(2.31g，产率87％)为黄色固体。LC/MS(ESI):m/z＝332.1[M+H] +.
于反应瓶中加入叔丁基3-(4,6-二氯-5-甲酰基嘧啶-2-基)氮杂环丁烷-1-羧酸酯(1.66g，5mmol)，四氯甲烷20mL，磺酰氯(1.01g，7.5mmol)，偶氮二异丁腈(41mg，0.25mmol)。升温至80℃搅拌反应4小时，冷却至室温，过滤，滤液减压蒸干，得到化合物叔丁基3-(4,6-二氯-5-(氯甲酰基)嘧啶-2-基)氮杂环丁烷-1-羧酸酯(1.83g，产率100％)为黄色固体。
于反应瓶中加入叔丁基3-(4,6-二氯-5-(氯甲酰基)嘧啶-2-基)氮杂环丁烷-1-羧酸酯(1.83g，5mmol)，四氢呋喃20mL，置于氨气氛围下。室温搅拌反应2小时，反应液减压蒸干，残余物用乙酸乙酯和水稀释，乙酸乙酯萃取，再用饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。得到化合物叔丁基叔丁基3-(4-氨基-5-氨甲酰基-6-氯嘧啶-2-基)氮杂环丁烷-1- 羧酸酯(1.33g，产率81％)为黄色固体。LC/MS(ESI):m/z＝328.1[M+H] +.
后续步骤用与实施例177中相似的方法得到化合物52(61mg，产率29％)为黄色固体。LC/MS(ESI):m/z＝424.1[M+H] +.
实施例53：1-(1-丙烯酰基氮杂环丁烷-3-基)-5-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1H-吡唑-4-甲酰胺(化合物53)的制备
Figure PCTCN2021141768-appb-000040
用与实施例129中相似的方法得到化合物3-(5-氨基-4-氰基-3-(7-甲氧基-5-甲基苯丙噻吩-2-基)-1H-吡唑-1-基)氮杂环丁烷-1-羧酸酯。LC/MS(ESI):m/z＝424.1[M+H] +.
于反应瓶中加入上一步中间体3-(5-氨基-4-氰基-3-(7-甲氧基-5-甲基苯丙噻吩-2-基)-1H-吡唑-1-基)氮杂环丁烷-1-羧酸酯(0.85g，2.0mmol)，4ml乙酸乙酯，4N 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洗涤，无水硫酸钠干燥，有机相减压蒸干得到化合物5-氨基-1-(氮杂环丁烷-3-基)-3-(7-甲氧基-5-甲基苯丙噻吩-2-基)-1H-吡唑-4-甲酰胺(0.61g，产率85％)。LC/MS(ESI):m/z＝358.1[M+H] +。
于反应瓶中加入化合物5-氨基-1-(氮杂环丁烷-3-基)-3-(7-甲氧基-5-甲基苯丙噻吩-2-基)-1H-吡唑-4-甲酰胺(179mg，0.5mmol)，三乙胺(76mg，0.75mmol)，二氯甲烷2mL，冰水浴冷却后缓慢滴加丙烯酰氯(78mg，0.75mmol)的0.5mL二氯甲烷溶液。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53(68mg，产率33％)为黄色固体。LC/MS(ESI):m/z＝412.1[M+H] +.
实施例54：(S)-2-(1-丙烯酰基吡咯烷-3-基)-4-氨基-6-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1H-嘧啶-6-甲酰胺(54)的制备
Figure PCTCN2021141768-appb-000041
用与实施例51相似的方法(原料换为(S)-叔丁基3-胍亚氨基吡咯烷-1-羧酸酯盐酸盐)得到化合物54(83mg，产率38％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:7.69(s,1H),7.21(s,1H),6.73(s,1H),6.32(dd,1H),5.76(dd,1H),5.02(dd,1H),4.11-3.73(m,7H),3.61-3.45(m,1H),2.41-1.95(m,5H)；LC/MS(ESI):m/z＝438.2[M+H] +.
实施例55：(S)-1-(1-丙烯酰基吡咯烷-3-基)-5-氨基-3-(7-甲氧基-5-甲基苯并[b]噻吩-2-基)-1H-吡唑-4-甲酰胺(化合物55)的制备
Figure PCTCN2021141768-appb-000042
用与实施例52中相似的方法得到化合物55(87mg，产率41％)为黄色固体。 1H NMR(400MHz,CD 3OD)δ:7.72(s,1H),7.16(s,1H),6.75(s,1H),6.34(dd,1H),5.75(dd,1H),5.04(dd,1H),4.11-4.03(m,1H),3.97-3.71(m,6H),3.59-3.45(m,1H),2.39-1.93(m,5H)；LC/MS(ESI):m/z＝426.2[M+H] +.
实施例56：对激酶FGFR1、FGFR2、FGFR3和FGFR4的体外活性抑制作用测试
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定FGFR1、FGFR2、FGFR3和FGFR4蛋白激酶活性。在DMSO中从0.2mM的工作浓度进行4倍梯度稀释，稀释10个浓度。向78μL 1×化合物缓冲液中加入2μL化合物。阴性对照和阳性对照各10个点。在摇板机上摇板20分钟。转移2μL的激酶到384反应板中,加入1μL的待测化合物到384反应板中，1000rpm/min，离心1min，25℃孵育10min。转移2μL底物混合物到384 反应板中，1000rpm/min，离心1min，25℃孵育50min。DMSO终浓度均为0.5％。用HTRF检测缓冲液配制2×Sa-XL 665/TK-antibody-Cryptate混合液。每孔加入5μL Sa-XL 665/TK-antibody-Cryptate，1000rpm/min离心30秒，室温反应1小时。用BMG读615nm(Cryptate)和665nm(XL665)的荧光信号。把转化率转化成抑制率数据(％抑制率＝(max-样品转化率)/(max-min)*100)。其中max是指DMSO对照的转化率,min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用Graphpad软件拟合曲线并计算IC 50。测定结果见下表显示化合物1-54对于激酶FGFR1、FGFR2、FGFR3和FGFR4的活性数据。活性利用IC 50表征，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。
Figure PCTCN2021141768-appb-000043
Figure PCTCN2021141768-appb-000044
结论：本发明大部分化合物对FGFR1-4均有很强的抑制活性，抑制活性达至小于10nm，其中部分化合物对FGFR1-4的抑制活性达至小于1nm。
实施例57：人肝癌细胞Hep3B存活试验
人肝癌Hep3B细胞株来源于ATCC。细胞用McCoy's 5A培养基，另外加入胎牛血清(10％FBS)。细胞在培养基中保持37℃、95％的湿度和5％的二氧化碳。实验时将Hep3B细胞以每孔3500个细胞的密度铺种于96孔板中，细胞悬液体积为每孔90μL，置于含5％CO 2 的细胞培养箱中于37℃培养。次日，受试化合物终浓度为1μM(作为IC 50测试的起始浓度)，四倍递减稀释9个浓度，9个浓度分别为：1μM、2.5μM、0.625μM、0.156μM、0.039μM、0.0098μM、0.0024μM、0.0006μM和0.000015μM，混匀离心，将1PL化合物DMSO溶液加入细胞培养基中，同时以IM DMSO作为对照，每个化合物的各浓度均设三个平行副孔。之后将细胞置于37℃培养箱,经连续72小时化合物处理后，向细胞培养基中添加50μL CellTiter-Glo(Promega,Madison WI)，并确定各孔的相对发光单位(RLU)并计算细胞存活率和化合物活性(IC 50)，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。实施例化合物对Hep3B细胞抑制活性结果如下表2所示：
表2对Hep3B细胞增殖的抑制活性
样品编号 IC 50(nM) 样品编号 IC 50(nM)
20 A 34 A
22 A 36 A
24 A 38 A
26 A Pemigatinib B
28 A infigratinib B
30 A Futibatinib A
32 A    
实施例58：人胃癌细胞和膀胱癌细胞增殖抑制活性评价
采用CellTiter-Glo<TM>活细胞检测试剂盒，测定受试化合物A对FGFR2基因扩增的人胃癌细胞(SNU-16)和FGFR3高表达及FGFR3-TACC3融合的人膀胱癌细胞(RT4)增殖的抑制作用。其中，RT4的培养基为添加终浓度为10％的胎牛血清、McCoy's 5A培养基。
试验步骤：用胰酶消化已达到80％细胞融合的SNU-16和RT4细胞，离心重悬计数，用培养基分别制成3500和6000个细胞/mL的SNU-16、RT4细胞悬液，加入96孔细胞培养板(90μL/孔)，置于含5％CO 2的细胞培养箱中于37℃培养。细胞培养24小时后，参考化合物表及受试化合物A用DMSO溶解成浓度为30mM的母液。用SNU-16和RT4的培养基将稀释好的化合物母液进行进一步稀释，并将稀释好的混合液分别转移至相应的细胞板中，受试化合物终浓度为1μM(作为IC50测试的起始浓度)，四倍递减稀释9个浓度，9个浓度分别为：1μM、2.5μM、0.625μM、0.156μM、0.039μM、0.0098μM、0.0024μM、0.0006μM和 0.000015μM，混匀离心，置于含5％CO 2的细胞培养箱中于37℃培养3天。取出96孔细胞培养板，加入CellTiterGlo(CTG，化学发光细胞活性检测试剂盒)试剂(100μL/孔)，混匀离心，于室温孵育10分钟。轻轻震荡后在SpectraMax M5Reader上测定450nm波长处的吸光度，以650nm处吸光度作为参比(即450nm吸光度-650nm吸光度)，计算抑制率。运用软件Graphpad Prism 6并采用计算公式XY-analysis/Nonlinear regression(curve fit)/Dose response-Inhibition/log(inhibitor)vs.response-Variable slope(four parameters)进行IC50曲线拟合并计算出IC 50值。
表2对SNU-16和RT4细胞增殖的抑制作用IC 50(nM)
样品编号 SNU-16 RT4
28 0.025 1.3
38 <0.015 3.4
Pemigatinib 0.249 6.0
infigratinib 0.572 11.8
Futibatinib 0.022 12.6
Erdafinib ND 1.8
结论：化合物对受试的人胃癌细胞(SNU-16)、人膀胱癌细胞(RT4)和人肝癌Hep3B细胞的增殖均有很强抑制活性，部分化合物其抑制活性强于对照化合物Pemigatinib、infigratinib、Futibatinib和Erdafinib等。
实施例59：hERG钾离子通道阻断的测定
实验方法概述如下：
细胞外液：140mM NaCl、3.5mM KCl、1mM MgCl2、2mM CaCl2、10mM D-glucose、10mM HEPES、1.25mM NaH2PO4、pH＝7.4。
电极内液：20mM KCl、115mM K-aspartate、1mM MgCl2、5mM EGTA、10mM HEPES、2mMNa2-ATP、pH＝7.2
细胞培养：采用了稳定表达hERG钾通道的HEK293细胞系，hERG钾通道细胞购于Creacell公司(货号：A-0320),在含有10％胎牛血清及0.8mg/mL G418的DMEM培养基中培养，培养温度为37℃，二氧化碳浓度为5％。除去旧培养基并用PBS洗一次，然后加入2mL TrypLE TMExpress溶液，37℃孵育1min左右。当细胞从皿底脱离，加入约5mL 37℃预热的完全培养基。将细胞悬液用吸管轻轻吹打使聚集的细胞分离。将细胞悬液转移至无菌 的离心管中，1000rpm离心5min收集细胞。扩增或维持培养，将细胞接种于10cm细胞培养皿，每个细胞培养皿接种细胞量为6105cells(最终体积：10mL)。为维持细胞的电生理活性，细胞密度必须不能超过80％。
全细胞膜片钳记录全细胞hERG钾电流的电压刺激方案如下：当形成全细胞封接后细胞膜电压钳制于-80mV。钳制电压由-80mV除极至-50mV维持0.5s(作为漏电流检测)，然后阶跃至30mV维持2.5s，再迅速恢复至-50mV维持4s可以激发出hERG通道的尾电流。每隔10s重复采集数据，观察药物对hERG尾电流的作用。以0.5s的-50mV刺激作为漏电流检测。试验数据由Qpatch进行采集并储存于连接的服务站中。
每个药物浓度设定为两次给药，时间至少为5分钟。测试化合物以及不含化合物的外液从低浓度到高浓度依次作用于细胞，每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组，独立重复检测两个细胞。所有电生理试验在24℃下进行。
首先将每一个药物浓度作用后的电流和空白对照电流标准化
Figure PCTCN2021141768-appb-000045
然后计算每一个药物浓度对应的抑制率
Figure PCTCN2021141768-appb-000046
对每一个浓度计算平均数和标准误，并用以下的方程计算每种化合物的半抑制浓度：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))用以上方程对剂量依赖效应进行非线性拟合，其中C代表受试物浓度，IC 50为半抑制浓度，h代表希尔系数。曲线拟合以及IC 50的计算利用Graphpad软件完成。
试验结果表明受试物28对hERG通道具有弱抑制或无抑制抑制作用；受试物38对hERG通道具有中度抑制作用。
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 (8)

  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 PCTCN2021141768-appb-100001
    其中：
    每个环B为苯环或者5-10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；
    每个L 1独立地选自键、-C 1-4烷基-、-C 2-4烯基-、-C 2-4炔基-；
    每个芳环Ar为6-10元杂芳环，其中上述的苯环和杂芳环任选被一个或多个R 1所取代；
    每个R 1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 2、-NR 2R 3、-C(O)NR 2R 3，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 4、-NR 4R 5、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
    每个U独立地选自-C 0-4烷基-、-CR 6R 7-、-C 1-2烷基(R 6)(OH)-、-C(O)-、-CR 6R 7O-、-OCR 6R 7-、-SCR 6R 7-、-CR 6R 7S-、-NR 6-、-NR 6C(O)-、-C(O)NR 6-、-NR 6C(O)NR 7-、-CF 2-、-O-、-S-、-S(O) m-、-NR 6S(O) 2-、-S(O) 2NR 6-；
    每个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3-8元杂环烷基、5-12元稠杂环基、5-12元螺杂环基者杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子，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；
    每个Z独立地选自氰基、-NR 8CN、
    Figure PCTCN2021141768-appb-100002
    键a为双键或者三键；
    当a为双键时，每个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；
    每个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，每个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；
    每个R 8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；
    每个G 1、G 2、G 3、G 4和G 5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 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) mR 10，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 12、-OC(O)NR 12R 13、-C(O)OR 12、-C(O)NR 12R 13、-C(O)R 12、-NR 12R 13、-NR 12C(O)R 13、-NR 12C(O)NR 13R 14、-S(O) mR 12或-NR 12S(O) mR 13的取代基所取代；
    每个R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 11、R 12、R 13和R 14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IIa所示：
    Figure PCTCN2021141768-appb-100003
    其中：
    每个X1、X2、X3、X4、X5各自独立地为CR 1或N，且X1、X2、X3、X4、X5中至少有一个为N；
    每个R 1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 2、-NR 2R 3、-C(O)NR 2R 3，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 4、-NR 4R 5、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
    每个环B为苯环或者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；
    每个U独立地选自-C 0-4烷基-、-CR 6R 7-、-C 1-2烷基(R 6)(OH)-、-C(O)-、-CR 6R 7O-、-OCR 6R 7-、-SCR 6R 7-、-CR 6R 7S-、-NR 6-、-NR 6C(O)-、-C(O)NR 6-、-NR 6C(O)NR 7-、-CF 2-、-O-、-S-、-S(O) m-、-NR 6S(O) 2-、-S(O) 2NR 6-；
    每个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3-8元杂环烷基、5-12元稠杂环基、5-12元螺杂环基者杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子，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；
    每个Z独立地选自氰基、-NR 8CN、
    Figure PCTCN2021141768-appb-100004
    键a为双键或者三键；
    当a为双键时，每个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；
    每个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，每个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；
    每个R 8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；
    每个G 1、G 2、G 3、G 4和G 5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 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) mR 10，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 12、-OC(O)NR 12R 13、-C(O)OR 12、-C(O)NR 12R 13、-C(O)R 12、-NR 12R 13、-NR 12C(O)R 13、-NR 12C(O)NR 13R 14、-S(O) mR 12或-NR 12S(O) mR 13的取代基所取代；
    每个R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 11、R 12、R 13和R 14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。
  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IIf所示：
    Figure PCTCN2021141768-appb-100005
    其中：
    X 1，X 2，X 3可以独立地选自N、CR 1；
    每个R 1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 2、-NR 2R 3、-C(O)NR 2R 3，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR 4、-NR 4R 5、C 1-6烷基、C 3-6环烷基或3-6元杂环烷基；
    每个环B为苯环或者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；
    每个U独立地选自-C 0-4烷基-、-CR 6R 7-、-C 1-2烷基(R 6)(OH)-、-C(O)-、-CR 6R 7O-、-OCR 6R 7-、-SCR 6R 7-、-CR 6R 7S-、-NR 6-、-NR 6C(O)-、-C(O)NR 6-、-NR 6C(O)NR 7-、-CF 2-、-O-、-S-、-S(O) m-、-NR 6S(O) 2-、-S(O) 2NR 6-；
    每个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3-8元杂环烷基、5-12元稠杂环基、5-12元螺杂环基者杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子，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；
    每个Z独立地选自氰基、-NR 8CN、
    Figure PCTCN2021141768-appb-100006
    键a为双键或者三键；
    当a为双键时，每个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；
    每个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，每个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；
    每个R 8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；
    每个G 1、G 2、G 3、G 4和G 5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 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) mR 10，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 12、-OC(O)NR 12R 13、-C(O)OR 12、-C(O)NR 12R 13、-C(O)R 12、-NR 12R 13、-NR 12C(O)R 13、-NR 12C(O)NR 13R 14、-S(O) mR 12或-NR 12S(O) mR 13的取代基所取代；
    每个R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 11、R 12、R 13和R 14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。
  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IIg所示：
    Figure PCTCN2021141768-appb-100007

    其中：
    环Ar为5-10元杂芳环，其中上述的5-10元杂芳环任选被一个或多个G 1所取代；
    环B独立地选自含有1-3个选自S，O，N和Se杂原子的5-14元杂芳环和5-14元芳环，上述的5-14元杂芳环和5-14元芳环被一个或多个G 2所取代；
    U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 3所取代；
    Z独立地选自氰基、-NR 9CN、
    Figure PCTCN2021141768-appb-100008

    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 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 6所取代；
    G 1、G 2、G 3、G 4、G 5和G 6各自独立选自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 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) mR 14的取代基所取代；R 7、R 8、R 10、R 11、R 12、R 13、R 14和R 15各自独立选自氢、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。
    其中，每个Ar选自在每次出现时独立地选自
    Figure PCTCN2021141768-appb-100009

    Figure PCTCN2021141768-appb-100010

    每个Ar在每次出现时独立地可选地被一个或多个G 1所取代；
    G 1各自独立选自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 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) mR 14的取代基所取代；
    R 10、R 11、R 12、R 13、R 14和R 15各自独立选自氢、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。
  5. [根据细则26改正24.01.2022]　
    根据权利要求1-7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 PCTCN2021141768-appb-100011
    Figure PCTCN2021141768-appb-100012
    Figure PCTCN2021141768-appb-100013
    Figure PCTCN2021141768-appb-100014
    或其前药、稳定同位素衍生物、可药用的盐、溶剂化物、异构体及其混合和形式。
  6. [根据细则26改正24.01.2022]　
    一种药物组合物，包含权利要求1-4所述的化合物或其前药、稳定同位素衍生物、药学上可接受的盐、溶剂化物、多晶型物或异构体，以及药学上可接受的载体。
  7. [根据细则26改正24.01.2022]　
    根据权利要求1-4中任一项所述的化合物或其前药、稳定同位素衍生物、药学上可接受的盐、溶剂化物、多晶型物或异构体在制备用来治疗FGFR介导的疾病的药物中的用途。
  8. [根据细则26改正24.01.2022]　
    根据权利要求6所述的用途，其中所述FGFR介导的疾病为非小细胞肺癌、食管癌、黑色素瘤、胃癌、多发性骨髓瘤、肝癌、胆管癌、前列腺癌、皮肤癌、卵巢癌、子宫内膜癌、宫颈癌、膀胱癌、乳腺癌、结肠癌、胶质瘤、以及横纹肌肉瘤中的一种或多种。
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WO2017202343A1 (zh) * 2016-05-24 2017-11-30 中国科学院上海药物研究所 五元杂环并[3,4-d]哒嗪酮类化合物、其制备方法、药物组合物及其应用
WO2017215485A1 (zh) * 2016-06-16 2017-12-21 中国科学院上海药物研究所 一种具有fgfr抑制活性的新型化合物及其制备和应用
WO2019034076A1 (zh) * 2017-08-15 2019-02-21 南京明德新药研发股份有限公司 Fgfr抑制剂及其医药用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017202343A1 (zh) * 2016-05-24 2017-11-30 中国科学院上海药物研究所 五元杂环并[3,4-d]哒嗪酮类化合物、其制备方法、药物组合物及其应用
WO2017215485A1 (zh) * 2016-06-16 2017-12-21 中国科学院上海药物研究所 一种具有fgfr抑制活性的新型化合物及其制备和应用
WO2019034076A1 (zh) * 2017-08-15 2019-02-21 南京明德新药研发股份有限公司 Fgfr抑制剂及其医药用途

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