WO2023280317A1 - Composé benzylamino tricyclique et son utilisation - Google Patents

Composé benzylamino tricyclique et son utilisation Download PDF

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Publication number
WO2023280317A1
WO2023280317A1 PCT/CN2022/104713 CN2022104713W WO2023280317A1 WO 2023280317 A1 WO2023280317 A1 WO 2023280317A1 CN 2022104713 W CN2022104713 W CN 2022104713W WO 2023280317 A1 WO2023280317 A1 WO 2023280317A1
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compound
stirred
added
dissolved
ethyl acetate
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PCT/CN2022/104713
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English (en)
Chinese (zh)
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吴凌云
代天资
赵乐乐
展震
孙建军
钱薏
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2023280317A1 publication Critical patent/WO2023280317A1/fr

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    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to benzylaminotricyclic compounds and applications thereof, in particular to compounds represented by formula (X) and pharmaceutically acceptable salts thereof.
  • RAS protein is a 21kDa guanine nucleoside-binding protein located on the cell membrane and possessing guanosine triphosphate hydrolase (GTPase) activity.
  • the RAS family mainly includes three subtypes, KRAS, NRAS and HRAS.
  • KRAS guanosine triphosphate hydrolase
  • NRAS guanosine triphosphate hydrolase
  • HRAS HRAS
  • GEFs guanine nucleoside exchange factors
  • SOS1 guanine nucleoside exchange factors
  • GEFs guanine nucleoside exchange factors
  • the activity of GTPase in RAS is increased by thousands of times, the GTP bound to it is hydrolyzed into GDP, and RAS re-enters the "off" state of GDP binding, thus completing a complete cycle.
  • GAPs GTPase activating proteins
  • RAS gene mutations are present in about 15% of tumor cases. Oncogenic RAS mutations can simultaneously inhibit intrinsic GTPase activity and GAP-activated GTPase activity, making the RAS cycle always in the "on" state of RAS-GTP, resulting in continuous activation of downstream signaling pathways to cause cancer. Therefore, KRAS-inhibiting mutants and abnormal activation of downstream pathways have become one of the hot targets for cancer treatment.
  • SOS1 (English full name Son of Sevenless 1) is a type of GEF that regulates the RAS protein GDP/GTP cycle. By binding to the catalytic site, SOS1 inhibitors can block the binding of SOS1 to RAS protein and reduce the level of RAS-GTP. Such inhibitors can effectively reduce the abnormal activation of RAS downstream signaling pathways (such as ERK phosphorylation) in cancer cells, thereby playing a role in the treatment of cancer.
  • RAS downstream signaling pathways such as ERK phosphorylation
  • AMG-510 is a potent, orally bioavailable, selective KRAS G12C covalent inhibitor developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer harboring a KRAS G12C mutation. Its structure is as follows:
  • the present invention provides a compound represented by formula (X) or a pharmaceutically acceptable salt thereof,
  • R 11 , R 12 form ring A together with the carbon atoms they are connected to, wherein ring A is selected from
  • E is selected from -(CH 2 CH 2 O) m -;
  • E 1 is selected from -(CR 8 R 9 ) n -;
  • E 2 is selected from -(CH 2 CH 2 O) t -;
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R a replaces;
  • R 3 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R b replaces;
  • R 4 is selected from H and CH 3 ;
  • R 5 and R 6 are independently selected from H, F, Cl, Br, I and -CN;
  • R 7 is selected from H, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3-8 membered Heterocycloalkyl, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3-
  • the 8-membered heterocycloalkyl group is independently optionally substituted by 1, 2, 3 or 4 R c ;
  • R 8 , R 9 and the carbon atom to which they are attached together form C 3-6 cycloalkyl or 3-7 membered heterocycloalkyl, wherein said C 3-6 cycloalkyl and 3-7 membered heterocycloalkyl are independently optionally replaced by 1, 2, 3 or 4 R e replaces;
  • R 6 , R 11 together with the carbon atoms they are attached to form ring B, wherein ring B is selected from
  • Each R 13 is independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, Wherein said C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are independently optionally substituted by 1, 2 or 3 Rh ;
  • Each Ra is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R b is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R c is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -OCH 3 , -N(CH 3 ) 2 and C 1-4 alkyl;
  • Each R d is independently selected from D, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 and -OCH 3 ;
  • Each Re is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 and -OCH 3 ;
  • R f and R g are independently selected from H, C 1-4 alkyl and 5-7 membered heterocycloalkyl, wherein C 1-4 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R aa substitutions;
  • R f , R g and the nitrogen atoms attached to them together form a 5-7 membered heterocycloalkyl group, wherein the 5-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 Rab ;
  • Rh is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R aa is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R ab is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl;
  • n is selected from 0, 1 or 2;
  • n is selected from 2, 3, 4 or 5;
  • t is selected from 0, 1 or 2;
  • hetero in the 3-8 membered heterocycloalkyl, 3-7 membered heterocycloalkyl, -CH 2 -3-8 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2 , 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and -N-.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from
  • E is selected from -(CH 2 CH 2 O) m -;
  • E 1 is selected from -(CR 8 R 9 ) n -;
  • E 2 is selected from -(CH 2 CH 2 O) t -;
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R a replaces;
  • R 3 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R b replaces;
  • R 4 is selected from H and CH 3 ;
  • R 5 and R 6 are independently selected from H, F, Cl, Br, I and -CN;
  • R 7 is selected from H, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3-8 membered Heterocycloalkyl, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3-
  • the 8-membered heterocycloalkyl group is independently optionally substituted by 1, 2, 3 or 4 R c ;
  • R 8 , R 9 and the carbon atom to which they are attached together form C 3-6 cycloalkyl or 3-7 membered heterocycloalkyl, wherein said C 3-6 cycloalkyl and 3-7 membered heterocycloalkyl are independently optionally replaced by 1, 2, 3 or 4 R e replaces;
  • Each Ra is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R b is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R c is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -OCH 3 , -N(CH 3 ) 2 and C 1-4 alkyl;
  • Each R d is independently selected from D, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 and -OCH 3 ;
  • Each Re is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 and -OCH 3 ;
  • R f and R g are independently selected from H, C 1-4 alkyl and 5-7 membered heterocycloalkyl, wherein C 1-4 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R aa substitutions;
  • R f , R g and the nitrogen atoms attached to them together form a 5-7 membered heterocycloalkyl group, wherein the 5-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 Rab ;
  • Each R aa is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R ab is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl;
  • n is selected from 0, 1 or 2;
  • n is selected from 2, 3, 4 or 5;
  • t is selected from 0, 1 or 2;
  • hetero in the 3-8 membered heterocycloalkyl, 3-7 membered heterocycloalkyl, -CH 2 -3-8 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2 , 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and -N-.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from
  • E is selected from -(CH 2 CH 2 O) m -;
  • E 1 is selected from -(CR 8 R 9 ) n -;
  • E 2 is selected from -(CH 2 CH 2 O) t -;
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R a replaces;
  • R 3 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R b replaces;
  • R 4 is selected from H and CH 3 ;
  • R 5 and R 6 are independently selected from H, F, Cl, Br, I and -CN;
  • Each R 7 is selected from H, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3-8 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3 -8-membered heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c ;
  • R 8 , R 9 and the carbon atom to which they are attached together form C 4-6 cycloalkyl or 5-7 membered heterocycloalkyl, wherein said C 4-6 cycloalkyl and 5-7 membered heterocycloalkyl are independently optionally replaced by 1, 2, 3 or 4 R e replaces;
  • Each Ra is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R b is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R c is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -OCH 3 , -N(CH 3 ) 2 and C 1-4 alkyl;
  • Each R is independently selected from D , F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each Re is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R f and R g are independently selected from H, C 1-4 alkyl and 5-7 membered heterocycloalkyl, wherein C 1-4 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R aa substitutions;
  • R f , R g and the nitrogen atoms attached to them together form a 5-7 membered heterocycloalkyl group, wherein the 5-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 Rab ;
  • Each R aa is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R ab is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl;
  • n is selected from 0, 1 or 2;
  • n is selected from 2, 3, 4 or 5;
  • t is selected from 0, 1 or 2;
  • Hetero in the 3-8 membered heterocycloalkyl, -CH 2 -3-8 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2, 3 or 4 independently selected A heteroatom or heteroatom group from -O-, -NH-, -S-, and -N-.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from
  • E is selected from -(CH 2 CH 2 O) m -;
  • E 1 is selected from -(CR 8 R 9 ) n -;
  • E 2 is selected from -(CH 2 CH 2 O) t -;
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R a replaces;
  • R 3 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R b replaces;
  • R 4 is selected from H and CH 3 ;
  • R 5 and R 6 are independently selected from H, F, Cl, Br, I and -CN;
  • Each R 7 is selected from H, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3-8 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3 -8-membered heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c ;
  • each R 8 , R 9 and the carbon atom to which they are attached together form C 4-6 cycloalkyl or 5-7 membered heterocycloalkyl, wherein said C 4-6 cycloalkyl and 5-7 membered heterocycloalkyl are independently optionally replaced by 1, 2, 3 or 4 R e replaces;
  • Each Ra is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R b is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R c is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -OCH 3 , -N(CH 3 ) 2 and C 1-4 alkyl;
  • Each R is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each Re is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R f and R g are independently selected from H, C 1-4 alkyl and 5-7 membered heterocycloalkyl, wherein C 1-4 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R aa substitutions;
  • R f , R g and the nitrogen atoms attached to them together form a 5-7 membered heterocycloalkyl group, wherein the 5-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 Rab ;
  • Each R aa is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R ab is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl;
  • n is selected from 0, 1 or 2;
  • n is selected from 2, 3, 4 or 5;
  • t is selected from 0, 1 or 2;
  • Hetero in the 3-8 membered heterocycloalkyl, -CH 2 -3-8 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2, 3 or 4 independently selected A heteroatom or heteroatom group from -O-, -NH-, -S-, and -N-.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R a replaces;
  • R 3 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R b replaces;
  • R 4 is selected from H and CH 3 ;
  • R 5 and R 6 are independently selected from H, F, Cl, Br, I and -CN;
  • Each R 7 is selected from H, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3-8 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -CH 2 -C 3-8 cycloalkyl and -CH 2 -3 -8-membered heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c ;
  • R 8 , R 9 and the carbon atoms connected to them together form a C 4-6 cycloalkyl group or a 5-7 membered heterocycloalkyl group, wherein the C 4-6 cycloalkyl group and the 5-7 membered heterocycle group are Alkyl groups are independently optionally substituted by 1, 2, 3 or 4 Re ;
  • Each Ra is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R b is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R c is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -OCH 3 , -N(CH 3 ) 2 and C 1-4 alkyl;
  • Each R is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each Re is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R f and R g are independently selected from H, C 1-4 alkyl and 5-7 membered heterocycloalkyl, wherein C 1-4 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R aa substitutions;
  • R f , R g and the nitrogen atoms attached to them together form a 5-7 membered heterocycloalkyl group, wherein the 5-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 Rab ;
  • Each R aa is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R ab is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl;
  • Hetero in the 3-8 membered heterocycloalkyl, -CH 2 -3-8 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2, 3 or 4 independently selected A heteroatom or heteroatom group from -O-, -NH-, -S-, and -N-.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R a replaces;
  • R 3 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally replaced by 1, 2 or 3 R b replaces;
  • R 4 is selected from H and CH 3 ;
  • R 5 and R 6 are independently selected from H, F, Cl, Br, I and -CN;
  • Each R 7 is selected from H, C 1-4 alkyl and -CH 2 -5-7 membered heterocycloalkyl, wherein said C 1-4 alkyl and -CH 2 -5-7 membered heterocycloalkyl are respectively independently optionally substituted with 1, 2, 3 or 4 Rc ;
  • R 8 , R 9 and the carbon atoms connected to them together form a C 4-6 cycloalkyl group or a 5-7 membered heterocycloalkyl group, wherein the C 4-6 cycloalkyl group and the 5-7 membered heterocycle group are Alkyl groups are independently optionally substituted by 1, 2, 3 or 4 Re ;
  • Each Ra is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R b is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R c is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -OCH 3 and -N(CH 3 ) 2 ;
  • Each R is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each Re is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R f and R g are independently selected from H, C 1-4 alkyl and 5-7 membered heterocycloalkyl, wherein C 1-4 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R aa substitutions;
  • R f , R g and the nitrogen atom attached to them together form a 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rab ;
  • Each R aa is independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Each R ab is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl;
  • hetero in the -CH 2 -5-7 membered heterocycloalkyl and 5-7 membered heterocycloalkyl means 1, 2, 3 or 4 are independently selected from -O-, -NH-, Heteroatoms or heteroatom groups of -S- and -N-.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 11 and R 12 are as defined in the present invention.
  • ring A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • each R a above is independently selected from F and -OH, and other variables are as defined in the present invention.
  • each R c mentioned above is independently selected from F, Cl, Br, -CH 3 , -OCH 3 and -N(CH 3 ) 2 , and other variables are as defined in the present invention.
  • each R c mentioned above is independently selected from -OCH 3 and -N(CH 3 ) 2 , and other variables are as defined in the present invention.
  • each R d above is independently selected from -OCH 3 , and other variables are as defined in the present invention.
  • each of the above-mentioned R aa , R b , R d and Re is independently selected from F, and other variables are as defined in the present invention.
  • each Rab mentioned above is independently selected from -CH 3 , and other variables are as defined in the present invention.
  • R f and R g are independently selected from H, -CH 3 and Other variables are as defined herein.
  • R f , R g and the nitrogen atoms connected to them together form which stated are independently and optionally substituted by 1, 2, 3 or 4 Rabs, and Rab and other variables are as defined in the present invention.
  • R 1 is selected from H, -NH 2 and -CN, and other variables are as defined in the present invention.
  • R 1 is selected from H and -NH 2 , and other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CH 3 , -CH 2 CH 3 and -CH 2 CH(CH 3 ) 2 , wherein -CH 3 , -CH 2 CH 3 and -CH 2 CH(CH 3 ) 2 are each independently optionally substituted by 1, 2, or 3 R a , and R a and other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN,, Ra and other variables are as defined herein.
  • R 2 is selected from H, F, -CN, -CHF 2 , -CF 3 , Other variables are as defined herein.
  • R 3 is selected from H, F and -CH 3 , and other variables are as defined in the present invention.
  • R 4 is selected from -CH 3 , and other variables are as defined in the present invention.
  • R 5 and R 6 are independently selected from H and F, and other variables are as defined in the present invention.
  • R 5 and R 6 are independently selected from H, and other variables are as defined in the present invention.
  • each R 7 above is selected from H, -CH 3 , -CH 2 CH 3 , Wherein -CH 3 , -CH 2 CH 3 , are independently and optionally substituted by 1, 2, 3 or 4 R c , R c and other variables are as defined in the present invention.
  • each R 7 above is selected from H, -CH 3 , -CH 2 CH 3 , Wherein -CH 3 , -CH 2 CH 3 , are independently and optionally substituted by 1, 2, 3 or 4 R c , R c and other variables are as defined in the present invention.
  • each R 7 above is selected from H, -CH 3 , -CH 2 CH 3 , Wherein -CH 3 , -CH 2 CH 3 , are independently and optionally substituted by 1, 2, 3 or 4 R c , R c and other variables are as defined in the present invention.
  • each R 7 above is selected from H, -CH 3 , -CH 2 CH 3 and Wherein -CH 3 , -CH 2 CH 3 and are independently and optionally substituted by 1, 2, 3 or 4 R c , R c and other variables are as defined in the present invention.
  • each R 7 above is selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 ,
  • Other variables are as defined herein.
  • each R 7 above is selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 ,
  • Other variables are as defined herein.
  • each R 7 above is selected from H, -CH 3 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 ,
  • Other variables are as defined herein.
  • each R 7 above is selected from H, -CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 and Other variables are as defined herein.
  • each of the above-mentioned R 8 and R 9 is independently selected from H, F, -CH 3 , -OCH 3 , -CH 2 CH 3 , Wherein said -CH 3 , -OCH 3 and -CH 2 CH 3 are independently optionally substituted by 1, 2 or 3 R d , R d and other variables are as defined in the present invention.
  • each of the above-mentioned R 8 and R 9 is independently selected from H, F, -CH 3 , -OCH 3 , -CH 2 CH 2 OCH 3 , Other variables are as defined herein.
  • each of the above-mentioned R 8 and R 9 is independently selected from H, -CH 3 , -OCH 3 , Other variables are as defined herein.
  • each R 8 above is independently selected from H, -CH 3 , -OCH 3 , Other variables are as defined herein.
  • each R 9 above is independently selected from H and -CH 3 , and other variables are as defined in the present invention.
  • R 8 , R 9 and the carbon atoms connected to them together form which stated are independently optionally substituted by 1, 2, 3 or 4 Re , Re and other variables are as defined in the present invention.
  • R 8 , R 9 and the carbon atoms connected to them together form which stated are independently optionally substituted by 1, 2, 3 or 4 Re , Re and other variables are as defined in the present invention.
  • R 8 , R 9 and the carbon atoms connected to them together form which stated are independently optionally substituted by 1, 2, 3 or 4 Re , Re and other variables are as defined in the present invention.
  • each R 13 above is independently selected from H and -CH 3 , and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined herein.
  • the above-mentioned ring A is selected from Other variables are as defined herein.
  • the above-mentioned ring A is selected from Other variables are as defined herein.
  • the above-mentioned ring A is selected from Other variables are as defined herein.
  • the above-mentioned ring A is selected from Other variables are as defined herein.
  • the above-mentioned ring A is selected from Other variables are as defined herein.
  • the above ring B is selected from Other variables are as defined herein.
  • the above compound has the formula (X-3), (X-4), (X-5), (X-6), (X-7), (X-8) or (X -9)
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 13 are as defined in the present invention.
  • the compounds described above have the formula (X-3A), (X-3B), (X-4A), (X-4B), (X-5A), (X-5B), (X -6A), (X-6B), (X-7A), (X-7B), (X-8A), (X-8B), (X-9A) or (X-9B):
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 13 are as defined in the present invention.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating KRAS mutant solid tumors.
  • the present application also provides a method for treating KRAS mutant solid tumors in a subject in need, comprising providing the subject with an effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the synthetic experimental scheme of above-mentioned compound:
  • X is a halogen
  • R' is C 1-6 alkyl
  • R" and R'" are independently selected from H, C 1-6 alkyl and 5-7 membered heterocycloalkyl, wherein C 1-6 alkyl and 5-7 membered heterocycloalkyl are independently optionally 1, 2, 3 or 4 R aa substitutions;
  • R" and the nitrogen atoms connected to them together form a C 4-6 cycloalkyl group or a 5-7 membered heterocycloalkyl group, wherein the C 4-6 cycloalkyl group and the 5-7 membered heterocycloalkyl group are Cycloalkyl is independently optionally substituted by 1, 2, 3 or 4 Re ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R aa and Re are as defined in the present invention.
  • the present invention also provides the biological experiment testing method of above-mentioned compound:
  • H358 cells with KRAS(G12C) mutation the KRAS signaling pathway was abnormally activated.
  • Small molecule SOS1 inhibitors inhibit the combination of SOS1 and RAS protein, reduce its GEF activity, and reduce the ratio of activated RAS-GTP. Further down-regulate the phosphorylation level of MEK/ERK pathway downstream of RAS to achieve the effect of inhibiting cell proliferation.
  • Small molecules were co-cultured with H358 cells in a 3D space, and then the cells were read out to indirectly reflect the proliferation inhibitory activity of SOS1 inhibitors on H358 cells.
  • RPMI1640 medium fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente, and low-melting point agarose was purchased from Sigma.
  • Almar blue reagent was purchased from Invitrogen.
  • NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
  • Plant H358 cells in a 96-well U-shaped plate first make a 2% mother solution of low-melting point agarose, heat the agarose mother solution in a microwave oven to completely melt it, and then put the agarose in a 42°C water bath Sugar remains in a liquid state.
  • After the bottom gel is solidified add 2% gel to the cell-containing medium to prepare a cell-containing upper gel with a gel concentration of 0.4%, and a cell density of 4 ⁇ 104 cells/ml.
  • 75 ⁇ l was added to the 96-well U-plate covered with bottom glue, and the cell density was 3000 cells per well. After the supernatant gel was solidified, the cell plate was cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 3 times to the ninth concentration with a row gun, that is, diluted from 6mM to 0.9 ⁇ M, and a double-well experiment was set up.
  • Add 100 ⁇ L of the mixed compound transfer 40 ⁇ L per well to the cell plate after mixing.
  • Compound concentrations ranged from 30 [mu]M to 4.5 nM transferred to the cell plate.
  • the cell plates were placed in a carbon dioxide incubator and cultured for another 7 days.
  • the compound was co-incubated with the cells for 14 days, and 20 ⁇ L of Almar blue detection reagent per well was added to the cell plate, and the dyed plate was placed on a horizontal shaker for 15 minutes, and then the plate was incubated at room temperature for 5 hours to stabilize the luminescent signal. Read using a multi-label analyzer.
  • the value of IC50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • the compound of the present invention has good KRAS(G12C)-SOS1 binding inhibitory activity, and has significant inhibitory activity on KRAS(G12C) mutated H358 cells and DLD-1 cell p-ERK proliferation, and then obtains excellent tumor growth inhibitory activity active.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key and straight dashed keys
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution was performed and the pure enantiomers recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • the linking direction is arbitrary, for example, In the ring C is at this time Include Two structural fragments. Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups.
  • C 1-4 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
  • C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl, etc.; it can be Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-4 alkoxy denotes those alkyl groups containing 1 to 4 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-4 alkoxy group includes C 1-3 , C 1-2 , C 2-4 , C 4 and C 3 alkoxy groups and the like.
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy and the like.
  • C 1-4 alkylamino denotes those alkyl groups containing 1 to 4 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-4 alkylamino group includes C 1-3 , C 1-2 , C 2-4 , C 4 , C 3 and C 2 alkylamino groups and the like.
  • C 1-4 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 3-8 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 8 carbon atoms, which includes monocyclic and bicyclic systems, wherein bicyclic systems include spiro rings, fused rings and bridge ring.
  • the C 3-8 cycloalkyl group includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl group, etc.; Can be monovalent, divalent or polyvalent.
  • C 3-8 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, spiroheptyl, and the like.
  • C 4-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 4 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
  • Examples of C 4-6 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-8 membered heterocycloalkyl includes 3-6, 3-5, 4-6, 5-6, 4, 5, 6, 7, 8-membered heterocycloalkyl, etc. .
  • 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidin,
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-7 membered heterocycloalkyl includes 3-6, 3-5, 4-6, 5-6, 3, 4, 5, 6, 7-membered heterocycloalkyl, etc. .
  • 3-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidin,
  • 5-7 membered heterocycloalkyl a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 5-7 membered heterocycloalkyl group includes 5-membered, 6-membered, 7-membered, 5-6-membered and 6-7-membered heterocycloalkyl groups.
  • Examples of 5-7 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl,
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxyl protecting group” or “mercapto protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and tert-butyldi Methylsilyl (TBS) and the like.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxy group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • the solvent used in the present invention is commercially available.
  • Alloc stands for allyloxycarbonyl
  • SEM stands for trimethylsilylethoxymethyl
  • OTs stands for 4-toluenesulfonyl
  • Boc stands for tert-butoxycarbonyl
  • DCM stands for dichloromethane
  • DIEA represents N,N-diisopropylethylamine
  • MeI represents iodomethane
  • PE represents petroleum ether
  • EA represents ethyl acetate
  • THF represents tetrahydrofuran
  • EtOH represents ethanol
  • MeOH represents methanol
  • Boc 2 O represents di-tert-butyl dicarbonate
  • NH 4 Cl stands for ammonium chloride
  • T 3 P stands for 1-propylphosphoric tricyclic acid anhydride
  • Pd/C stands for palladium/carbon catalyst
  • TMSN 3 stands for azidotrimethylsilane
  • NCS stands for N-chlorobutadiene Imide
  • HBr stands for
  • Ethyl bromodifluoroacetate (3.37g, 16.6mmol) was dissolved in dimethylsulfoxide (20mL), and copper powder (1.06g, 16.6mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. Then compound A-1 (2.00 g, 6.65 mmol) was added to the reaction liquid, and the reaction was stirred at 70° C. for 12 hours. The reaction solution was poured into 20 mL of ice water, ethyl acetate (20 mL) was added, filtered, and the filtrate was extracted with ethyl acetate (20 mL ⁇ 3).
  • compound A-3 (677mg, 1.82mmol) was dissolved in toluene (10mL), and methylmagnesium bromide solution (3M, 2.43mL) was added at 0°C. The reaction solution was stirred and reacted at 25° C. for 2 hours. Add saturated ammonium chloride solution (10 mL) to quench, and extract with ethyl acetate (10 mL ⁇ 2).
  • compound A-4 (441 mg, 1.56 mmol) was dissolved in toluene (5 mL), compound A-5 (1.87 g, 5.19 mmol) and bistriphenylphosphine palladium dichloride (109 mg, 0.16 mmol), the reaction solution was stirred and reacted at 120°C for 12 hours. After cooling down to room temperature, it was quenched by adding saturated potassium fluoride solution (20 mL), and extracted with ethyl acetate (15 mL ⁇ 2). Filter and concentrate under reduced pressure to obtain compound A-6.
  • compound B-1 (3.00g, 14.8mmol) was dissolved in dry dichloromethane (30mL), diethylaminosulfur trifluoride (3.57g, 22.2mmol) was added dropwise at 0°C, and the reaction solution was Stir at 25°C for 12 hours, add ice water (20 mL) to the reaction solution, extract with dichloromethane (20 mL ⁇ 1), wash the organic phase with saturated brine (20 mL ⁇ 1), dry over anhydrous sodium sulfate, filter, Concentrate under reduced pressure, and the residue is separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 10/1, V/V) to obtain compound B-2.
  • compound B-2 (3.10g, 13.8mmol) was dissolved in dry toluene (50mL), tributyl(1-ethoxyethylene)tin (9.95g, 27.6mmol) was added, and bistrimethyl Phenylphosphine palladium dichloride (967mg, 1.38mmol), the reaction solution was stirred at 110°C for 12 hours, and after cooling down to room temperature, saturated potassium fluoride aqueous solution (200mL) was added to the reaction solution, and ethyl acetate (200mL ⁇ 1) Extraction, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound B-3, which was directly used in the next step.
  • compound B-3 (2.98g, 13.8mmol) was dissolved in acetone (90mL), and concentrated hydrochloric acid (12M, 9.19mL) was added dropwise at 0°C, and the reaction solution was stirred at 25°C for 1 hour, and the reaction solution Alkaline the pH to 8 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (200mL ⁇ 2), wash the organic phase with saturated brine (200mL ⁇ 1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use Compound B-4 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 10/1, V/V).
  • compound C-1 (6.00 g, 23.3 mmol) was dissolved in dry toluene (100 mL), compound A-5 (12.6 g, 34.9 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.63g, 2.33mmol), the reaction solution was stirred at 120°C for 12 hours, and after cooling down to room temperature, saturated potassium fluoride aqueous solution (100mL) was added to the reaction solution, extracted with ethyl acetate (100mL ⁇ 2), and the organic phase was used Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound C-2, which is directly used in the next step.
  • compound D-1 (5.00 g, 25.5 mmol) was dissolved in dry toluene (50 mL), compound A-5 (10.2 g, 28.3 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.79g, 2.55mmol), the reaction solution was stirred at 120°C for 12 hours, and after cooling down to room temperature, saturated potassium fluoride aqueous solution (50mL) was added to the reaction solution, extracted with ethyl acetate (50mL ⁇ 2), and the organic phase was washed with Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound D-2, which is directly used in the next step.
  • compound E-3 (15.2g, 89.5mmol) was dissolved in acetonitrile (100mL), and triethylamine (14.6g, 144mmol) and magnesium chloride (9.33g, 98.0mmol) were added successively at 0°C, The reaction was stirred for 2 hours. After cooling to 0°C, a solution of compound E-2 (10.8g, 42.6mmol) in acetonitrile (50mL) was added dropwise, and the reaction was stirred at 15°C for 12 hours.
  • reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution (100 mL) was added to the residue, stirred and reacted at 25°C for 2 hours, extracted with ethyl acetate (50 mL ⁇ 3), and the organic phase was washed with saturated brine (100 mL ⁇ 1) Wash, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 12-4.
  • compound 14-2 (2.05g, 6.03mmol) was dissolved in toluene (30mL), bistriphenylphosphine palladium dichloride (423mg, 603 ⁇ mol) and compound A-5 (2.61g, 7.23 mmol), stirred and reacted at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride solution (50 mL) was added to the reaction solution, filtered, and the filtrate was extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 14-3.
  • reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was separated and purified by preparative high performance liquid chromatography (column: Waters Xbridge 150mm ⁇ 25mm ⁇ 3 ⁇ m; mobile phase: 0.05% ammonia solution-acetonitrile; gradient: acetonitrile 38%-68%, 8min) to obtain compound 16.
  • compound 18-3 (5.20g, 22.8mmol) was dissolved in methanol (60mL), N,N-dimethylformamide (20mL) and triethylamine (20mL), and 1,1-bis (Diphenylphosphine)ferrocenepalladium chloride (1.67g, 2.28mmol), stirred and reacted at 80°C for 72 hours.
  • Dissolve compound 24-4 (2.00g, 5.03mmol) in methanol (20mL), add formaldehyde (1.12mL, 15.1mmol, 37% purity) and acetic acid (1.15mL, 20.1mmol), and stir at 25°C for 2 hours , and sodium cyanoborohydride (949 mg, 15.1 mmol) was added, and the reaction was stirred at 25° C. for 1 hour.
  • Add water 60 mL
  • extract with dichloromethane 60 mL and 30 mL
  • reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was separated and purified by preparative high-performance liquid chromatography (column: 3-Phenomenex Luna C18 75mm ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 8%-28%, 8min) to obtain the salt of compound 24 salt.
  • compound 2-3 (1.00g, 3.20mmol) was dissolved in dimethyl sulfoxide (15mL), and 25-1 (1.29g, 9.61mmol), potassium carbonate (1.33g, 9.61mmol) were added, and the After the reaction was stirred at °C for 0.5 hours, 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (234mg, 320 ⁇ mol) was added, and the reaction was stirred at 100°C for 12 hours.
  • compound 28-2 (12.5g, 53.2mmol) was dissolved in trifluoroacetic acid (100mL) and sulfuric acid (10mL), and N-bromosuccinimide (11.4g, 63.8mmol) was added, and at 25 The reaction was stirred at °C for 12 hours.
  • compound 28-3 (13.8g, 43.9mmol) was dissolved in toluene (100mL), and A-5 (21.1g, 58.4mmol) and bis(triphenylphosphine)palladium dichloride (3.08g, 4.39mmol), stirred and reacted at 120°C for 12 hours. After cooling down to room temperature, saturated potassium fluoride aqueous solution (300 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 28-4.

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Abstract

L'invention concerne un composé benzylamino tricyclique et son utilisation, qui se rapporte en particulier à un composé tel que représenté par la formule (X), et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/104713 2021-07-09 2022-07-08 Composé benzylamino tricyclique et son utilisation WO2023280317A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023180345A1 (fr) * 2022-03-22 2023-09-28 Jazz Pharmaceuticals Ireland Limited Phtalazines tricycliques et leurs dérivés utilisés comme inhibiteurs de sos1
CN117285413A (zh) * 2023-08-09 2023-12-26 重庆恩联生物科技有限公司 一种特布他林关键中间体3，5-二羟基苯乙酮的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0449203A1 (fr) * 1990-03-30 1991-10-02 Mitsubishi Chemical Corporation Dérivés de 4-phénylphthalazine
CN1208404A (zh) * 1996-10-01 1999-02-17 协和发酵工业株式会社 含氮杂环化合物
WO2021127429A1 (fr) * 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2022017339A1 (fr) * 2020-07-20 2022-01-27 江苏恒瑞医药股份有限公司 Dérivé pyridazinique condensé, son procédé de préparation et son utilisation pharmaceutique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0449203A1 (fr) * 1990-03-30 1991-10-02 Mitsubishi Chemical Corporation Dérivés de 4-phénylphthalazine
CN1208404A (zh) * 1996-10-01 1999-02-17 协和发酵工业株式会社 含氮杂环化合物
WO2021127429A1 (fr) * 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2022017339A1 (fr) * 2020-07-20 2022-01-27 江苏恒瑞医药股份有限公司 Dérivé pyridazinique condensé, son procédé de préparation et son utilisation pharmaceutique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023180345A1 (fr) * 2022-03-22 2023-09-28 Jazz Pharmaceuticals Ireland Limited Phtalazines tricycliques et leurs dérivés utilisés comme inhibiteurs de sos1
CN117285413A (zh) * 2023-08-09 2023-12-26 重庆恩联生物科技有限公司 一种特布他林关键中间体3，5-二羟基苯乙酮的合成方法

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