WO2022171118A1 - 一种具有抗肿瘤活性的化合物及其用途 - Google Patents

一种具有抗肿瘤活性的化合物及其用途 Download PDF

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WO2022171118A1
WO2022171118A1 PCT/CN2022/075635 CN2022075635W WO2022171118A1 WO 2022171118 A1 WO2022171118 A1 WO 2022171118A1 CN 2022075635 W CN2022075635 W CN 2022075635W WO 2022171118 A1 WO2022171118 A1 WO 2022171118A1
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membered
alkyl
cycloalkyl
aryl
alkenyl
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张朝再
胡继明
安会
范丽雪
齐非
滑新星
张颜
蒋春华
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石药集团中奇制药技术（石家庄）有限公司
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of medical technology, in particular, to a compound as an inhibitor of SOS1 and a preparation method and use of the compound.
  • KRAS Kerrsten rat sarcoma virus oncogene homolog
  • NRAS nerveroblastoma RAS virus oncogene homolog
  • HRAS Hard murine sarcoma virus oncogene
  • RAS family proteins are a class of small-molecule GTPases and the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates. Binding of GTPase activating proteins (GAPs) such as NF1 increases the GTPase activity of RAS family proteins.
  • GAPs GTPase activating proteins
  • KRAS mutations eg amino acids G12, G13, Q61, A146
  • NRAS eg amino acids G12, G13, Q61, A146
  • HRAS eg amino acids G12, G13, Q61
  • RAS family proteins eg, mutation, overexpression, gene amplification
  • cancer drugs such as the EGFR antibodies cetuximab and panitumumab
  • EGFR tyrosine kinase inhibitor osimertinib e.g., EGFR antibodies cetuximab and panitumumab
  • osimertinib EGFR tyrosine kinase inhibitor
  • GAP activity is attenuated or greatly reduced, resulting in permanent activation, which underlies oncogenic RAS signaling.
  • Direct inhibition of RAS has been demonstrated due to the picomolar affinity of GTP for its binding site, the lack of other well-defined pockets, and the interaction of RAS with GEFs, GAPs, and effectors through an extended and flat protein-protein interaction surface is extremely challenging and difficult to cure. Therefore, there may be new hope to inhibit RAS activation by targeting the upstream guanine nucleotide exchange factor protein SOS.
  • SOS1 Two human isoforms of SOS exist, SOS1 and SOS2, but most studies have focused on SOS1.
  • Human SOS1 consists of 1333 amino acids (15kDa) and consists of an N-terminal domain, a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, including a Ras exchanger motif (Rem) domain and a Cdc25 structure domain and the C-terminal region.
  • DH Dbl homology
  • PH pleckstrin homology
  • Rem Ras exchanger motif
  • Cdc25 structure domain and the C-terminal region.
  • PH, Rem and Cdc25 are the components of the core catalytic domain of SOS cat .
  • One aspect of the present application provides a compound represented by the following formula (I), and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogs,
  • X when When it is a single bond, X is selected from C(R A )(R A ), NR A , O, S; when When being a double bond, X is selected from CRA , N;
  • R A is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 Membered heterocyclyl, -C(O)-C 1-6 alkyl, -C(O)-C 3-10 cycloalkyl, -C(O)-3-10 membered heterocyclyl, -C 1- 6 alkyl-C(O)-C 1-6 alkyl, -C 1-6 alkyl C(O)-C 3-10 cycloalkyl, -C 1-6 alkyl C(O)-3- 10-membered heterocyclyl and 5-10-membered heteroaryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10-membered heterocycle, -C(O)-C 1-6 alkyl, -
  • R a1 is independently selected from -ORc , -NRcRc , halogen, -CN, -C(O) Rc , -C(O) ORc , -C ( O ) NRcRc , -S(O) 2 R c , -S(O) 2 NR c R c , -NHC(O) R c , -N(C 1-4 alkyl) C(O) R c , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group,
  • R c is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- 10-membered heterocyclyl and 5-10-membered heteroaryl;
  • Y when When it is a single bond, Y is selected from C 1-6 alkyl; when When being a double bond, Y is selected from O, S;
  • Z when When it is a single bond, Z is selected from CH, N, O, S, when Z is selected from O, S, R 2 does not exist; when When it is a double bond, Z is selected from C and N, and when Z is selected from N, R 2 does not exist;
  • R 1 when When it is a double bond, R 1 is O; when When it is a single bond, R 1 is selected from -OR B , optionally substituted C 2-4 alkyl, C 2-4 alkenyl, C 3-12 carbocyclyl, C 6-10 aryl, 3-12 membered Heterocyclyl and 5-10 membered heteroaryl;
  • R B is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the C 1-6 alkyl , C 3-10 cycloalkyl and 3-10 membered heterocyclyl are optionally substituted by one or more identical or different R b1 ;
  • R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)C(O)R c1 , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 member
  • R c1 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- 10-membered heterocyclyl and 5-10-membered heteroaryl;
  • R 1 is selected from C 3-12 carbocyclic group, C 6-10 aryl group, 3-12-membered heterocyclic group and 5-10-membered heteroaryl group, the C 3-12 carbocyclic group , C 6-10 aryl, 3-12-membered heterocyclyl and 5-10-membered heteroaryl are optionally substituted by one or more of the same or different R a2 ;
  • R c2 is independently selected from hydrogen, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3 -10-membered heterocyclyl and 5-10-membered heteroaryl;
  • R 1 is selected from C 2-4 alkyl and C 2-4 alkenyl, the C 2-4 alkyl and C 2-4 alkenyl are optionally the same or different by one or more The R b2 substitution;
  • R b2 is independently selected from -C(O)R c3 , -C(O)OR c3 , -C(O)NR c3 R c3 , -C(O)NHOR c3 and -C(O)-N (C 1-4 alkyl)-OR c3 ;
  • R c3 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
  • R 2 is selected from hydrogen, C 1-6 alkyl, -OC 1-4 alkyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) (C 1-4 alkyl) 4 alkyl) and halogen;
  • R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 alkyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) (C 1-4 alkyl) and halogen;
  • Ring A is selected from C 4-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl, 5-12 membered heteroaryl;
  • compositions comprising the compound represented by formula (I) described in the present application or its stereoisomer, geometric isomer, tautomer, hydrate , solvates, isotopically labeled analogs, prodrugs or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.
  • Another aspect of the present application provides the compound represented by the formula (I) described in the present application or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, isotopically labeled analogs
  • a drug, a prodrug or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described herein in the preparation of a medicament for the treatment of a disease mediated by an SOS1 inhibitor.
  • Another aspect of the present application provides the compound represented by the formula (I) described in the present application or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, isotopically labeled analogs
  • the purpose of the present application is to provide a compound with a novel structure as an SOS1 inhibitor, a preparation method of the compound and its use in the treatment of diseases mediated by an SOS1 inhibitor.
  • One aspect of the present application provides a compound represented by the following formula (I), and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogs,
  • X when When it is a single bond, X is selected from C(R A )(R A ), NR A , O, S; when When being a double bond, X is selected from CRA , N;
  • R A is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 Membered heterocyclyl, -C(O)-C 1-6 alkyl, -C(O)-C 3-10 cycloalkyl, -C(O)-3-10 membered heterocyclyl, -C 1- 6 alkyl-C(O)-C 1-6 alkyl, -C 1-6 alkyl C(O)-C 3-10 cycloalkyl, -C 1-6 alkyl C(O)-3- 10-membered heterocyclyl and 5-10-membered heteroaryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10-membered heterocycle, -C(O)-C 1-6 alkyl, -
  • R a1 is independently selected from -ORc , -NRcRc , halogen, -CN, -C(O) Rc , -C(O) ORc , -C ( O ) NRcRc , -S(O) 2 R c , -S(O) 2 NR c R c , -NHC(O) R c , -N(C 1-4 alkyl) C(O) R c , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group,
  • R c is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- 10-membered heterocyclyl and 5-10-membered heteroaryl;
  • Y when When it is a single bond, Y is selected from C 1-6 alkyl; when When being a double bond, Y is selected from O, S;
  • Z when When it is a single bond, Z is selected from CH, N, O, S, when Z is selected from O, S, R 2 does not exist; when When it is a double bond, Z is selected from C and N, and when Z is selected from N, R 2 does not exist;
  • R 1 when When it is a double bond, R 1 is O; when When it is a single bond, R 1 is selected from -OR B , optionally substituted C 2-4 alkyl, C 2-4 alkenyl, C 3-12 carbocyclyl, C 6-10 aryl, 3-12 membered Heterocyclyl and 5-10 membered heteroaryl;
  • R B is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the C 1-6 alkyl , C 3-10 cycloalkyl and 3-10 membered heterocyclyl are optionally substituted by one or more identical or different R b1 ;
  • R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)C(O)R c1 , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 member
  • R c1 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- 10-membered heterocyclyl and 5-10-membered heteroaryl;
  • R 1 is selected from C 3-12 carbocyclic group, C 6-10 aryl group, 3-12-membered heterocyclic group and 5-10-membered heteroaryl group, the C 3-12 carbocyclic group , C 6-10 aryl, 3-12-membered heterocyclyl and 5-10-membered heteroaryl are optionally substituted by one or more of the same or different R a2 ;
  • R c2 is independently selected from hydrogen, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3 -10-membered heterocyclyl and 5-10-membered heteroaryl;
  • R 1 is selected from C 2-4 alkyl and C 2-4 alkenyl, the C 2-4 alkyl and C 2-4 alkenyl are optionally the same or different by one or more The R b2 substitution;
  • R b2 is independently selected from -C(O)R c3 , -C(O)OR c3 , -C(O)NR c3 R c3 , -C(O)NHOR c3 and -C(O)-N (C 1-4 alkyl)-OR c3 ;
  • R c3 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
  • R 2 is selected from hydrogen, C 1-6 alkyl, -OC 1-4 alkyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) (C 1-4 alkyl) 4 alkyl) and halogen;
  • R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 alkyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) (C 1-4 alkyl) and halogen;
  • Ring A is selected from C 4-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl, 5-12 membered heteroaryl;
  • X when When it is a single bond, X is selected from C(R A )(R A ), NR A , O, S; when When being a double bond, X is selected from CRA , N;
  • R A is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 Membered heterocyclyl, -C(O)-C 1-6 alkyl, -C(O)-C 3-10 cycloalkyl, -C(O)-3-10 membered heterocyclyl, -C 1- 6 alkyl-C(O)-C 1-6 alkyl, -C 1-6 alkyl C(O)-C 3-10 cycloalkyl, -C 1-6 alkyl C(O)-3- 10-membered heterocyclyl and 5-10-membered heteroaryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10-membered heterocycle, -C(O)-C 1-6 alkyl, -
  • R a1 is independently selected from -ORc , -NRcRc , halogen, -CN, -C(O) Rc , -C(O) ORc , -C ( O ) NRcRc , -S(O) 2 R c , -S(O) 2 NR c R c , -NHC(O) R c , -N(C 1-4 alkyl) C(O) R c , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group,
  • R c is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- 10-membered heterocyclyl and 5-10-membered heteroaryl;
  • Y when When it is a single bond, Y is selected from C 1-6 alkyl; when When being a double bond, Y is selected from O, S;
  • Z when When it is a single bond, Z is selected from CH, N, O, S, when Z is selected from O, S, R 2 does not exist; when When it is a double bond, Z is selected from C and N, and when Z is selected from N, R 2 does not exist;
  • R 1 when When it is a double bond, R 1 is O; when When it is a single bond, R 1 is selected from -OR B , optionally substituted C 2-4 alkyl, C 2-4 alkenyl, C 3-12 carbocyclyl, C 6-10 aryl, 3-12 membered Heterocyclyl and 5-10 membered heteroaryl;
  • R B is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the C 3-10 cycloalkane and 3-10 membered heterocyclyl are optionally substituted with one or more of the same or different R b1 ;
  • R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)C(O)R c1 , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 member
  • R c1 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- 10-membered heterocyclyl and 5-10-membered heteroaryl;
  • R 1 is selected from C 3-12 carbocyclic group, C 6-10 aryl group, 3-12-membered heterocyclic group and 5-10-membered heteroaryl group, the C 3-12 carbocyclic group , C 6-10 aryl, 3-12-membered heterocyclyl and 5-10-membered heteroaryl are optionally substituted by one or more of the same or different R a2 ;
  • R c2 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
  • R 1 is selected from C 2-4 alkyl and C 2-4 alkenyl, the C 2-4 alkyl and C 2-4 alkenyl are optionally the same or different by one or more The R b2 substitution;
  • R b2 is independently selected from -C(O)R c3 , -C(O)OR c3 , -C(O)NR c3 R c3 , -C(O)NHOR c3 and -C(O)-N (C 1-4 alkyl)-OR c3 ;
  • R c3 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
  • R 2 is selected from hydrogen, C 1-6 alkyl, -OC 1-4 alkyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) (C 1-4 alkyl) 4 alkyl) and halogen;
  • R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 alkyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) (C 1-4 alkyl) and halogen;
  • Ring A is selected from C 4-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl, 5-12 membered heteroaryl;
  • X is selected from C( RA )( RA ), NR A , O, S; wherein, RA is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, C 6-8 aryl, 3-6 membered heterocyclyl, -C(O)-C 1-6 alkyl, -C(O)-C 4-6 ring Alkyl, -C(O)-3-6 membered heterocyclyl, -C 1-6 alkyl-C(O)C 1-6 alkyl, -C 1-6 alkyl-C(O)-C 4-6 cycloalkyl, -C 1-6 alkyl-C(O)-3-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein the C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-6 cycl
  • each occurrence of R a1 is independently selected from -OR c , -NR c R c , halogen, -CN, -C(O)R c , -C(O)OR c , - C(O)NR c R c , -S(O) 2 R c , -S(O) 2 NR c R c , -NHC(O)R c , -N(C 1-4 alkyl)C(O ) R c , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycle base and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4 -6-
  • each occurrence of R is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl.
  • X is selected from C( RA )( RA ), NR A , O, S; wherein, RA is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 4-6 cycloalkyl, C 6-8 aryl, 3-6 membered heterocyclyl, -C(O)-C 1-6 alkyl, -C(O)-C 4-6 ring Alkyl, -C(O)-3-6 membered heterocyclyl, -C 1-6 alkyl-C(O)C 1-6 alkyl, -C 1-6 alkyl-C(O)-C 4-6 cycloalkyl, -C 1-6 alkyl-C(O)-3-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein the C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 4-6 cycl
  • each occurrence of R a1 is independently selected from -OR c , -NR c R c , halogen, -CN, -C(O)R c , -C(O)OR c , -C(O) NRcRc ,-S(O ) 2Rc ,-S(O ) 2NRcRc ,-NHC(O )Rc , -N( C1-4alkyl ) C ( O)R c , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4-6 membered hetero Cyclic group and 5-6 membered heteroaryl group, wherein said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 4-6 cycloalkyl group, C 6-10 aryl group, The 4-6
  • each occurrence of R is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl , vinyl, ethynyl, C 4-6 cycloalkyl, C 6 aryl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl.
  • R 1 is -OR B ;
  • R B is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl and 3-10 A membered heterocyclyl is optionally substituted with one or more of the same or different R b1 ;
  • R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)C(O)R c1 , oxo, C 1-6 alkyl groups, C 3-10 cycloalkyl groups, C 6-10 aryl groups, 3-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the C 1-6 alkyl groups, C 3- 10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more of
  • R c1 is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl.
  • R 1 is -OR B ;
  • R B is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the C 3-10 cycloalkyl and 3-10 membered heterocyclyl are optionally is substituted with one or more identical or different R b1 ;
  • R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)C(O)R c1 , oxo, C 1-6 alkyl groups, C 3-10 cycloalkyl groups, C 6-10 aryl groups, 3-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the C 1-6 alkyl groups, C 3- 10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more of
  • R c1 is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl.
  • R 1 is -OR B ; wherein, R B is selected from C 1-4 alkyl, C 4-6 cycloalkyl and 4-6 membered heterocyclyl, the C 1-4 alkyl, C 4-6 cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more identical or different R b1 ; in some embodiments, R B is selected from n-propyl, isopropyl, n-propyl Butyl, isobutyl, methyl optionally substituted with one or more R b1 , ethyl optionally substituted with one or more R b1 , C 5-6 optionally substituted with one or more R b1 Cycloalkyl, 5-6 membered heterocyclyl optionally substituted with one or more R b1 .
  • R 1 is -OR B ; wherein, R B is selected from C 1-4 alkyl, C 4-6 cycloalkyl and 4-6 membered heterocyclyl, the C 4-6 cycloalkyl and 4-6 membered heterocyclyl optionally substituted with one or more of the same or different R b1 ; in some embodiments, R B is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl, C 5-6 cycloalkyl optionally substituted with one or more R b1 , 5-6 membered heterocyclyl optionally substituted with one or more R b1 .
  • each occurrence of R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O )NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)-C(O)R c1 , oxo, C 1-4 alkyl.
  • each occurrence of R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O )NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)-C(O)R c1 , oxo group.
  • each occurrence of R c1 is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 5-10 Member heteroaryl; more preferably, each occurrence of R c1 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl base.
  • R 1 is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 3-10 carbocyclyl , C 6-10 aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more of the same or different R a2 .
  • R 1 is selected from C 4-9 cycloalkyl, C 4-9 cycloalkenyl, C 6-10 aryl, 4-10-membered heterocyclyl and 5-10-membered heteroaryl, the C 4-9 cycloalkyl, C 4-9 cycloalkenyl, C 6-10 aryl, 4-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally replaced by one or more of the same or different R a2 is substituted.
  • R 1 is selected from C 4 monocycloalkyl, C 5 monocycloalkyl, C 6 monocycloalkyl, C 7 monocycloalkyl, 3-/4-membered spirocycloalkyl, 4 Member/3-membered spirocycloalkyl, 4-membered/4-membered spirocycloalkyl, 4-membered/5-membered spirocycloalkyl, 5-membered/4-membered spirocycloalkyl, 5-membered/5-membered spirocycloalkyl, 4-membered/5-membered spirocycloalkyl 6-membered/6-membered spirocycloalkyl, 6-membered/4-membered spirocycloalkyl, 3-membered/4-membered fused cycloalkyl, 4-membered/3-membered fused cycloalkyl, 4-membered/4-membered fused
  • each occurrence of R c2 is independently selected from hydrogen, OH, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 5 -10 membered heteroaryl; in some embodiments, each occurrence of R c2 is independently selected from hydrogen, OH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl base, C 3-6 cycloalkyl, phenyl, 3-6 membered heterocyclyl.
  • each occurrence of R c2 is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 5-10 Member heteroaryl; in some embodiments, each occurrence of R is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n - butyl, isobutyl, C3 -6 cycloalkyl, phenyl, 3-6 membered heterocyclyl.
  • R b2 is independently selected from -C(O)R c3 , -C(O)OR c3 , -C(O)NR c3 R c3 , -C(O)NHOR c3 and -C(O)N ( C 1-4 alkyl)-OR c3 ;
  • R c3 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl.
  • when it is a double bond is a single key.
  • when it is a single key is a double bond.
  • X when When it is a single bond, X is selected from C(R A )(R A ), NR A , O, S; when When being a double bond, X is selected from CRA , N;
  • Each occurrence of R A is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)-C 1-6 alkyl, -C 1-6 Alkyl-C(O)-C 1-6 alkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)-C 1-6 alkane base, -C 1-6 alkyl-C(O)-C 1-6 alkyl are optionally substituted with one or more (eg, 1, 2 or 3) the same or different R a1 ; Each occurrence of R a1 is independently selected from halogen, -CN, C 1-6 alkyl.
  • X when When it is a single bond, X is selected from C(R A )(R A ), NR A , O, S; when When a double bond, X is selected from CRA, N; each occurrence of R A is independently selected from hydrogen and C1-6 alkyl.
  • X when When a single bond, X is selected from NR A and O; when When a double bond, X is N; each occurrence of RA is independently selected from hydrogen and C1-6 alkyl (eg, methyl, ethyl).
  • Z when When it is a single bond, Z is N; when When it is a double bond, Z is C.
  • R 1 when When it is a double bond, R 1 is O; when When a single bond, R1 is selected from -ORB , optionally substituted C3-12 carbocyclyl, C6-10 aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl.
  • R 1 when When a single bond, R 1 is selected from -OR B , optionally substituted C 3-6 carbocyclyl, C 6-10 aryl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl.
  • R 1 when When it is a single bond, R 1 is selected from -OR B , and R B is selected from C 1-6 alkyl, C 3-6 cycloalkyl and 3-6-membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more (eg, 1, 2 or 3) R b1 which are the same or different.
  • R 1 when When it is a single bond, R 1 is selected from -OR B , and R B is selected from C 1-6 alkyl, C 5-6 cycloalkyl and 5-6 membered heterocyclic group, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more (eg, 1, 2 or 3) R b1 which are the same or different.
  • each occurrence of R b1 is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C( O)NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)C(O)R c1 , oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl are optionally substituted with one or more (eg, 1, 2, or 3) of the same or different R c1 ; each occurrence of R c1 is independently selected from hydrogen, C 1-6 alkyl,
  • each occurrence of R b1 is each independently selected from -OR c1 , -C(O)R c1 , -C(O)OR c1 , and C 1-6 alkyl, wherein said C 1-6 Alkyl is optionally substituted with one or more (eg, 1, 2, or 3) of the same or different R c1 ; each occurrence of R c1 is independently selected from hydrogen, C 1-6 alkyl (eg, , methyl, tert-butyl) and C 3-6 cycloalkyl (eg, cyclopropyl).
  • the C 3-8 carbocyclic group , C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by one or more (eg, 1, 2 or 3) of the same or different R a2 ;
  • R c2 is independently selected from hydrogen, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3 -6-membered heterocyclyl and 3-6 membered heteroaryl.
  • R 1 is selected from C 5-6 carbocyclic group, C 6 aryl group, 5-10-membered heterocyclic group and 5-10-membered heteroaryl group
  • the C 5-6 carbocyclic group, C 6 -aryl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more (eg, 1, 2 or 3) of the same or different R a2 ;
  • Each occurrence of R a2 is independently selected from -OR c2 , -C(O)R c2 , -C 0-4 alkyl C(O)NR c2 R c2 , oxo, C 1-6 alkyl, wherein all The C 1-6 alkyl is optionally substituted with one or more (eg, 1, 2 or 3) the same or different R c2 ;
  • R c2 is independently selected from hydrogen, OH, C 1-6 alkyl and 5-6 membered heterocyclyl.
  • R 1 when is a single bond, R 1 is selected from
  • R 2 is selected from hydrogen, C 1-4 alkyl, -OC 1-4 alkyl and halogen; in some embodiments, R 2 is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , - O-CHCH 3 CH 3 , -O-CH 2 CHCH 3 CH 3 , -O-CH 2 CH 2 CH 2 CH 3 ; when Z is selected from O, S, R 2 does not exist.
  • R 2 is -O-CH 3 .
  • R 3 is selected from hydrogen, C 1-4 alkyl, -OC 1-4 alkyl and halogen; in some embodiments, R 3 is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
  • Ring A is selected from C 4-8 cycloalkyl, 4-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl; in some embodiments , Ring A is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl; in some embodiments, Ring A is selected from C 6 aryl base and 5-6 membered heteroaryl.
  • Ring A is phenyl or thienyl .
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen, -NH 2 , C 1-4 alkyl, halogen, C 1-4 haloalkyl, -OC 1-4 alkyl, - OC 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -OC 3-6 cycloalkyl, -OC 6 -10 aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 cycloalkyl, -O-CH 2 -C 6- 10 -aryl, -O-CH 2 -5-10-membered heteroaryl, -O-CH 2 -3-6-membered heterocyclic group, wherein C 3-6 cycloalkyl, C 6-10 aryl, 5- 10-membered heteroaryl,
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen, -NH 2 , C 1-4 alkyl, halogen, C 1-4 haloalkyl, -OC 1-4 alkyl, -OC 1- 4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -OC 3-6 cycloalkyl, -OC 6-10 aryl base, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 cycloalkyl, -O-CH 2 -C 6-10 aryl , -O-CH 2 -5-10-membered heteroaryl, -O-CH 2 -3-6-membered heterocyclic group, wherein C 3-6 cycloalkyl, C 6-10 aryl, 5-10-membered heterocyclic Aryl, 3-6
  • each occurrence of R4 is independently selected from hydrogen, -NH2 , methyl, ethyl, n-propyl, isopropyl, F, Cl, Br, CHF2 , CF3 , -O -CH 3 , -O-CF 3 , 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 6 -aryl, 5-membered heteroaryl, 6-membered heteroaryl, the 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, C 6 aryl, 5-membered heteroaryl, 6-membered heteroaryl optionally
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen, -NH 2 , C 1-4 alkyl, halogen, C 1-4 haloalkyl, -OC 1-4 alkyl, -OC 1- 4 haloalkyl, C 3-6 cycloalkyl, C 6 aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, -OC 3-6 cycloalkyl, -OC 6 aryl, -O -5-6 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 cycloalkyl, -O-CH 2 -C 6 aryl, -O-CH 2 -5-6-membered heteroaryl, -O-CH 2 -3-6-membered heterocyclic group, wherein C 3-6 cycloalkyl, C 6 -aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclic group, where
  • compounds of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or Isotope-labeled analogs wherein the compound represented by formula (I) has the structure represented by formula (Ia):
  • compounds of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or Isotope-labeled analogs wherein the compound represented by formula (I) has a structure selected from the group consisting of formula (II) to formula (X):
  • each substituent in formula (II) to formula (X) has the same definition as formula (I).
  • compounds of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or Isotope-labeled analogs wherein the compound represented by formula (I) further has a structure selected from the group consisting of formula (II) to formula (Xa):
  • compounds of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or Isotopically labeled analogs wherein the compound is selected from the group consisting of:
  • the purpose of this application also includes the provision of the preparation of the compound represented by formula (I), and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analog method.
  • the method can be prepared, for example, by the method shown in the following scheme, and can be linked by halogenation and nucleophilic substitution to synthesize the target compound.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound shown in the present application, or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrated compounds, solvates or isotopically labeled analogs, and pharmaceutically acceptable excipients.
  • the compounds shown herein, or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogs thereof, can be administered in pure form form or any acceptable mode of administration in the form of a suitable pharmaceutical composition.
  • the pharmaceutical compositions of the present application can be prepared by combining the compounds shown herein with suitable pharmaceutically acceptable excipients.
  • the pharmaceutical compositions of the present application can be formulated into solid or liquid preparations. Generally, the above-mentioned pharmaceutical compositions can be prepared by conventional preparation methods using conventional excipients in the formulation field.
  • the present application also provides the compounds shown in the present application, or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled Use of the analog or the pharmaceutical composition described herein in the manufacture of a medicament for treating a disease mediated by an SOS1 inhibitor.
  • the SOS1 inhibitor-mediated disease is cancer or tumor, and related diseases.
  • the present application also provides the compounds shown in the present application, or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled Use of the analog or the pharmaceutical composition described in this application in the preparation of a medicament for treating diseases caused by RAS mutation.
  • the disease caused by the RAS mutation includes neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-dynamic Venous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), LEGIUS SYNDROME, and hereditary gingival fibromatosis.
  • NF1 neurofibromatosis type 1
  • NS Noonan syndrome
  • NML Noonan syndrome with multiple spots
  • CM-AVM capillary malformation-dynamic Venous malformation syndrome
  • CS Costello syndrome
  • CFC cardio-facial-cutaneous syndrome
  • LEGIUS SYNDROME LEGIUS SYNDROME
  • hereditary gingival fibromatosis hereditary gingival fibromatosis.
  • the application also provides a method of preventing and/or treating a disease mediated by an SOS1 inhibitor, comprising administering to the patient a therapeutically effective dose of the compound shown in the application, or a stereoisomer, geometrical Isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled analogs, or pharmaceutical compositions described herein.
  • the SOS1 inhibitor-mediated disease is cancer or tumor, and related diseases.
  • the present application also provides a method for preventing and/or treating a disease caused by RAS mutation, comprising administering to a patient a therapeutically effective dose of the compound shown in the present application, or a stereoisomer or geometric isomer thereof , tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled analogs or pharmaceutical compositions described herein.
  • the disease caused by the RAS mutation includes neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-dynamic Venous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), LEGIUS SYNDROME, and hereditary gingival fibromatosis.
  • NF1 neurofibromatosis type 1
  • NS Noonan syndrome
  • NML Noonan syndrome with multiple spots
  • CM-AVM capillary malformation-dynamic Venous malformation syndrome
  • CS Costello syndrome
  • CFC cardio-facial-cutaneous syndrome
  • LEGIUS SYNDROME LEGIUS SYNDROME
  • hereditary gingival fibromatosis hereditary gingival fibromatosis.
  • the present application also provides the compounds shown in the present application for preventing and/or treating diseases mediated by SOS1 inhibitors, or their stereoisomers, geometric isomers, tautomers, drugs Use salts, prodrugs, hydrates, solvates, isotopically labeled analogs, or pharmaceutical compositions described herein.
  • the present application also provides the compounds shown in the present application for preventing and/or treating diseases caused by RAS mutations, or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, Prodrugs, hydrates, solvates, isotopically labeled analogs, or pharmaceutical compositions described herein.
  • the present application also provides the compounds shown in the present application, or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled Use of an analog or a pharmaceutical composition described herein in the treatment of a disease mediated by an SOS1 inhibitor.
  • the present application also provides the compounds shown in the present application, or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled Use of the analog or the pharmaceutical composition described herein in the treatment of diseases caused by RAS mutations.
  • compound as used herein includes all stereoisomeric, geometric isomeric, tautomeric and isotopic forms of a compound.
  • substituted or “substituted” refer to the substitution of any one or more hydrogen atoms on a specified atom with a substituent, so long as the valence of the specified atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms on the same carbon atom are replaced by oxygen atoms. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • Cmn in this context is that the moiety has an integer number of carbon atoms in the given range.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • any variable eg, R
  • its definition in each case is independent. So, for example, if a group is substituted with 2 Rs, each R has independent options.
  • Amino refers to the -NH2 group.
  • Carboxyl refers to the -COOH group.
  • Cyano refers to the -CN group.
  • Niro refers to the -NO 2 group.
  • Boc means tert-butoxycarbonyl
  • Halogen and halo refer to F, Cl, Br, I.
  • Carbocyclyl or “carbocycle” refers to a non-aromatic cyclic hydrocarbon radical having from 3 to 14 ring carbon atoms (“ C3-14 carbocyclyl”), and There are no heteroatoms in the non-aromatic ring system.
  • Carbocyclyl includes “cycloalkyl” and “cycloalkenyl”. In some embodiments, carbocyclyl groups have 3-12 ring carbon atoms (“C 3-12 carbocyclyl”), or 4-12 ring carbon atoms (“C 4-12 carbocyclyl”) , or 3 to 10 ring carbon atoms ("C 3-10 carbocyclyl”).
  • carbocyclyl groups have 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl”). In some embodiments, carbocyclyl groups have 3 to 7 ring carbon atoms ("C 3-7 carbocyclyl”). In some embodiments, carbocyclyl groups have 4 to 6 ring carbon atoms ("C 4-6 carbocyclyl”). In some embodiments, carbocyclyl groups have 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”), or 5 to 7 ring carbon atoms ("C 5-7 carbocyclyl”) .
  • Exemplary C3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3 ) , cyclopropenyl (C3 ) , cyclobutyl ( C4 ), cyclobutenyl ( C4 ), cyclo Pentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and the like.
  • Exemplary C3-8 carbocyclyl groups include, but are not limited to, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl ( C7 ), cycloheptenyl ( C7 ), cycloheptanedi Alkenyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptyl (C 7 ), dicyclo[2.2.1]heptyl (C 7 ) Cyclo[2.2.2]octyl (C 8 ) and the like.
  • Exemplary C3-10 carbocyclyl groups include, but are not limited to, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl ( C9 ), cyclononenyl ( C9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like.
  • the carbocyclyl group is monocyclic (“monocyclic carbocyclyl”) or a fused (fused ring), bridged (bridged ring) ) or spiro-fused (spirocyclyl) ring systems, such as a bicyclic ring system (“bicyclic carbocyclyl”) and may be saturated or may be partially unsaturated.
  • Carbocyclyl also includes ring systems in which the carbocyclyl ring, as defined above, is fused by one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring and at In such cases, the number of members of the carbocyclyl ring system is the number of carbons in the carbocyclic ring system after fusion.
  • each instance of a carbocyclyl group is independently optionally substituted, eg, unsubstituted (an "unsubstituted carbocyclyl") or substituted by one or more substituents substituted (a "substituted carbocyclyl").
  • the carbocyclyl group is an unsubstituted C3-10 carbocyclyl group.
  • the carbocyclyl group is a substituted C3-10 carbocyclyl group.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, straight or branched, containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (ie, C 1-10 alkyl), further preferably contains 1-8 carbon atoms (C 1-8 alkyl), more preferably contains 1-6 carbon atoms (i.e. C 1-6 alkyl) or 1-4 carbon atoms (i.e. C 1-4 alkyl) or 2-4 carbon atoms (ie C 2-4 alkyl), for example "C 1-6 alkyl” means that the group is an alkyl group, and the number of carbon atoms on the carbon chain Between 1-6 (specifically 1, 2, 3, 4, 5 or 6).
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl , n-octyl, etc.
  • haloalkyl refers to an alkyl group as defined above in which one, two or more or all of the hydrogen atoms are replaced by halogen.
  • Haloalkyl may be C 1-8 haloalkyl, C 1-6 haloalkyl or C 1-4 haloalkyl.
  • Representative examples of haloalkyl include CCl3 , CF3 , CHCl2 , CH2Cl , CH2Br , CH2I , CH2CF3 , CHF2 , CF2CH3 , CF2CF3 , and the like .
  • alkoxy refers to -O-alkyl, as defined above, ie, containing 1-20 carbon atoms, preferably, 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy oxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-dimethylpropoxy, 1-ethylpropoxy, etc.
  • alkenyl refers to a straight or branched chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms having at least one double bond.
  • the alkenyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (ie, C 2-10 alkenyl), more preferably 2-8 carbon atoms (C 2-8 alkene) base), more preferably containing 2-6 carbon atoms (i.e. C 2-6 alkenyl), 2-5 carbon atoms (i.e. C 2-5 alkenyl), 2-4 carbon atoms (i.e.
  • C 2-4 alkenyl) alkenyl 1,3-butadienyl, and the like.
  • C 2-6 alkenyl means that the group is an alkenyl , and the number of carbon atoms on the carbon chain is between 2-6 (specifically 2, 3, 4, 5 or 6).
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond.
  • the alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (ie C 2-10 alkynyl), more preferably 2-8 carbon atoms (C 2-8 alkynyl) base), more preferably containing 2-6 carbon atoms (ie C 2-6 alkynyl), 2-5 carbon atoms (ie C 2-5 alkynyl), 2-4 carbon atoms (ie C 2-4 alkynyl) alkynyl), 2-3 carbon atoms (ie C 2-3 alkynyl), 2 carbon atoms (ie C 2 alkynyl), for example "C 2-6 alkynyl” means that the group is alkynyl , and the number of carbon atoms on the carbon chain is between 2-6 (specifically 2, 3, 4, 5
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms, preferably containing 3-12 carbon atoms (ie, C 3-12 cycloalkyl), more preferably containing 4-12 carbon atoms (C 4-12 cycloalkyl), 3-10 carbon atoms (C 3-10 cycloalkyl), more preferably 4-9 carbon atoms (C 4-9 cycloalkyl), 4-8 carbon atoms (C 4-8 cycloalkyl), 3-6 carbon atoms (C 3-6 cycloalkyl), 4-6 carbon atoms (C 4-6 cycloalkyl), 5- 6 carbon atoms (C 5-6 cycloalkyl).
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
  • cycloalkenyl means consisting of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings, however, the system is unsaturated, i.e. there is at least one CC double bond but no aromatic system.
  • cycloalkenyl preferably contains 3-12 carbon atoms (ie, C 3-12 cycloalkenyl), more preferably 3-10 carbon atoms (C 3-10 cycloalkenyl), Further preferred are 4-9 carbon atoms (C 4-9 cycloalkenyl), 3-6 carbon atoms (C 3-6 cycloalkenyl), 4-6 carbon atoms (C 4-6 cycloalkenyl), 5-6 carbon atoms (C 5-6 cycloalkenyl).
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent, non-aromatic structure, containing 3-20 ring atoms, of which 1, 2 , 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C.
  • heterocyclyl preferably contains 3-12 ring atoms, more preferably 4-12 ring atoms, or 4-10 ring atoms, or 3-10 ring atoms, or 3-8 ring atoms, or 4-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms.
  • the heteroatoms are preferably 1-4, more preferably 1-3 (ie 1, 2 or 3).
  • Examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, 1,4-isoxazinyl, pyrazolyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazine base, pyranyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spirocyclyl refers to a fully saturated or partially unsaturated (but not fully saturated aromatic), 5- to 20-membered monocyclic polycyclic ring that shares one carbon atom (called a spiro atom).
  • the spirocyclic group is preferably 6 to 14 membered, more preferably 6 to 10 membered, 7 to 9 membered, 9 membered or 10 membered.
  • the spiro rings are divided into single spiro rings, double spiro rings or poly spiro rings, preferably single spiro rings, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro ring.
  • spiro rings include
  • spirocycloalkyl refers to a fully saturated spirocyclyl group.
  • spiroheterocyclyl refers to a heteroatom (preferably 1 or 2 heteroatoms, preferably N, O and/or N) in which one or more ring atoms of the spiro ring are selected from sulfur, silicon, phosphorus, oxygen and/or nitrogen. or S heteroatom), the remaining ring atoms are carbon.
  • the spiroheterocyclyl group is preferably 6 to 14 membered, more preferably 6 to 10 membered or 7 to 9 membered or 10 membered.
  • the spiro heterocycles can be divided into single spiro heterocycles, double spiro heterocycles or poly spiro heterocycles, preferably single spiro heterocycles, more preferably 4-membered/4-membered, 4-membered /5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocycle, preferably each ring contains 1 heteroatom selected from N, O and/or S.
  • spiroheterocycles include
  • spiroheterocycloalkyl refers to a fully saturated spiroheterocyclyl group.
  • bridged cyclyl refers to a fully saturated or partially unsaturated (but not fully saturated aromatic) all carbon polycyclic ring having 5 to 20 ring atoms and two rings sharing 3 or more ring atoms . Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, more preferably bicyclic.
  • bridge rings include:
  • bridged cycloalkyl refers to a fully saturated bridged ring group.
  • bridged heterocyclyl refers to a heteroatom (preferably 1 or 2 heteroatoms, preferably N, O and/or N) in which one or more ring atoms of the bridged ring are selected from sulfur, silicon, phosphorus, oxygen and/or nitrogen. or S heteroatom), the remaining ring atoms are carbon.
  • the bridged heterocyclyl group is preferably 6 to 14 membered, more preferably 6 to 10 membered, 7 to 9 membered, 7 membered or 8 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycles, preferably bicyclic or tricyclic, more preferably bicyclic.
  • bridged heterocycles include
  • bridged heterocycloalkyl refers to a fully saturated bridged heterocyclyl group.
  • fused ring group refers to a fully saturated or partially unsaturated (but not fully saturated aromatic) all carbon polycyclic ring having 5 to 20 membered ring atoms and two rings sharing 2 ring atoms. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, more preferably bicyclic.
  • union loops include:
  • fused cycloalkyl refers to a fully saturated fused ring group.
  • fused heterocyclyl refers to a heteroatom (preferably 1 or 2 heteroatoms, preferably N, O and/or N) in which one or more ring atoms in the ring are selected from sulfur, silicon, phosphorus, oxygen and/or nitrogen. or S heteroatom), the remaining ring atoms are carbon.
  • the fused heterocyclic group is preferably 6 to 14 membered, more preferably 6 to 10 membered, 7 to 10 membered, 7 membered, 8 membered or 9 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic or polycyclic bridged heterocycles, preferably bicyclic.
  • fused heterocycles include
  • fused heterocycloalkyl refers to a fully saturated fused heterocyclyl group.
  • heterocycloalkyl refers to a monocyclic, saturated “heterocyclyl” or “heterocycle” as defined above, and the ring atoms are as defined above, ie, containing 3 to 20 ring atoms ("3 -20-membered heterocycloalkyl”), the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein the heteroatoms
  • the atoms are each independently selected from N, O or S.
  • It preferably contains 3 to 12 ring atoms ("3-12 membered heterocycloalkyl”), more preferably contains 3 to 10 ring atoms ("3-10 membered heterocycloalkyl”), still more preferably contains 3 to 8 ring atoms ("3-8 membered heterocycloalkyl”), more preferably 4 to 7 ring atoms ("4-7 membered heterocycloalkyl”), still more preferably 5-10 ring atoms ("5-10 membered heterocycloalkyl”), more preferably containing 5-6 ring atoms ("5-6 membered heterocycloalkyl”).
  • each instance of heterocycloalkyl is independently optionally substituted, eg, unsubstituted (an "unsubstituted heterocycloalkyl") or substituted by one or more substituents substituted (a "substituted heterocycloalkyl").
  • heterocycloalkyl have been given above in the “heterocyclyl” or “heterocycle” section, also including, but not limited to, aziridine, oxiranyl, thiirane base, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , oxathicyclohexyl, oxazolidinyl, dioxanyl, dithiahexyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinidine, etc.
  • aryl refers to monocyclic, bicyclic and tricyclic rings containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms
  • aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, or pyrenyl, and the like.
  • heteroaryl refers to an aromatic monocyclic or polycyclic ring containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, and more preferably a 5-6 membered structure system wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3 indivual.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl , tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiooxadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridyl, purinyl, indium dolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrole Do[2,3-b]pyr
  • the aforementioned groups may be optionally substituted with one or more (eg, 1, 2, or 3) substituents.
  • the terms “pharmaceutically acceptable salts”, “pharmaceutically acceptable salts” or “pharmaceutically acceptable salts” are intended to be suitable, within the scope of sound medical judgment, for use in contact with mammalian, particularly human tissue, without undue Salts commensurate with a reasonable benefit/risk ratio for toxicity, irritation, allergic reactions, etc.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the present application, or separately by reacting the free base or free acid with a suitable reagent. For example, the free base function can be reacted with a suitable acid.
  • solvate means a physical association of a compound of the present application with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of isolation. Solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate” encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • isotopically-labeled analogs refers to isotopically-labeled molecules of compounds of Formulas I to II, thereby providing isotopically-labeled analogs that may have improved pharmacological activity.
  • Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S.
  • isotopically labeled compounds can be used to study the distribution of medicinal molecules in tissues.
  • deuterium 3 H and carbon 13 C are more widely used because of their ease of labeling and detection.
  • substitution of certain heavy isotopes, such as deuterium ( 2 H) can enhance metabolic stability, prolong half-life and thus provide therapeutic advantages for the purpose of reducing dosage.
  • Isotopically labeled compounds are generally synthesized from labeled starting materials, and their synthesis is accomplished using known synthetic techniques as for non-isotopically labeled compounds.
  • prodrug refers to a drug that is converted to the parent drug in vivo. Prodrugs are often useful because in some cases they may be easier to administer than the parent drug. For example, they are bioavailable by oral administration, whereas the parent is not. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug.
  • An example of, but not limited to, a prodrug can be any compound of formula I, which is administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once in Intracellular water solubility is beneficial, which is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity.
  • Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.
  • the terms “optionally substituted”, “optionally substituted”, “optionally substituted” mean that the hydrogen at the substitutable position of the group is unsubstituted, or replaced by one or more Substituents are substituted, the substituents are preferably selected from the following group of substituents: halogen, hydroxyl, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 -membered aryl group or 5-10-membered heteroaromatic ring group, wherein the C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3 -10 cycloal
  • treatment generally refers to the administration of a compound or formulation described herein to achieve the desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, disorder, and condition, ie, preventing its progression; or (b) alleviating the symptoms of the disease, disorder, and condition, ie, causing Regression of the disease or symptoms; or (c) amelioration or elimination of the disease, disorder and condition or one or more symptoms associated with the disease.
  • terapéuticaally effective amount means (i) treating a particular disease, disorder or condition, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, disorder or condition, or (iii) delaying as described herein
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • pharmaceutically acceptable excipients refers to those excipients that are not significantly irritating to organisms (eg, humans) and that do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • This application designs a class of compounds with novel structures, which provides a new direction for the development of SOS-1 inhibitors.
  • In vitro enzyme activity inhibitory activity studies show that these compounds have strong inhibitory effects on SOS-1, and can be used as promising compounds for the treatment of SOS-1 inhibitor-mediated diseases.
  • the present application studies a specific synthesis method, which is simple in process, convenient in operation, and beneficial for large-scale industrial production and application.
  • the structures of the compounds of the present application were determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) or/and liquid chromatography (HPLC) and/or electrospray ionization mass spectrometry (ESI-MS) .
  • NMR nuclear magnetic resonance
  • LC-MS liquid chromatography-mass spectrometry
  • HPLC liquid chromatography
  • ESI-MS electrospray ionization mass spectrometry
  • DIPEA N,N-Diisopropylethylamine
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • EDTA ethylenediaminetetraacetic acid
  • BSA bovine serum albumin
  • IGEPAL octylphenyl-polyethylene glycol
  • E-2 (981 mg, 4.36 mmol), THF (10 mL), water (5 mL) and sodium hydroxide (523 mg, 13.08 mmol) were sequentially added to a 100 mL reaction flask, and the temperature was raised to 60° C. for 3 h. The completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, and the pH value was adjusted to 5 with 1N hydrochloric acid. The solid was precipitated, and the solid was collected by suction filtration. The solid was rinsed with water and dried to obtain E-3 (699 mg, 3.31 mmol, 76%).
  • ESI-MS (m/z): 212.08 [M+H] + .
  • E-4 (598 mg, 2.85 mmol), pyridine (2 mL) and 15 mL of acetonitrile were added to a 100 mL reaction flask, and ethyl chloroformate (616 mg, 5.70 mmol) dissolved in 5 mL of acetonitrile was added dropwise at 0°C. After completion, the temperature was slowly raised to the reflux of the system. After the completion of the reaction, the heating was stopped and cooled to room temperature, the reaction solution was poured into cold water, a white solid was precipitated, and E-5 (552 mg, 2.34 mmol, 85%) was obtained after filtration. ESI-MS (m/z): 237.08 [M+H] + .
  • E-9a (70 mg, 138 ⁇ mol) was dissolved in DMF (1 mL), DIPEA (93.6 ⁇ L, 555 ⁇ mol) and TBTU (66.4 mg, 207 ⁇ mol) were added and the mixture was stirred at room temperature for 15 min. Then acetic acid (12.4 mg, 207 ⁇ mol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by chromatography (acetonitrile/water) to give the product E-10a (55 mg, 100.74 ⁇ mol, 73%). ESI-MS (m/z): 551.20 [M+H] + .
  • Methyl 2-amino-4-methoxybenzoate 500 mg, 2.76 mmol was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of iodomethane (588 mg, 4.14 mmol) and anhydrous carbonic acid Cesium (1.80 g, 5.52 mmol), the system was reacted at 100° C. for 48 h, and no raw materials remained in LCMS monitoring.
  • G-1 300 mg, 1.54 mmol was dissolved in glacial acetic acid (15 mL), then an aqueous solution of potassium cyanate (250 mg, 3.08 mmol, 5 mL) was added, and the system was reacted at room temperature for 24 h, and then continued to react at 100 ° C for 4 h , LCMS monitoring raw materials no remaining. The temperature was cooled to room temperature, water (50 mL) was added to the reaction solution, a large amount of solid was precipitated, filtered and dried to obtain G-2 (250 mg, 1.21 mmol, 79%).
  • ESI-MS m/z: 207.10 [M+H] + .
  • G-3b-1 (0.21 g, 1.08 mmol) was dissolved in glacial acetic acid (10 mL), followed by the addition of an aqueous solution of potassium cyanate (0.17 g, 2.16 mmol, 2 mL). The system was reacted overnight at room temperature. The next day, the system was reacted at 80 °C for 3 h, and no raw materials remained in LCMS monitoring. After filtration, the filter cake was washed with water to give G-3b (0.16 g, 0.78 mmol, 72% yield). ESI-MS (m/z): 207.11 [M+H] + .
  • G-3c-1 (500mg, 2.09mmol) was dissolved in glacial acetic acid (15mL), then potassium cyanate aqueous solution (339mg, 4.18mmol, 5mL) was added, the whole system was stirred at room temperature for 24h, and then at 100°C Continue to stir the reaction for 4h, TLC monitoring and tracking until no raw material remains. The temperature was cooled to room temperature, water (50 mL) was added to the reaction solution, a large amount of solid was precipitated, filtered and dried to obtain G-3c (300 mg, 1.19 mmol, 57%). ESI-MS (m/z): 251.12 [M+H] + .
  • G-3b (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by addition of B-7a (74 mg, 0.36 mmol), benzotriazol-1-oxyhexafluorophosphate Tris(dimethylamino)phosphorus (140 mg, 0.31 mmol), 1,8-diazabicycloundec-7-ene (55 mg, 0.36 mmol), and the system was reacted at room temperature for 8 h.
  • G-3c (40 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by B-7a (50 mg, 0.24 mmol), 1,8-diazabicycloundec -7-ene (73mg, 0.48mmol), benzotriazole-1-oxytris(dimethylamino)phosphorus hexafluorophosphate (93mg, 0.21mmol), the whole system was stirred and reacted at room temperature for 24h, followed by TLC monitoring until No raw material remained, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride (50 mL ⁇ 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • B-7a 50 mg, 0.24 mmol
  • 1,8-diazabicycloundec -7-ene 73mg, 0.48
  • N,N-dimethylformamide (10 mL), C-6 (50 mg, 0.23 mmol), and (S)-3-hydroxytetrahydrofuran p-toluenesulfonate (56 mg, 0.23 mmol) were sequentially added to a 50 mL reaction flask. and cesium carbonate (90 mg, 0.28 mmol).
  • N,N-dimethylformamide (10 mL), 48-1 (25 mg, 0.086 mmol), B-7b (29 mg, 0.13 mmol), and benzotriazole-hexafluorophosphate were sequentially added to a 50 mL reaction flask.
  • -Oxytris(dimethylamino)phosphorus 53 mg, 0.12 mmol
  • 1,8-diazabicycloundec-7-ene 41 mg, 0.27 mmol
  • the synthetic method is the same as compound 48-1, except that (R)-3-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester is used instead of (S)-3-hydroxytetrahydrofuran-p-toluenesulfonate to obtain 50 -1, 80% yield, ESI-MS (m/z): 392.17 [M+H] + .
  • 53-1 (105 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of B-7b (91 mg, 0.41 mmol), benzotriazol-1-oxyhexafluorophosphate Tris(dimethylamino)phosphorus (154 mg, 0.35 mmol), 1,8-diazabicycloundec-7-ene (122 mg, 0.81 mmol), and the system was reacted at room temperature for 8 h.
  • G-3a 300 mg, 1.05 mmol was dissolved in N,N-dimethylformamide (30 mL), followed by B-7b (239 mg, 1.27 mmol), 1,8-diazabicycloundec -7-ene (484mg, 3.18mmol), benzotriazole-1-oxytris(dimethylamino)phosphorus hexafluorophosphate (610mg, 1.38mmol), the whole system was stirred and reacted at room temperature for 24h, followed by TLC monitoring until No raw material remained, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride (50 mL ⁇ 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • B-7b 239 mg, 1.27 mmol
  • 1,8-diazabicycloundec -7-ene 484mg, 3.18m
  • 57-1 (50 mg, 0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of cesium carbonate (72 mg, 0.22 mmol), 1-methyl-6-oxo-1,6 - Dihydropyridine-3-boronic acid pinacol ester (40 mg, 0.17 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.4 mg, 0.006 mmol) under nitrogen Replace three times, so that the whole system is under nitrogen atmosphere. The system was refluxed and stirred at 100 °C, and the reaction was carried out for 3 h. No remaining raw materials were monitored by TLC.
  • G-3a (300 mg, 1.05 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by B-7a (260 mg, 1.27 mmol), 1,8-diazabicycloundec -7-ene (484mg, 3.18mmol), benzotriazole-1-oxytris(dimethylamino)phosphorus hexafluorophosphate (610mg, 1.38mmol), the whole system was stirred and reacted at room temperature for 24h, followed by TLC monitoring until No raw material remained, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride (50 mL ⁇ 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • B-7a 260 mg, 1.27 mmol
  • 1,8-diazabicycloundec -7-ene (484mg, 3.
  • 57-1 (50 mg, 0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of cesium carbonate (72 mg, 0.22 mmol), 3-hydroxymethylbenzeneboronic acid (21 mg, 0.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.4 mg, 0.006 mmol), which was replaced three times with nitrogen, and the whole system was placed under a nitrogen atmosphere. The system was stirred under reflux at 100 °C, and the reaction was carried out for 3 h, and no remaining raw materials were monitored by TLC.
  • 57-1 (50 mg, 0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of (4-carbamoylphenyl)boronic acid (27 mg, 0.17 mmol), [1,1' -Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10mg, 0.01mmol) and cesium carbonate (107mg, 0.33mmol), nitrogen was replaced three times, the system was reacted at 100°C for 3h.
  • 57-1 (50 mg, 0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of (3-carbamoylphenyl)boronic acid (27 mg, 0.17 mmol), [1,1' -Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10mg, 0.01mmol) and cesium carbonate (107mg, 0.33mmol), nitrogen was replaced three times, the system was reacted at 100°C for 3h.
  • 57-1 (300 mg, 0.66 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of cesium carbonate (420 mg, 1.29 mmol), N-Boc-1,2,5,6-tetra Hydropyridine-4-boronic acid pinacol ester (263 mg, 0.85 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (29 mg, 0.04 mmol), replaced three times with nitrogen, The entire system was placed under a nitrogen atmosphere. The system was stirred under reflux at 100 °C, and the reaction was carried out for 3 h, and no remaining raw materials were monitored by TLC.
  • 64-1 (142 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of B-7b (156 mg, 0.69 mmol), benzotriazol-1-oxyhexafluorophosphate Tris(dimethylamino)phosphorus (265 mg, 0.60 mmol), 1,8-diazabicycloundec-7-ene (210 mg, 1.38 mmol), and the system was reacted at room temperature for 8 h.
  • This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12D.
  • Compounds were assayed for K by homogeneous time-resolved fluorescence (HTRF) binding of GST-KRas G12D bound by anti-GST-Europium (FRET donor) to His-tagged hSOS1 (FRET acceptor) bound by anti-6His-XL665 - Inhibition of Ras G12D with hSOS1.
  • HTRF time-resolved fluorescence
  • Buffers (5 mM HEPES pH 7.4, 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BSA pH 7.0, 0.0025% IGEPAL and 100 mM KF);
  • GST-hK-RasG12D 10 nM (final concentration) and anti-GST-Europium 2 nM (final concentration) were mixed in assay buffer and kept at room temperature prior to use.
  • His-tagged hSOS1 20 nM (final concentration) and anti-6His-XL665 10 nM (final concentration) were mixed in assay buffer and kept at room temperature prior to use.
  • the compounds to be tested were dissolved in DMSO at a concentration 100 times the experimental concentration. Pipette 50nL into black microtiter plates by using Hummingbird liquid handler or Echo acoustic system.
  • IC50 values were calculated and analyzed using a 4-parameter logistic model.

Abstract

一类式(I)化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐及其用途。式(I)中各基团如说明书中所定义。

Description

一种具有抗肿瘤活性的化合物及其用途
相关申请的交叉引用
本申请要求于2021年02月10日向中国国家知识产权局提交的第202110183102.1号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请涉及医药技术领域，具体而言，涉及作为SOS1抑制剂的化合物以及所述化合物的制备方法及用途。
背景技术
目前已知的RAS家族共有三个基因：KRAS(Kirsten大鼠肉瘤病毒癌基因同源物)，
NRAS(神经母细胞瘤RAS病毒致癌基因同源物)和HRAS(Harvey鼠肉瘤病毒致癌基因)。RAS家族蛋白是一类小分子GTP酶，也是第一个在人类肿瘤中被鉴定出来的致癌基因。RAS家族蛋白具有弱的固有GTP酶活性和缓慢的核苷酸交换率。如NF1的GTP酶活化蛋白(GAP)的结合增加了RAS家族蛋白的GTP酶活性。
RAS酶的突变与肿瘤发生密切相关，在不同类型的肿瘤中，RAS突变类型也不同。在人类肿瘤中，KRAS突变(例如氨基酸G12、G13、Q61、A146)是最为常见的，约占85％，NRAS(例如氨基酸G12、G13、Q61、A146)和HRAS(例如氨基酸G12、G13、Q61)分别占12％和3％。RAS家族蛋白的改变(例如突变、过表达、基因扩增)亦已描述为针对诸如以下癌症药物的抗性机制：EGFR抗体西妥昔单抗(cetuximab)及帕尼单抗(panitumumab))及EGFR酪氨酸激酶抑制剂奥希替尼(osimertinib)。对于致癌的RAS突变体，GAP活性被削弱或大大降低，导致永久性激活，这是致癌的RAS信号传导基础。由于GTP对它的结合位点具有皮摩尔亲和力，缺乏其他明确定义的口袋，以及RAS与GEF、GAP和效应子通过扩展的和平坦的蛋白质-蛋白质相互作用表面相互作用，因此直接抑制RAS已证明是极具挑战性和难以成药的。因此，通过靶向上游鸟嘌呤核苷酸交换因子蛋白SOS，抑制RAS的激活可能会有新的希望。
SOS存在两个人类同种型，即SOS1和SOS2，但大多数研究都集中在SOS1上。人SOS1包括1333个氨基酸(15kDa)，由N端结构域、Dbl同源性(DH)结构域、pleckstrin同源性(PH)结构域，包括Ras交换子基序(Rem)结构域和Cdc25结构域以及C端区域。其中，PH、Rem和Cdc25为SOS cat核心催化结构域的组分。
在过去的几十年中，RAS家族蛋白-SOS1蛋白相互作用获得了越来越多的认可。另外，最近，已经进行研究将合理设计和筛选平台组合以鉴定对SOS1的小分子抑制剂，即与SOS1结合并且抑制与RAS家族蛋白的蛋白-蛋白相互作用的化合物。如CN110167928/CN111372932以及WO2018172250/WO2019201848，描述了喹唑啉及其类似物的SOS1抑制剂。
尽管已公开了一些SOS1小分子抑制剂，但目前还没有SOS1抑制剂开发上市，因此开发新的具有上市潜力的，具有更好药效、药代结果的化合物仍是迫切需要的。本申请设计了系列具有通式所示的新结构的化合物，并发现具有此类结构的化合物呈现出优异的效果和作用，对SOS1抑制剂的开发具有积极意义。
发明概述
本申请的一方面，提供了一种如下式(I)所示的化合物，及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物，
Figure PCTCN2022075635-appb-000001
其中，
Figure PCTCN2022075635-appb-000002
表示单键或双键，
Figure PCTCN2022075635-appb-000003
和
Figure PCTCN2022075635-appb-000004
不同时为双键，
Figure PCTCN2022075635-appb-000005
和
Figure PCTCN2022075635-appb-000006
不同时为双键；
当
Figure PCTCN2022075635-appb-000007
为单键时，X选自C(R A)(R A)、NR A、O、S；当
Figure PCTCN2022075635-appb-000008
为双键时，X选自CR A、N；
R A每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-10环烷基、-C(O)-3-10元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基C(O)-C 3-10环烷基、-C 1-6烷基C(O)-3-10元杂环基和5-10元杂芳基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-10环烷基、-C(O)-3-10元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基C(O)-C 3-10环烷基、-C 1-6烷基C(O)-3-10元杂环基和5-10元杂芳基均任选地被一个或多个相同或不同的R a1取代；
R a1每次出现各自独立地选自-OR c、-NR cR c、卤素、-CN、-C(O)R c、-C(O)OR c、-C(O)NR cR c、-S(O) 2R c、-S(O) 2NR cR c、-NHC(O)R c、-N(C 1-4烷基)C(O)R c、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c取代；
R c每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
当
Figure PCTCN2022075635-appb-000009
为单键时，Y选自C 1-6烷基；当
Figure PCTCN2022075635-appb-000010
为双键时，Y选自O、S；
当
Figure PCTCN2022075635-appb-000011
为单键时，Z选自CH、N、O、S，当Z选自O、S时，R 2不存在；当
Figure PCTCN2022075635-appb-000012
为双键时，Z选自C和N，当Z选自N时，R 2不存在；
当
Figure PCTCN2022075635-appb-000013
为双键时，R 1是O；当
Figure PCTCN2022075635-appb-000014
为单键时，R 1选自-O-R B、任选取代的C 2-4烷基、C 2-4烯基、C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基；
其中，当
Figure PCTCN2022075635-appb-000015
为单键，且R 1选自-O-R B时，R B选自C 1-6烷基、C 3-10环烷基和3-10元杂环基，其中所述C 1-6烷基、C 3-10环烷基和3-10元杂环基任选地被一个或多个相同或不同的R b1取代；
R b1每次出现各自独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、- C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基均任选地被一个或多个相同或不同的R c1取代；
R c1每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
或者，当
Figure PCTCN2022075635-appb-000016
为单键，且R 1选自C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基时，所述C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R a2取代；
R a2每次出现独立地选自-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C 0-4烷基C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-4烷基)C(O)R c2、-NHC(O)OR c2、氧代基、＝NH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c2取代；
R c2每次出现独立地选自氢、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
或者当
Figure PCTCN2022075635-appb-000017
为单键，且R 1选自C 2-4烷基和C 2-4烯基时，所述C 2-4烷基和C 2-4烯基任选地被一个或多个相同或不同的R b2取代；
R b2每次出现独立地选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3和-C(O)-N(C 1-4烷基)-OR c3；
R c3每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
R 2选自氢、C 1-6烷基、-O-C 1-4烷基、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基)(C 1-4烷基)和卤素；
R 3选自氢、C 1-4烷基、C 1-4卤代烷基、-O-C 1-4烷基、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基)(C 1-4烷基)和卤素；
环A选自C 4-12环烷基、4-12元杂环基、C 6-10芳基、5-12元杂芳基；
R 4每次出现分别独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基、-CH＝CH-C 3-6环烷基、-CH＝CH-C 6-10芳基、-CH＝CH-5-10元杂芳基、-CH＝CH-3-6元杂环基、-CH＝CH-CH 2-C 3-6环烷基、-CH＝CH-CH 2-C 6-10芳基、-CH＝CH-CH 2-5-10元杂芳基、-CH＝CH-CH 2-3-6元杂环基、-SO 2-C 1-4烷基，其中C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基、-CH＝CH-C 3-6环烷基、-CH＝CH-C 6-10芳基、-CH＝CH-5-10元杂芳基、-CH＝CH-3-6元杂环基、-CH＝CH-CH 2-C 3-6环烷基、- CH＝CH-CH 2-C 6-10芳基、-CH＝CH-CH 2-5-10元杂芳基、-CH＝CH-CH 2-3-6元杂环基的基团，所述基团任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)、C 2-6烯基、C 2-6炔基的基团所取代；其中w＝0,1,2,3,4。
本申请的另一方面，提供了一种药物组合物，其包含本申请所述的式(I)所示的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，以及药学上可接受的辅料。
本申请的另一方面，提供了本申请所述的式(I)所示的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐或本申请所述的药物组合物在制备治疗由SOS1抑制剂介导的疾病的药物中的用途。
本申请的另一方面，提供了本申请所述的式(I)所示的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐或本申请所述的药物组合物在制备治疗RAS突变导致的疾病的药物中的用途。
发明详述
本申请的目的在于提供一种作为SOS1抑制剂的具有全新结构的化合物、其化合物的制备方法及其治疗由SOS1抑制剂介导的疾病方面的用途。
本申请的一方面，提供了一种如下式(I)所示的化合物，及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物，
Figure PCTCN2022075635-appb-000018
其中，
Figure PCTCN2022075635-appb-000019
表示单键或双键，
Figure PCTCN2022075635-appb-000020
和
Figure PCTCN2022075635-appb-000021
不同时为双键，
Figure PCTCN2022075635-appb-000022
和
Figure PCTCN2022075635-appb-000023
不同时为双键；
当
Figure PCTCN2022075635-appb-000024
为单键时，X选自C(R A)(R A)、NR A、O、S；当
Figure PCTCN2022075635-appb-000025
为双键时，X选自CR A、N；
R A每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-10环烷基、-C(O)-3-10元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基C(O)-C 3-10环烷基、-C 1-6烷基C(O)-3-10元杂环基和5-10元杂芳基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-10环烷基、-C(O)-3-10元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基C(O)-C 3-10环烷基、-C 1-6烷基C(O)-3-10元杂环基和5-10元杂芳基均任选地被一个或多个相同或不同的R a1取代；
R a1每次出现各自独立地选自-OR c、-NR cR c、卤素、-CN、-C(O)R c、-C(O)OR c、-C(O)NR cR c、-S(O) 2R c、-S(O) 2NR cR c、-NHC(O)R c、-N(C 1-4烷基)C(O)R c、氧代基、C 1-6烷基、 C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c取代；
R c每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
当
Figure PCTCN2022075635-appb-000026
为单键时，Y选自C 1-6烷基；当
Figure PCTCN2022075635-appb-000027
为双键时，Y选自O、S；
当
Figure PCTCN2022075635-appb-000028
为单键时，Z选自CH、N、O、S，当Z选自O、S时，R 2不存在；当
Figure PCTCN2022075635-appb-000029
为双键时，Z选自C和N，当Z选自N时，R 2不存在；
当
Figure PCTCN2022075635-appb-000030
为双键时，R 1是O；当
Figure PCTCN2022075635-appb-000031
为单键时，R 1选自-O-R B、任选取代的C 2-4烷基、C 2-4烯基、C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基；
其中，当
Figure PCTCN2022075635-appb-000032
为单键，且R 1选自-O-R B时，R B选自C 1-6烷基、C 3-10环烷基和3-10元杂环基，其中所述C 1-6烷基、C 3-10环烷基和3-10元杂环基任选地被一个或多个相同或不同的R b1取代；
R b1每次出现各自独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基均任选地被一个或多个相同或不同的R c1取代；
R c1每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
或者，当
Figure PCTCN2022075635-appb-000033
为单键，且R 1选自C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基时，所述C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R a2取代；
R a2每次出现独立地选自-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C 0-4烷基C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-4烷基)C(O)R c2、-NHC(O)OR c2、氧代基、＝NH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6- 10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c2取代；
R c2每次出现独立地选自氢、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
或者当
Figure PCTCN2022075635-appb-000034
为单键，且R 1选自C 2-4烷基和C 2-4烯基时，所述C 2-4烷基和C 2-4烯基任选地被一个或多个相同或不同的R b2取代；
R b2每次出现独立地选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3和-C(O)-N(C 1-4烷基)-OR c3；
R c3每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
R 2选自氢、C 1-6烷基、-O-C 1-4烷基、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基)(C 1-4烷基)和卤素；
R 3选自氢、C 1-4烷基、C 1-4卤代烷基、-O-C 1-4烷基、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基)(C 1-4烷基)和卤素；
环A选自C 4-12环烷基、4-12元杂环基、C 6-10芳基、5-12元杂芳基；
R 4每次出现分别独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基、-CH＝CH-C 3-6环烷基、-CH＝CH-C 6-10芳基、-CH＝CH-5-10元杂芳基、-CH＝CH-3-6元杂环基、-CH＝CH-CH 2-C 3-6环烷基、-CH＝CH-CH 2-C 6-10芳基、-CH＝CH-CH 2-5-10元杂芳基、-CH＝CH-CH 2-3-6元杂环基、-SO 2-C 1-4烷基，其中C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基、-CH＝CH-C 3-6环烷基、-CH＝CH-C 6-10芳基、-CH＝CH-5-10元杂芳基、-CH＝CH-3-6元杂环基、-CH＝CH-CH 2-C 3-6环烷基、-CH＝CH-CH 2-C 6-10芳基、-CH＝CH-CH 2-5-10元杂芳基、-CH＝CH-CH 2-3-6元杂环基的基团，所述基团任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)、C 2-6烯基、C 2-6炔基的基团所取代；其中w＝0,1,2,3,4。
在本申请的一些实施方案中，上述式(I)中，
Figure PCTCN2022075635-appb-000035
表示单键或双键，
Figure PCTCN2022075635-appb-000036
和
Figure PCTCN2022075635-appb-000037
不同时为双键，
Figure PCTCN2022075635-appb-000038
和
Figure PCTCN2022075635-appb-000039
不同时为双键；
当
Figure PCTCN2022075635-appb-000040
为单键时，X选自C(R A)(R A)、NR A、O、S；当
Figure PCTCN2022075635-appb-000041
为双键时，X选自CR A、N；
R A每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-10环烷基、-C(O)-3-10元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基C(O)-C 3-10环烷基、-C 1-6烷基C(O)-3-10元杂环基和5-10元杂芳基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-10环烷基、-C(O)-3-10元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基C(O)-C 3-10环烷基、-C 1-6烷基C(O)-3-10元杂环基和5-10元杂芳基均任选地被一个或多个相同或不同的R a1取代；
R a1每次出现各自独立地选自-OR c、-NR cR c、卤素、-CN、-C(O)R c、-C(O)OR c、-C(O)NR cR c、-S(O) 2R c、-S(O) 2NR cR c、-NHC(O)R c、-N(C 1-4烷基)C(O)R c、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c取代；
R c每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳 基、3-10元杂环基和5-10元杂芳基；
当
Figure PCTCN2022075635-appb-000042
为单键时，Y选自C 1-6烷基；当
Figure PCTCN2022075635-appb-000043
为双键时，Y选自O、S；
当
Figure PCTCN2022075635-appb-000044
为单键时，Z选自CH、N、O、S，当Z选自O、S时，R 2不存在；当
Figure PCTCN2022075635-appb-000045
为双键时，Z选自C和N，当Z选自N时，R 2不存在；
当
Figure PCTCN2022075635-appb-000046
为双键时，R 1是O；当
Figure PCTCN2022075635-appb-000047
为单键时，R 1选自-O-R B、任选取代的C 2-4烷基、C 2-4烯基、C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基；
其中，当
Figure PCTCN2022075635-appb-000048
为单键，且R 1选自-O-R B时，R B选自C 1-6烷基、C 3-10环烷基和3-10元杂环基，其中所述C 3-10环烷基和3-10元杂环基任选地被一个或多个相同或不同的R b1取代；
R b1每次出现各自独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基均任选地被一个或多个相同或不同的R c1取代；
R c1每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
或者，当
Figure PCTCN2022075635-appb-000049
为单键，且R 1选自C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基时，所述C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R a2取代；
R a2每次出现独立地选自-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C 0-4烷基C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-4烷基)C(O)R c2、-NHC(O)OR c2、氧代基、＝NH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6- 10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c2取代；
R c2每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
或者当
Figure PCTCN2022075635-appb-000050
为单键，且R 1选自C 2-4烷基和C 2-4烯基时，所述C 2-4烷基和C 2-4烯基任选地被一个或多个相同或不同的R b2取代；
R b2每次出现独立地选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3和-C(O)-N(C 1-4烷基)-OR c3；
R c3每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
R 2选自氢、C 1-6烷基、-O-C 1-4烷基、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基)(C 1-4烷基)和卤素；
R 3选自氢、C 1-4烷基、C 1-4卤代烷基、-O-C 1-4烷基、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷 基)(C 1-4烷基)和卤素；
环A选自C 4-12环烷基、4-12元杂环基、C 6-10芳基、5-12元杂芳基；
R 4每次出现分别独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基、-CH＝CH-C 3-6环烷基、-CH＝CH-C 6-10芳基、-CH＝CH-5-10元杂芳基、-CH＝CH-3-6元杂环基、-CH＝CH-CH 2-C 3-6环烷基、-CH＝CH-CH 2-C 6-10芳基、-CH＝CH-CH 2-5-10元杂芳基、-CH＝CH-CH 2-3-6元杂环基、-SO 2-C 1-4烷基，其中C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基、-CH＝CH-C 3-6环烷基、-CH＝CH-C 6-10芳基、-CH＝CH-5-10元杂芳基、-CH＝CH-3-6元杂环基、-CH＝CH-CH 2-C 3-6环烷基、-CH＝CH-CH 2-C 6-10芳基、-CH＝CH-CH 2-5-10元杂芳基、-CH＝CH-CH 2-3-6元杂环基的基团，所述基团任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)、C 2-6烯基、C 2-6炔基的基团所取代；其中w＝0,1,2,3,4。
在本申请的一些实施方案中，
Figure PCTCN2022075635-appb-000051
为单键，X选自C(R A)(R A)、NR A、O、S；其中，R A选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-8芳基、3-6元杂环基、-C(O)-C 1-6烷基、-C(O)-C 4-6环烷基、-C(O)-3-6元杂环基、-C 1-6烷基-C(O)C 1-6烷基、-C 1-6烷基-C(O)-C 4-6环烷基、-C 1-6烷基-C(O)-3-6元杂环基和5-6元杂芳基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-8芳基、3-6元杂环基、-C(O)-C 1-6烷基、-C(O)-C 4-6环烷基、-C(O)-3-6元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基-C(O)-C 4-6环烷基、-C 1-6烷基-C(O)-3-6元杂环基和5-6元杂芳基任选地被一个或多个相同或不同的R a1取代。
在本申请的一些实施方案中，R a1每次出现独立地选自-OR c、-NR cR c、卤素、-CN、-C(O)R c、-C(O)OR c、-C(O)NR cR c、-S(O) 2R c、-S(O) 2NR cR c、-NHC(O)R c、-N(C 1-4烷基)C(O)R c、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基任选地被一个或多个相同或不同的R c取代。
在本申请的一些实施方案中，R c每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基。
在本申请的一些实施方案中，
Figure PCTCN2022075635-appb-000052
为单键，X选自C(R A)(R A)、NR A、O、S；其中，R A选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-8芳基、3-6元杂环基、-C(O)-C 1-6烷基、-C(O)-C 4-6环烷基、-C(O)-3-6元杂环基、-C 1-6烷基-C(O)C 1-6烷基、-C 1-6烷基-C(O)-C 4-6环烷基、-C 1-6烷基-C(O)-3-6元杂环基和5-6元杂芳基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-8芳基、3-6元杂环基、-C(O)-C 1-6烷基、-C(O)-C 4-6环烷基、-C(O)-3-6元杂环基、-C 1-6烷基-C(O)C 1-6烷基、-C 1-6烷基-C(O)-C 4-6环烷基、-C 1-6烷基-C(O)-3-6元杂环基和5-6元杂芳基任选地被一个或多个相同或不同的R a1取代。
在本申请的一些实施方案中，R a1每次出现各自独立地选自-OR c、-NR cR c、卤素、-CN、-C(O)R c、-C(O)OR c、-C(O)NR cR c、-S(O) 2R c、-S(O) 2NR cR c、-NHC(O)R c、-N(C 1-4烷基)C(O)R c、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基任选地被一个或多个相同或不同的R c取代。
在本申请的一些实施方案中，R c每次出现各自独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、环丁基、乙烯基、乙炔基、C 4-6环烷基、C 6芳基、5-6元杂环基和5-6元杂芳基。
在本申请的一些实施方案中，
Figure PCTCN2022075635-appb-000053
为单键，且R 1是-O-R B；
其中，R B选自C 1-6烷基、C 3-10环烷基和3-10元杂环基，其中所述C 1-6烷基、C 3-10环烷基和3-10元杂环基任选地被一个或多个相同或不同的R b1取代；
R b1每次出现独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c1取代；
R c1每次出现各自独立地选自氢、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基。
在本申请的一些实施方案中，
Figure PCTCN2022075635-appb-000054
为单键，且R 1是-O-R B；
其中，R B选自C 1-6烷基、C 3-10环烷基和3-10元杂环基，其中所述C 3-10环烷基和3-10元杂环基任选地被一个或多个相同或不同的R b1取代；
R b1每次出现独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c1取代；
R c1每次出现各自独立地选自氢、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基。
在本申请的一些实施方案中，
Figure PCTCN2022075635-appb-000055
为单键，且R 1是-O-R B；其中，R B选自C 1-4烷基、C 4-6环烷基和4-6元杂环基，所述C 1-4烷基、C 4-6环烷基和4-6元杂环基任选地被一个或多个相同或不同的R b1取代；在一些实施方案中，R B选自正丙基、异丙基、正丁基、异丁基、任选被一个或多个R b1取代的甲基、任选被一个或多个R b1取代的乙基、任选被一个或多个R b1取代的C 5-6环烷基、任选被一个或多个R b1取代的5-6元杂环基。
在本申请的一些实施方案中，
Figure PCTCN2022075635-appb-000056
为单键，且R 1是-O-R B；其中，R B选自C 1-4烷基、C 4-6环烷基和4-6元杂环基，所述C 4-6环烷基和4-6元杂环基任选地被一个或多个相同或不同的R b1取代；在一些实施方案中，R B选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、任 选被一个或多个R b1取代的C 5-6环烷基、任选被一个或多个R b1取代的5-6元杂环基。
在一些实施方案中，R b1每次出现独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)-C(O)R c1、氧代基、C 1-4烷基。
在一些实施方案中，R b1每次出现独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)-C(O)R c1、氧代基。
在一些实施方案中，R c1每次出现独立地选自氢、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；更进一步优选的，R c1每次出现各自独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、环丁基。
在本申请的一些实施方案中，
Figure PCTCN2022075635-appb-000057
为单键，且R 1选自C 3-10碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基，其中所述C 3-10碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R a2取代。
在一些实施方案中，
Figure PCTCN2022075635-appb-000058
为单键，且R 1选自C 4-9环烷基、C 4-9环烯基、C 6-10芳基、4-10元杂环基和5-10元杂芳基，所述C 4-9环烷基、C 4-9环烯基、C 6-10芳基、4-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R a2取代。
在一些实施方案中，R 1为选自C 4单环烷基、C 5单环烷基、C 6单环烷基、C 7单环烷基、3元/4元螺环烷基、4元/3元螺环烷基、4元/4元螺环烷基、4元/5元螺环烷基、5元/4元螺环烷基、5元/5元螺环烷基、4元/6元螺环烷基、6元/4元螺环烷基、3元/4元稠环烷基、4元/3元稠环烷基、4元/4元稠环烷基、4元/5元稠环烷基、5元/4元稠环烷基、5元/5元稠环烷基、4元/6元稠环烷基、6元/4元稠环烷基、C 4单环烯基、C 5单环烯基、C 6单环烯基、C 7单环烯基、3元/4元螺环烯基、4元/3元螺环烯基、4元/4元螺环烯基、4元/5元螺环烯基、5元/4元螺环烯基、5元/5元螺环烯基、4元/6元螺环烯基、6元/4元螺环烯基、3元/4元稠环烯基、4元/3元稠环烯基、4元/4元稠环烯基、4元/5元稠环烯基、5元/4元稠环烯基、5元/5元稠环烯基、4元/6元稠环烯基、6元/4元稠环烯基、4元单杂环基、5元单杂环基、6元单杂环基、7元单杂环基、3元/4元螺杂环基、4元/3元螺杂环基、4元/4元螺杂环基、4元/5元螺杂环基、5元/4元螺杂环基、5元/5元螺杂环基、4元/6元螺杂环基、6元/4元螺杂环基、3元/4元稠杂环基、4元/3元稠杂环基、4元/4元稠杂环基、4元/5元稠杂环基、5元/4元稠杂环基、5元/5元稠杂环基、4元/6元稠杂环基、6元/4元稠杂环基、5元/6元稠杂环基、C 6芳基、5元杂芳基、6元杂芳基的基团，其中，所述基团任选被一个或多个相同或不同的R a2取代。
在一些实施方案中，R a2每次出现独立地选自C 1-6烷基、-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-4烷基)C(O)R c2、-NHC(O)OR c2、-C 0-4烷基-C(O)NR c2R c2、氧代基、＝NH。
在一些实施方案中，R a2每次出现独立地选自C 1-6烷基、-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-4烷基)C(O)R c2、-NHC(O)OR c2、-C 0-4烷基-C(O)NR c2R c2、氧代基、＝NH，其中所述 C 1-6烷基任选被一个或多个相同或不同的R c2取代。
在一些实施方案中，R c2每次出现独立地选自氢、OH、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；在一些实施方案中，R c2每次出现独立地选自氢、OH、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、C 3-6环烷基、苯基、3-6元杂环基。
在一些实施方案中，R c2每次出现独立地选自氢、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；在一些实施方案中，R c2每次出现独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、C 3-6环烷基、苯基、3-6元杂环基。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000059
为单键，且R 1选自C 2-4烷基和C 2-4烯基时，所述C 2- 4烷基和C 2-4烯基任选地被一个或多个R b2取代；
R b2每次出现独立地选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3和-C(O)N(C 1-4烷基)-OR c3；
R c3每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000060
为双键时，
Figure PCTCN2022075635-appb-000061
为单键。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000062
为单键时，
Figure PCTCN2022075635-appb-000063
为双键。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000064
为单键时，X选自C(R A)(R A)、NR A、O、S；当
Figure PCTCN2022075635-appb-000065
为双键时，X选自CR A、N；
R A每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、-C(O)-C 1-6烷基、-C 1-6烷基-C(O)-C 1-6烷基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C(O)-C 1-6烷基、-C 1-6烷基-C(O)-C 1-6烷基均任选地被一个或多个(例如，1个、2个或3个)相同或不同的R a1取代；R a1每次出现各自独立地选自卤素、-CN、C 1-6烷基。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000066
为单键时，X选自C(R A)(R A)、NR A、O、S；当
Figure PCTCN2022075635-appb-000067
为双键时，X选自CR A、N；R A每次出现独立地选自氢和C 1-6烷基。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000068
为单键时，X选自NR A和O；当
Figure PCTCN2022075635-appb-000069
为双键时，X为N；R A每次出现独立地选自氢和C 1-6烷基(例如，甲基、乙基)。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000070
为单键时，Z为N；当
Figure PCTCN2022075635-appb-000071
为双键时，Z为C。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000072
为双键时，R 1是O；当
Figure PCTCN2022075635-appb-000073
为单键时，R 1选自-O-R B、任选取代的C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000074
为单键时，R 1选自-O-R B、任选取代的C 3-6碳环基、C 6-10芳基、3-6元杂环基和5-6元杂芳基。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000075
为单键时，R 1选自-O-R B，R B选自C 1-6烷基、C 3-6环 烷基和3-6元杂环基，其中所述C 1-6烷基、C 3-6环烷基和3-6元杂环基任选地被一个或多个(例如，1个、2个或3个)相同或不同的R b1取代。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000076
为单键时，R 1选自-O-R B，R B选自C 1-6烷基、C 5-6环烷基和5-6元杂环基，其中所述C 1-6烷基、C 3-6环烷基和3-6元杂环基任选地被一个或多个(例如，1个、2个或3个)相同或不同的R b1取代。
在一些实施方案中，R b1每次出现各自独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基均任选地被一个或多个(例如，1个、2个或3个)相同或不同的R c1取代；R c1每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-10芳基、3-6元杂环基和5-6元杂芳基。
在一些实施方案中，R b1每次出现各自独立地选自-OR c1、-C(O)R c1、-C(O)OR c1和C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个(例如，1个、2个或3个)相同或不同的R c1取代；R c1每次出现各自独立地选自氢、C 1-6烷基(例如，甲基、叔丁基)和C 3-6环烷基(例如，环丙基)。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000077
为单键，且R 1选自C 3-8碳环基、C 6-10芳基、3-10元杂环基和5-10元杂芳基时，所述C 3-8碳环基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个(例如，1个、2个或3个)相同或不同的R a2取代；
R a2每次出现独立地选自-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C 0-4烷基C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-4烷基)C(O)R c2、-NHC(O)OR c2、氧代基、＝NH、C 1-6烷基、C 2-6烯基、C 2-6炔基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基任选地被一个或多个相同或不同的R c2取代；
R c2每次出现独立地选自氢、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-10芳基、3-6元杂环基和3-6元杂芳基。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000078
为单键，且R 1选自C 5-6碳环基、C 6芳基、5-10元杂环基和5-10元杂芳基时，所述C 5-6碳环基、C 6芳基、5-10元杂环基和5-10元杂芳基任选地被一个或多个(例如，1个、2个或3个)相同或不同的R a2取代；
R a2每次出现独立地选自-OR c2、-C(O)R c2、-C 0-4烷基C(O)NR c2R c2、氧代基、C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个(例如，1个、2个或3个)相同或不同的R c2取代；
R c2每次出现独立地选自氢、OH、C 1-6烷基和5-6元杂环基。
在本申请的一些实施方案中，当
Figure PCTCN2022075635-appb-000079
为单键，R 1选自
Figure PCTCN2022075635-appb-000080
Figure PCTCN2022075635-appb-000081
在本申请的一些实施方案中，R 2选自氢、C 1-4烷基、-O-C 1-4烷基和卤素；在一些实施方案中，R 2选自氢、-F、-Cl、-Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、-O-CH 3、-O-CH 2CH 3、-O-CH 2CH 2CH 3、-O-CHCH 3CH 3、-O-CH 2CHCH 3CH 3、-O-CH 2CH 2CH 2CH 3；当Z选自O、S时，R 2不存在。
在本申请的一些实施方案中，R 2为-O-CH 3。
在本申请的一些实施方案中，R 3选自氢、C 1-4烷基、-O-C 1-4烷基和卤素；在一些实施方案中，R 3选自氢、-F、-Cl、-Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基。
在本申请的一些实施方案中，环A选自C 4-8的环烷基、4-8元杂环基、C 6-10芳基、5-10元杂芳基；在一些实施方案中，环A选自C 5-6的环烷基、5-6元杂环基、C 6-10芳基、5-6元杂芳基；在一些实施方案中，环A选自C 6芳基和5-6元杂芳基。
在一些实施方案中，环A为苯基或噻吩基 。
在本申请的一些实施方案中，R 4每次出现独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基，其中C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、 -O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)、C 2-6烯基、C 2-6炔基的基团所取代；其中w＝0,1,2,3,4。
在一些实施方案中，R 4每次出现独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基，其中C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)的基团所取代；其中w＝0，1,2,3,4。
在一些实施方案中，R 4每次出现独立地为选自氢、-NH 2、甲基、乙基、正丙基、异丙基、F、Cl、Br、CHF 2、CF 3、-O-CH 3、-O-CF 3、3元杂环基、4元杂环基、5元杂环基、6元杂环基、环丙基、环丁基、环戊基、环己基、C 6芳基、5元杂芳基、6元杂芳基，所述3元杂环基、4元杂环基、5元杂环基、6元杂环基、环丙基、环丁基、环戊基、环己基、C 6芳基、5元杂芳基、6元杂芳基任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)的基团所取代；其中w＝0,1,2,3,4。
在一些实施方案中，R 4每次出现独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6芳基、5-6元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6芳基、-O-5-6元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6芳基、-O-CH 2-5-6元杂芳基、-O-CH 2-3-6元杂环基，其中C 3-6环烷基、C 6芳基、5-6元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6芳基、-O-5-6元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6芳基、-O-CH 2-5-6元杂芳基、-O-CH 2-3-6元杂环基任选被一个或多个(例如，1个、2个或3个)相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)、C 2-6烯基、C 2-6炔基的基团所取代；其中w＝0,1,2,3,4。
在一些实施方案中，R 4每次出现独立地选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、C 6芳基、3-6元杂环基，其中C 6芳基和3-6元杂环基任选被一个或多个(例如，1个、2个或3个)相同或不同的选自羟基、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1- 4烷基)(C 1-4烷基)的基团所取代；其中w＝0,1,2或3。
在一些实施方案中，R 4每次出现独立地选自-NH 2、-CF 3、-F、-CHF 2、-CF 2CH 3、
Figure PCTCN2022075635-appb-000082
Figure PCTCN2022075635-appb-000083
且w＝0,1,2或3。
在本申请的一些实施方案中，结构单元
Figure PCTCN2022075635-appb-000084
选自
Figure PCTCN2022075635-appb-000085
Figure PCTCN2022075635-appb-000086
在本申请的一些实施方案中，式(I)所示的化合物，及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物，其中式(I)所示的化合物具有如式(Ia)所示结构：
Figure PCTCN2022075635-appb-000087
在本申请的一些实施方案中，式(I)所示的化合物，及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物，其中，式(I)所示的化合物具有选自式(Ⅱ)～式(Ⅹ)所示的结构：
Figure PCTCN2022075635-appb-000088
Figure PCTCN2022075635-appb-000089
其中，式(Ⅱ)～式(Ⅹ)中各取代基定义同式(I)。
在本申请的一些实施方案中，式(I)所示的化合物，及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物，其中，式(I)所示的化合物进一步具有选自式(Ⅱ)～式(Ⅹa)所示的结构：
Figure PCTCN2022075635-appb-000090
式(Ⅱ)～式(Ⅹa)中各取代基定义同式(I)。
在本申请的一些实施方案中，式(I)所示的化合物，及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物，其中，所述化合物选自如下化合物：
Figure PCTCN2022075635-appb-000091
Figure PCTCN2022075635-appb-000092
Figure PCTCN2022075635-appb-000093
Figure PCTCN2022075635-appb-000094
本申请目的还包括提供制备式(I)所示化合物，及其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物的方法。
所述方法例如可以使用下述方案中示出的方法来制备，可以通过卤化及亲核取代进行连接，合成得到目标化合物。
Figure PCTCN2022075635-appb-000095
另一方面，本申请还提供一种药用组合物，其包含本申请所示的化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物，以及药学上可接受的辅料。
本申请所示的化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物的给药可以以纯的形式或适宜的药物组合物的形式的任何可接受的给药方式来进行。本申请的药物组合物可通过将本申请所示的化合物与适宜的药学上可接受的辅料相组合而制备。本申请的药物组合物可配制成固态或液态制剂。一般地，上述药物组合物可以采用制剂领域中常规的赋形剂通过常规的制备方法制备。
另一方面，本申请还提供本申请所示的化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物或本申请所述的药物组合物在制备治疗由SOS1抑制剂介导的疾病的药物中的用途。
在一些实施方案中，所述SOS1抑制剂介导的疾病为癌症或肿瘤，及其相关疾病。
另一方面，本申请还提供本申请所示的化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物或本申请所述的药物组合物在制备治疗RAS突变导致的疾病的药物中的用途。
在一些实施方案中，所述RAS突变导致的疾病包括1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征(LEGIUS SYNDROME)和遗传性牙龈纤维瘤病。
另一方面，本申请还提供一种预防和/或治疗由SOS1抑制剂介导的疾病的方法，其包括向患者施用治疗有效剂量的本申请的所示化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物、同位素标记的类似物或本申请所述药物组合物。
在一些实施方案中，所述SOS1抑制剂介导的疾病为癌症或者肿瘤，及其相关疾病。
另一方面，本申请还提供一种预防和/或治疗RAS突变导致的疾病的方法，其包括向患者施用治疗有效剂量的本申请的所示化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物、同位素标记的类似物或本申请所述药物组合物。
在一些实施方案中，所述RAS突变导致的疾病包括1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科 斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征(LEGIUS SYNDROME)和遗传性牙龈纤维瘤病。
另一方面，本申请还提供用于预防和/或治疗由SOS1抑制剂介导的疾病的本申请所示的化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物、同位素标记的类似物或本申请所述的药物组合物。
另一方面，本申请还提供用于预防和/或治疗RAS突变导致的疾病的本申请所示的化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物、同位素标记的类似物或本申请所述的药物组合物。
另一方面，本申请还提供本申请所示的化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物或本申请所述的药物组合物在治疗由SOS1抑制剂介导的疾病中的用途。
另一方面，本申请还提供本申请所示的化合物，或其立体异构体、几何异构体、互变异构体、药用盐、前药、水合物、溶剂合物或同位素标记的类似物或本申请所述的药物组合物在治疗RAS突变导致的疾病中的用途。
在以下描述中，阐述了某些具体细节以便提供对本申请的各种实施方案的全面理解。然而，本领域技术人员将理解，可以在没有这些细节的情况下实践本发明。
除非上下文另有要求，否则在本说明书全文和权利要求书中，词语“包括/包含(comprise)”及其变型，例如“包括/包含(comprises)”和“包括/包含(comprising)”应被解释为开放式的包含性含义，即作为“包括，但不限于”。
本说明书全文中引用“一个实施方案”或“一些实施方案”意指结合该实施方案描述的特定特征、结构或特性包括在本申请的至少一个实施方案中。因此，本说明书全文中在各个地方出现的短语“在一个实施方案中”或“在一些实施方案中”不一定都指的是相同的实施方案。此外，具体特征、结构或特性可以以任何合适的方式组合在一个或多个实施方案中。
除非另外定义，否则本文使用的所有技术和科学术语具有与本申请所属领域的技术人员通常理解相同的含义。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本文所用的术语“化合物”包括化合物的所有立体异构体形式、几何异构体形式、互变异构体形式和同位素形式。
术语“取代的”或“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着同一个碳原子上的两个氢原子被氧原子取代。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。
“氨基”是指-NH 2基团。
“羧基”是指-COOH基团。
“氰基”是指-CN基团。
“羟基”是指-OH基团。
“硝基”是指-NO 2基团。
“氧代基”是指＝O取代基。
“硫代基”是指＝S取代基。
“Boc”是指叔丁氧羰基。
“卤素”以及“卤代”是指F、Cl、Br、I。
除另有规定外，“碳环基”或“碳环”是指具有从3到14个环碳原子的一种非芳香族环状烃基(“C 3-14碳环基”)，并且在该非芳香族环系统中不具有杂原子。“碳环基”包括“环烷基”和“环烯基”。在一些实施例中，碳环基基团具有3-12个环碳原子(“C 3-12碳环基”)、或4-12个环碳原子(“C 4-12碳环基”)、或3到10个环碳原子(“C 3-10碳环基”)。在一些实施例中，碳环基基团具有3到8个环碳原子(“C 3-8碳环基”)。在一些实施例中，碳环基基团具有3到7个环碳原子(“C 3-7碳环基”)。在一些实施例中，碳环基基团具有4到6个环碳原子(“C 4-6碳环基”)。在一些实施例中，碳环基基团具有5到10个环碳原子(“C 5-10碳环基”)、或5到7个环碳原子(“C 5-7碳环基”)。示例性C 3-6碳环基基团包括，但不限于环丙基(C 3)、环丙烯基(C 3)、环丁基(C 4)、环丁烯基(C 4)、环戊基(C 5)、环戊烯基(C 5)、环己基(C 6)、环己烯基(C 6)、环己二烯基(C 6)等。示例性C 3-8碳环基基团包括，但不限于前面提到的C 3-6碳环基基团以及环庚基(C 7)、环庚烯基(C 7)、环庚二烯基(C 7)、环庚三烯基(C 7)、环辛基(C 8)、环辛烯基(C 8)、二环[2.2.1]庚烷基(C 7)、二环[2.2.2]辛烷基(C 8)等。示例性C 3-10碳环基基团包括，但不限于前面提到的C 3-8碳环基基团以及环壬基(C 9)、环壬烯基(C 9)、环癸基(C 10)、环癸烯基(C 10)、八氢-1H-茚基(C 9)、十氢萘基(C 10)、螺[4.5]癸烷基(C 10)等。
如上述实例说明，在某些实施例中，该碳环基基团是单环的(“单环碳环基”)或是一种稠合的(稠环基)、桥接的(桥环基)或螺接-稠合(螺环基)的环系统，如一个双环系统(“双环碳环基”)并且可以是饱和的或可以是部分不饱和的。“碳环基”还包括其中如上所定义的该碳环基环被一个或多个芳基或杂芳基基团稠合的环系统，其中附接点是在该碳环基环上，并且在此类情况下，碳环基环系统的元数为稠合后该碳环系统的碳的数目。在某些实施例中，碳环基基团的每个例子独立地是可任选取代的，例如，未取代的(一种“未取代的碳环基”)或 被一个或多个取代基取代的(一种“取代的碳环基”)。在某些实施例中，该碳环基基团是未取代的C 3-10碳环基。在某些实施例中，该碳环基基团是一种取代的C 3-10碳环基。
除另有规定外，术语“烷基”指一价饱和脂肪族烃基团，包含1-20个碳原子的直链或支链基团，优选包含1-10个碳原子(即C 1-10烷基)，进一步优选包含1-8个碳原子(C 1-8烷基)，更优选包含1-6个碳原子(即C 1-6烷基)或1-4个碳原子(即C 1-4烷基)或2-4个碳原子(即C 2-4烷基)，例如“C 1-6烷基”指的是该基团为烷基，且碳链上的碳原子数量在1-6之间(具体地为1个、2个、3个、4个、5个或6个)。实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、新戊基、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、正庚基、正辛基等。
术语“卤代烷基”是指如上所定义的烷基中一个、两个或多个氢原子或全部氢原子被卤素取代。“卤代烷基”可以为C 1-8卤代烷基、C 1-6卤代烷基或C 1-4卤代烷基。卤代烷基的代表性例子包括CCl 3、CF 3、CHCl 2、CH 2Cl、CH 2Br、CH 2I、CH 2CF 3、CHF 2、CF 2CH 3、CF 2CF 3等。
除另有规定外，术语“烷氧基”指-O-烷基，所述烷基的定义同上，即包含1-20个碳原子，优选地，包含1-10个碳原子，较佳地1-8个碳原子，更佳地1-6个碳原子(具体地为1个、2个、3个、4个、5个或6个)。代表的例子包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、1-甲基丙氧基、2-甲基丙氧基、叔丁氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基、1,1-二甲基丙氧基、1,2-二甲基丙氧基、2,2-二甲基丙氧基、1-乙基丙氧基等。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。在一些实施方案中，烯基可以包含2-20个碳原子，优选包含2-10个碳原子(即C 2-10烯基)，进一步优选包含2-8个碳原子(C 2-8烯基)，更优选包含2-6个碳原子(即C 2-6烯基)、2-5个碳原子(即C 2-5烯基)、2-4个碳原子(即C 2-4烯基)、2-3个碳原子(即C 2-3烯基)、2个碳原子(即C 2烯基)，例如“C 2-6烯基”指的是该基团为烯基，且碳链上的碳原子数量在2-6之间(具体地为2个、3个、4个、5个或6个)。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基和1,3-丁二烯基等。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个叁键的不饱和脂肪族烃基。在一些实施方案中，炔基可以包含2-20个碳原子，优选包含2-10个碳原子(即C 2-10炔基)，进一步优选包含2-8个碳原子(C 2-8炔基)，更优选包含2-6个碳原子(即C 2-6炔基)、2-5个碳原子(即C 2-5炔基)、2-4个碳原子(即C 2-4炔基)、2-3个碳原子(即C 2-3炔基)、2个碳原子(即C 2炔基)，例如“C 2-6炔基”指的是该基团为炔基，且碳链上的碳原子数量在2-6之间(具体地为2个、3个、4个、5个或6个)。炔基的非限制性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基和1-丁炔基等。
除另有规定外，术语“环烷基”指的是具有特定碳原子数的单环饱和脂烃基，优选地包含3-12个碳原子(即C 3-12环烷基)，更优选包含4-12个碳原子(C 4-12环烷基)、3-10个碳原子(C 3-10环烷基)，进一步优选4-9个碳原子(C 4-9环烷基)、4-8个碳原子(C 4-8环烷基)、3-6个碳原子(C 3-6环烷基)、4-6个碳原子(C 4-6环烷基)、5-6个碳原子(C 5-6环烷基)。实例包括但不限于环丙基、环丁基、环戊基、环己基、甲基环丙基、2-乙基-环戊基、二甲基环 丁基等。
除另有规定外，“环烯基”是指由子基团单环烃环、双环烃环和螺-烃环构成，然而，体系是不饱和的，即存在至少一个C-C双键但没有芳香族体系。在一些实施方案中，“环烯基”优选地包含3-12个碳原子(即C 3-12环烯基)，更优选包含3-10个碳原子(C 3-10环烯基)，进一步优选4-9个碳原子(C 4-9环烯基)、3-6个碳原子(C 3-6环烯基)、4-6个碳原子(C 4-6环烯基)、5-6个碳原子(C 5-6环烯基)。
除另有规定外，术语“杂环基”指饱和或部分不饱和单环、双环或多环环状烃取代基，为非芳香结构，包含3-20个环原子，其中1个、2个、3个或更多个环原子选自N、O或S，其余环原子为C。在一些实施方案中，“杂环基”优选包含3-12个环原子，进一步优选包含4-12个环原子，或4-10个环原子，或3-10个环原子，或3-8个环原子，或4-8个环原子，或3-6个环原子，或4-6个环原子，或5-6个环原子。杂原子优选1-4个，更优选1-3个(即1个、2个或3个)。单环杂环基的实例包括氧杂环丁烷基、吡咯烷基、1,4-异噁嗪基、吡唑基、咪唑烷基、四氢呋喃基、二氢吡咯基、哌啶基、哌嗪基、吡喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺环基”是指完全饱和的或部分不饱和的(但不是完全饱和的芳香族)，5至20元单环之间共用一个碳原子(称螺原子)的多环。螺环基优选为6至14元，更优选为6至10元、7至9元、9元或10元。根据环与环之间共用螺原子的数目将螺环分为单螺环、双螺环或多螺环，优选为单螺环，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。螺环的非限制性实例包括
Figure PCTCN2022075635-appb-000096
Figure PCTCN2022075635-appb-000097
术语“螺环烷基”是指完全饱和的螺环基。
术语“螺杂环基”指螺环中一个或多个环原子选自硫、硅、磷、氧和/或氮的杂原子(优选1或2个杂原子，优选选自N、O和/或S的杂原子)，其余环原子为碳。螺杂环基优选为6至14元，更优选为6至10元或7至9元或10元。根据环与环之间共用螺原子的数目将螺杂环分为单螺杂环、双螺杂环或多螺杂环，优选为单螺杂环，更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环，优选各环中各自含有1个选自N、O和/或S的杂原子。螺杂环的非限制性实例包括
Figure PCTCN2022075635-appb-000098
Figure PCTCN2022075635-appb-000099
术语“螺杂环烷基”是指完全饱和的螺杂环基。
术语“桥环基”指完全饱和的或部分不饱和的(但不是完全饱和的芳香族)具有5至20元环原子，并且两个环共用3个或3个以上环原子的全碳多环。优选为6至14元，更优选为6至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环，优选为双环或三环，更优选为双环。桥环的非限制性实例包括：
Figure PCTCN2022075635-appb-000100
Figure PCTCN2022075635-appb-000101
术语“桥环烷基”指完全饱和的桥环基。
术语“桥杂环基”指桥环中一个或多个环原子选自硫、硅、磷、氧和/或氮的杂原子(优选1或2个杂原子，优选选自N、O和/或S的杂原子)，其余环原子为碳。桥杂环基优选为6至14元，更优选为6至10元、7至9元、7元或8元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环，优选为双环或三环，更优选为双环。桥杂环的非限制性实例包括
Figure PCTCN2022075635-appb-000102
术语“桥杂环烷基”指完全饱和的桥杂环基。
术语“稠环基”指完全饱和的或部分不饱和的(但不是完全饱和的芳香族)具有5至20元环原子，并且两个环共用2个环原子的全碳多环。优选为6至14元，更优选为6至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环，优选为双环或三环，更优选为双环。并环的非限制性实例包括：
Figure PCTCN2022075635-appb-000103
Figure PCTCN2022075635-appb-000104
术语“稠环烷基”指完全饱和的稠环基。
术语“稠杂环基”指并环中一个或多个环原子选自硫、硅、磷、氧和/或氮的杂原子(优选1或2个杂原子，优选选自N、O和/或S的杂原子)，其余环原子为碳。稠杂环基优选为6至14元，更优选为6至10元、7至10元、7元、8元或9元。根据组成环的数目可以分为双环、三环或多环桥杂环，优选为双环。稠杂环的非限制性实例包括
Figure PCTCN2022075635-appb-000105
Figure PCTCN2022075635-appb-000106
术语“稠杂环烷基”指完全饱和的稠杂环基。
除另有规定外，“杂环烷基”是指单环、饱和的如上文定义的“杂环基”或“杂环”，环原子定义同上，即包含3～20个环原子(“3-20元杂环烷基”)，杂原子数量为1～4个(1个、2个、3个或4个)，优选1～3个(1个、2个或3个)，其中杂原子各自独立地选自N、O或S。优选包含3～12个环原子(“3-12元杂环烷基”)，进一步优选包含3～10个环原子(“3-10元杂环烷基”)，更进一步优选包含3～8个环原子(“3-8元杂环烷基”)，更进一步优选包含4～7个环原子(“4-7元杂环烷基”)，更进一步优选地包含5-10个环原子(“5-10元杂环烷基”)，更进一步优选包含5-6个环原子(“5-6元杂环烷基”)。在某些实施例中，杂环烷基的每个例子独立地是可任选取代的，例如，未取代的(一种“未取代的杂环烷基”)或被一个或多个取代基取代的(一种“取代的杂环烷基”)。上文“杂环基”或“杂环”部分已给出了部分示例性的“杂环烷基”，还包括，但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、氧杂环己烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂硫杂环己基、噁唑烷基、二噁烷基、二硫杂环己基、噻唑烷基、吡咯烷基、吡唑烷基、咪唑啉啶等。
除另有规定外，术语“芳基”表示含有6-16个碳原子，或6-14个碳原子，或6-12个碳原子，或6-10个碳原子的单环、双环和三环的芳香碳环体系，优选6-10个碳原子，术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括但不限于苯基、萘基、蒽基、菲基或芘基等。
除另有规定外，术语“杂芳基”表示含有5-12元结构，或优选5-10元结构，5-8元结构，更优选5-6元结构的芳香单环或者多环环状系统，其中1个、2个、3个或更多个环原子为杂原子且其余原子为碳，杂原子独立地选自O、N或S，杂原子数量优选为1个、2个或3个。杂芳基的实例包括但不限于呋喃基、噻吩基、噁唑基、噻唑基、异噁唑基、噁二唑基、噻二唑基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、硫代二唑基、三嗪基、酞嗪基、喹啉基、异喹啉基、喋啶基、嘌呤基、吲哚基、异吲哚基、吲唑基、苯并呋喃基、苯并噻吩基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、苯并咪唑基、苯并酞嗪基、吡咯并[2,3-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基等。
上述基团可被一个或多个(例如，1个、2个或3个)取代基任选地取代。
除另有规定外，术语“药物上可接受的盐”、“药用盐”或“可药用盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐。可以在本申请化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐。例如，游离碱功能可以与合适的酸反应。
除另有规定外，术语“溶剂合物”意指本申请化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
除另有规定外，术语“同位素标记的类似物”是指式I至式II化合物中被同位素标记的分子，从而提供可能具有改善的药理活性的同位素标记的类似物。通常用作同位素标记的同位素是：氢同位素， 2H和 3H；碳同位素： 11C, 13C和 14C；氯同位素： 35Cl和 37Cl；氟同位素： 18F；碘同位素： 123I和 125I；氮同位素： 13N和 15N；氧同位素： 15O, 17O和 18O和硫同位素 35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘 3H和碳 13C，由于它们容易标记且方便检测，运用更为广泛。某些重同位素，比如重氢( 2H)，的取代能增强代谢的稳定性，延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始，用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
除另有规定外，术语“前药”是指在体内转化为母体药物的药物。前药通常是有用的，因为在某些情况下，它们可能比母体药物更容易给药。例如，它们可以通过口服而被生物利用，而母体则不能。与母体药物相比，前药在药物组合物中的溶解度也有所提高。前药的一个例子，但不限于此，可以是任何式I的化合物，其作为酯(“前药”)给药，以促进穿过细胞膜的传递，其中水溶性对迁移性有害，但一旦进入细胞内水溶性是有益的，其随后被代谢水解成羧酸，即活性实体。前药的另一个例子可以是与酸基团结合的短肽(聚氨基酸)，其中肽被代谢以显示活性部分。
除另有规定外，术语“任选取代”、“任选被……取代”、“任选……取代”指所述基团的可取代位点的氢未被取代，或被一个或多个取代基所取代，所述取代基优先选自下组的取代基：卤素、羟基、巯基、氰基、硝基、氨基、叠氮基、氧代基、羧基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、C 3-10环烷基磺酰基、3-10元杂环烷基、C 6-14芳基或5-10元杂芳环基，其中，所述C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、C 3-10环烷基磺酰基、3-10元杂环烷基、C 6-14芳基或5-10元杂芳环基可任选地被选自卤素、羟基、氨基、氰基、C 1-6烷基或C 1-6烷氧基中的一个或多个所取代，所述氧代基是指相同取代位的两个H被同一个O替代形成双键的基团，所述“＝NH”是指相同取代位的两个H被同一个-NH-替代形成双键的基团。
术语“治疗”一般是指将本申请所述化合物或制剂进行给药以获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病、病症和病况的症状，即阻止其发展；或(b)缓解疾病、病症和病况的症状，即，导致疾病或症状消退；或(c)改善或消除疾病、病症和病况或与所述疾病相关的一个或多个症状。
术语“治疗有效量”意指(i)治疗特定疾病、病症或病况，(ii)减轻、改善或消除特定疾病、病症或病况的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病症或病况的一 种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的辅料”是指对有机体(例如人)无明显刺激作用，而且不会损害活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本申请的有益效果为：
本申请设计了一类结构新颖的化合物，为SOS-1抑制剂类的药物的发展提供了一个新的方向。体外酶活抑制活性研究显示，这些化合物对SOS-1都具有较强的抑制作用，可作为治疗SOS-1抑制剂介导的疾病的前景化合物。此外，本申请研究了特定的合成方法，该合成方法工艺简单，操作便捷，利于规模化工业生产和应用。
具体实施方式
下面结合具体实施例，进一步阐述本申请。应理解，这些实施例仅用于说明本申请而不用于限制本申请的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或者按照制造厂商所建议的条件。除非另行定义，文中所使用的所有专业与科学用语与本领域专业人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本申请方法之中。文中所示的较佳实施方法与材料仅做示范之用。
本申请的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)或/和液相色谱(HPLC)和/或电喷雾离子源质谱(ESI-MS)来确定的。NMR的测定使用的仪器是Bruker AVANCE III 600MHz，LC-MS使用的仪器是LCMS WATERS ACQUITY UPLC H-Class PLUS或/和SQD2；HPLC使用的仪器是WATERS e2695_2998或/和Agilent 1100。
本申请实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
术语或缩写说明：
Et：乙基
Boc：叔丁氧羰基
BOP：苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐
DIEA：二异丙基乙胺
DMF：N,N-二甲基甲酰胺
EA：乙酸乙酯
DCM：二氯甲烷
THF：四氢呋喃
DMSO：二甲基亚砜
DIPEA：N,N-二异丙基乙胺
ACN：乙腈
HATU：O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯
Pd(dppf)Cl 2：[1,1’-双(二苯基膦基)二茂铁]二氯化钯
Pd(amphos) 2Cl 2：二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)
HEPES：4-(2-羟乙基)哌嗪-1-乙磺酸
EDTA：乙二胺四乙酸
DTT：二硫苏糖醇
BSA：牛血清白蛋白
IGEPAL：辛基苯基-聚乙烯二醇
FRET：荧光能量共振转移
一、制备例
1、中间体A-6a的合成
Figure PCTCN2022075635-appb-000107
中间体A-2的合成
在100mL的反应瓶中加入A-1(1.00g,5.05mmol)、BOP(1.12g,2.53mmol)、DIEA(1.30g,10.10mmol)和DMF(25mL)，滴加NH 4OH，室温搅拌反应2小时。反应完成后，将反应液倒入150mL水中，EA萃取三次，合并有机相并用水洗涤三次，无水Na 2SO 4干燥后浓缩除去溶剂，硅胶柱层析分离纯化得到目标产物A-2(897mg,4.55mmol,90％)。ESI-MS(m/z)：198.07[M+H] +。
中间体A-3的合成
在100mL的反应瓶中加入A-2(500mg,2.54mmol)、吡啶(2mL)、15mL乙腈，在0℃下滴加溶于5mL乙腈中的氯甲酸乙酯(551mg,5.08mmol)，滴加完成后，缓慢升温至体系回流。反应完成后，停止加热冷却至室温，将反应液倾倒入冷水中，有白色固体析出，过滤后即得A-3(464mg,2.08mmol,82％)。ESI-MS(m/z)：224.05[M+H] +。
中间体A-4的合成
室温下向A-3(464mg,2.08mmol)在甲烷磺酸(5mL)中的悬浮液中，添加DL-甲硫氨酸(466mg,3.12mmol)。将反应混合物加热至80℃持续16h。将反应混合物用冰水淬灭并且用2N NaOH溶液碱化。滤出沉淀物得到产物A-4(261mg,1.25mmol,60％)。ESI-MS(m/z)：210.03[M+H] +。
中间体A-5的合成
将A-4(261mg,1.25mmol)、(S)-四氢呋喃-3-基4-甲基苯磺酸盐(605mg,2.50mmol)和Cs 2CO 3(652mg,2.00mmol)在DMF(10mL)中的悬浮液加热至100℃持续12h。在减 压下除去溶剂，将残余物溶解于DCM中，用NaHCO 3饱和溶液萃取，并且将水相用DCM洗涤。将合并的有机层经Na 2SO 4干燥，过滤并且在真空中除去溶剂。将粗产物通过色谱法纯化，得到产物A-5(252mg,0.90mmol,72％)。ESI-MS(m/z)：280.07[M+H] +。
中间体A-6a的合成
在100mL的反应瓶中加入A-5、DIEA和适量体积的三氯氧磷，在80℃下反应2小时。反应完成后，停止加热冷却至室温，浓缩除去溶剂，所得淡黄色固体即为A-6a。ESI-MS(m/z)：298.04[M+H] +。
中间体A-6b至A-6d的合成
自不同A-1起始以合成中间体A-6a相同的方法合成中间体A-6b至A-6d
Figure PCTCN2022075635-appb-000108
2、中间体B-7a的合成
Figure PCTCN2022075635-appb-000109
中间体B-2的合成
将B-1(1.00g，3.70mmol)溶解于1,4-二噁烷(10mL)中。然后添加NEt 3(1.03mL)，并且将溶液用氮气吹扫5min。添加三丁基(1-乙氧基乙烯基)锡(1.74g，4.82mmol)和双(三苯基膦)氯化钯(II)(0.26g，0.37mmol)，并且将反应混合物加热至110℃持续反应12h。将反应用1N HCl淬灭并且用乙酸乙酯萃取。将合并的有机层经Na 2SO 4干燥，过滤并且在真空中除去溶剂。硅胶柱层析分离纯化(乙酸乙酯/石油醚)，得到产物B-2(550mg，2.36mmol，64％)。ESI-MS(m/z)：234.03[M+H] +。
中间体B-3的合成
将B-2(529mg，2.27mmol)溶解于THF中。在室温下添加(R)-(+)-2-甲基-2-丙烷亚磺酰胺(413mg；3.41mmol)和Ti(OEt) 4(1.29g，5.68mmol)，并且将所得反应混合物加热至80℃持续5h。将反应混合物冷却至室温并且用冰水淬灭。将沉淀物溶解于乙酸乙酯中并且通过硅藻土过滤。将有机层在真空中浓缩。硅胶柱层析分离纯化(乙酸乙酯/石油醚)，得到产物B-3(404mg,1.20mmol,53％)。ESI-MS(m/z)：337.08[M+H] +。
中间体B-4的合成
在-78℃下，向B-3(3.36g，10.00mmol)在THF(50mL)和水(5mL)中的搅拌溶液中添加硼氢化钠(0.68g,18.00mmol)。将反应温度升至室温并且通过TLC监测。将反应混合物用冰水淬灭，用乙酸乙酯萃取并且在真空中浓缩。硅胶柱层析分离纯化(乙酸乙酯/石油醚)将所述非对映体混合物分离。B-4是主要产物(2.33g,6.90mmol,69％)。ESI-MS(m/z)：339.09[M+H] +。
中间体B-6的合成
向B-4(1.70g，5.02mmol)在1,4-二噁烷(10mL)中的搅拌溶液中添加4M HCl的二噁烷溶液(10mL)。通过TLC监测反应。完成后，将反应混合物在真空中浓缩，过滤并且用Et 2O洗涤以获得产物B-6。所获得的中间体B-6为HCl盐形式。ESI-MS(m/z)：235.06[M+H] +。
中间体B-7a的合成
将B-6(976mg，4.17mmol)溶解于MeOH(10mL)中，添加10％钯碳(200mg)，并且将反应用H 2气体吹扫。通过TLC监测反应。完成后，将反应混合物在硅藻土上过滤，并且将滤液在真空中浓缩。将残余物用水洗涤得到产物B-7a。ESI-MS(m/z)：205.09[M+H] +。
自不同B-1起始以合成中间体B-7a相同的方法合成中间体B-7b至B-7f
Figure PCTCN2022075635-appb-000110
Figure PCTCN2022075635-appb-000111
3、中间体C-8a、C-8b的合成
Figure PCTCN2022075635-appb-000112
中间体C-2的合成
在100mL的反应瓶中加入C-1(1.00g,4.74mmol)、氢化钠(60％,379mg,9.48mmol)，在0℃下搅拌反应30min，随后滴加碘甲烷(1009mg,7.11mmol)，滴加完成后，缓慢升温至80℃。反应完成后，停止加热冷却至室温，将反应液倾倒入冷水中，EA萃取三次，合并有机相，无水Na 2SO 4干燥后浓缩除去溶剂，硅胶柱层析分离纯化得到目标产物C-2(981mg,4.36mmol,92％)。ESI-MS(m/z)：226.10[M+H] +。
中间体C-3的合成
在100mL的反应瓶中依次加入C-2(981mg,4.36mmol)、THF(10mL)、水(5mL)和氢氧化钠(523mg，13.08mmol)，升温至60℃反应3h。TLC监控反应完毕，反应液冷却至室温，用1N的盐酸调节pH值至5，析出固体，抽滤收集固体，固体用水淋洗并干燥，得到C-3(699mg，3.31mmol,76％)。ESI-MS(m/z)：212.08[M+H] +。
中间体C-4的合成
在100mL的反应瓶中加入C-3(699mg，3.31mmol)、BOP(732mg,1.66mmol)、DIEA(854mg,6.62mmol)和DMF(25mL)，滴加NH 4OH的DMF溶液(5mL)，室温搅拌反应2小时。反应完成后，将反应液倒入150mL水中，EA萃取三次，合并有机相并用水洗涤三次，无水Na 2SO 4干燥后浓缩除去溶剂，硅胶柱层析分离纯化得到目标产物C-4(598mg,2.85mmol,86％)。ESI-MS(m/z)：211.10[M+H] +。
中间体C-5的合成
在100mL的反应瓶中加入C-4(598mg,2.85mmol)、吡啶(2mL)、15mL乙腈，在0℃下滴加溶于5mL乙腈中的氯甲酸乙酯(616mg,5.70mmol)，滴加完成后，缓慢升温至体系回流。反应完成后，停止加热冷却至室温，将反应液倾倒入冷水中，有白色固体析出，过滤后即得C-5(552mg,2.34mmol,85％)。ESI-MS(m/z)：237.08[M+H] +。
中间体C-6的合成
在室温下向C-5(552mg,2.34mmol)在甲烷磺酸(5mL)中的悬浮液中添加DL-甲硫氨酸(466mg,3.12mmol)。将反应混合物加热至80℃持续16h。将反应混合物用冰水淬灭并且用2N NaOH溶液碱化。滤出沉淀物得到产物C-6(353mg,1.59mmol,68％)。ESI-MS(m/z)：223.06[M+H] +。
中间体C-7的合成
将C-6(353mg,1.59mmol)、(S)-四氢呋喃-3-基4-甲基苯磺酸盐(3.18mmol)和Cs 2CO 3(1037mg,3.18mmol)在DMF(15mL)中的悬浮液加热至100℃持续12h。在减压下除去溶剂，将残余物溶解于DCM中，用NaHCO 3(饱和)萃取，并且将水相用DCM洗涤。将合并的有机层经Na 2SO 4干燥，过滤并且在真空中除去溶剂。硅胶柱层析分离纯化，得到产物C-7(242mg,0.83mmol,52％)。ESI-MS(m/z)：293.11[M+H] +。
中间体C-8a的合成
在100mL的反应瓶中加入C-5(200mg，0.85mmol)、DIEA(219mg，1.70mmol)和三氯氧磷(5mL)，在80℃下反应2小时。反应完成后，停止加热冷却至室温，浓缩除去溶剂，所得淡黄色固体即为C-8a。ESI-MS(m/z)：255.05[M+H] +。
中间体C-8b的合成
在100mL的反应瓶中加入C-7(150mg，0.51mmol)、DIEA(133mg，1.02mmol)和三氯氧磷(5mL)，在80℃下反应2小时。反应完成后，停止加热冷却至室温，浓缩除去溶剂，所得淡黄色固体即为C-8b。ESI-MS(m/z)：311.07[M+H] +。
以下中间体可自不同C-1起始以与合成C-8a、C-8b相同方法获得。
Figure PCTCN2022075635-appb-000113
4、中间体D-7a的合成
Figure PCTCN2022075635-appb-000114
中间体D-2的合成
将D-1(15.00g，78.53mmol)溶解于甲苯(150mL)中，添加乙二醇(4.87g,78.53mmol)及催化量的对甲苯磺酸(1.35g,7.85mmol)。使反应混合物回流，直至观察到原料的完全转化为止。使溶剂在减压下蒸发，用DCM稀释残余物并用碳酸氢钠水溶液洗涤。将有机层合并，Na 2SO 4干燥并在减压下浓缩。硅胶柱层析分离纯化(正己烷：乙酸乙酯＝10:1)，得到产物D-2(13.41g,57.33mmol,73％)。ESI-MS(m/z)：235.00[M+H] +。
中间体D-3的合成
将D-2(3135mg，11.50mmol)及B-7b(1450mg,7.67mmol)溶解于无水DMSO(10mL)中，且添加DIPEA(2670μL,15.33mmol)。将反应混合物在80℃下搅拌6小时，直至达成B-5a的完全转化为止。将反应混合物过滤且通过碱性反相色谱纯化(水：乙腈＝1:4-3:4)，得到产物D-3(2.52g,6.52mmol,85％)。ESI-MS(m/z)：388.10[M+H] +。
中间体D-4的合成
将D-3(80.00g,340.33mmol)溶解于DMSO(400mL)中，再加入碳酸铯(220.53g,680.66mmol)及丙二酸二甲酯(49.42g,374.36mmol)进行反应。将所得混合物加热至80℃持续10小时。在原料完全转化之后，用乙酸乙酯稀释反应混合物且倾倒于冰冷水上。用乙酸乙酯萃取水层。将有机层合并并用0.1N甲酸水溶液洗涤。Na 2SO 4干燥有机层，并在减压浓缩。硅胶柱层析分离纯化(正己烷：乙酸乙酯＝10:3)，得到产物D-4(92.08g,190.58mmol,56％)。ESI-MS(m/z)：484.16[M+H] +。
中间体D-5的合成
将D-4(40.00g,120.95mmol)于DMSO(120mL)中，再加入氯化锂(20.32g,483.79mmol)搅拌反应，且加热至120℃持续2小时。在原料完全转化之后，用乙醚稀释所得反应混合物且倾倒于冰水中。用乙醚萃取水层，将有机层合并，Na 2SO 4干燥并在减压下浓缩。硅胶柱层析分离纯化(正己烷；乙酸乙酯＝5:1)，得到产物D-5(24.68g,58.06mmol,48％)。ESI-MS(m/z)：426.16[M+H] +。
中间体D-7a的合成
将D-5(200.0mg,0.470mmol)溶解于DMSO(2mL)及ACN(1mL)中。添加氢氧化钠水溶液(20％,313μL,1.881mmol)，且将所得混合物搅拌30分钟，直至观察到原料的完全转化为止。添加三乙胺(130μL,0.933mmol)、1-甲基-丙胺盐酸盐(62.8mg,0.583mmol)及HATU(266.3mg,0.700mmol)，且将所得混合物搅拌20分钟，直至观察到完全转化为止。添加水并用DCM稀释该混合物。用DCM萃取水层，将有机层合并并经硫酸镁干燥。所得产物D-7a。ESI-MS(m/z)：467.22[M+H] +。
以下中间体以D-7a相同合成方式获得。
Figure PCTCN2022075635-appb-000115
5、中间体E-6a的合成
Figure PCTCN2022075635-appb-000116
中间体E-2的合成
在100mL的反应瓶中加入E-1(1.00g,4.74mmol)、氢化钠(60％,379mg,9.48mmol)，在0℃下搅拌反应30min，随后滴加碘甲烷(1009mg,7.11mmol)，滴加完成后，缓慢升温至80℃。反应完成后，停止加热冷却至室温，将反应液倾倒入冷水中，EA萃取三次，合并有机相，无水Na 2SO 4干燥后浓缩除去溶剂，硅胶柱层析分离纯化得到目标产物E-2(981mg,4.36mmol,92％)。ESI-MS(m/z)：226.10[M+H] +。
中间体E-3的合成
在100mL的反应瓶中依次加入E-2(981mg,4.36mmol)、THF(10mL)、水(5mL)和氢氧化钠(523mg，13.08mmol)，升温至60℃反应3h。TLC监控反应完毕，反应液冷却至室温，用1N的盐酸调节pH值至5，析出固体，抽滤收集固体，固体用水淋洗并干燥，得到E-3(699mg，3.31mmol,76％)。ESI-MS(m/z)：212.08[M+H] +。
中间体E-4的合成
在100mL的反应瓶中加入E-3(699mg，3.31mmol)、BOP(732mg,1.66mmol)、DIEA(854mg,6.62mmol)和DMF(25mL)，滴加NH 4OH的DMF溶液(5mL)，室温搅拌反应2h。反应完成后，将反应液倒入150mL水中，EA萃取三次，合并有机相并用水洗涤三次，无水Na 2SO 4干燥后浓缩除去溶剂，硅胶柱层析分离纯化，得到目标产物E-4(598mg,2.85mmol,86％)。ESI-MS(m/z)：211.10[M+H] +。
中间体E-5的合成
在100mL的反应瓶中加入E-4(598mg,2.85mmol)、吡啶(2mL)、15mL乙腈，在0℃下滴加溶于5mL乙腈中的氯甲酸乙酯(616mg,5.70mmol)，滴加完成后，缓慢升温至体系回流。反应完成后，停止加热冷却至室温，将反应液倾倒入冷水中，有白色固体析出，过滤后即得E-5(552mg,2.34mmol,85％)。ESI-MS(m/z)：237.08[M+H] +。
中间体E-6a的合成
在100mL的反应瓶中加入E-5、DIEA和适量体积的三氯氧磷，在80℃下反应2h。反应完成后，停止加热冷却至室温，浓缩除去溶剂，所得淡黄色固体即为E-6a。ESI-MS(m/z)：334.94[M+H] +。
以下中间体可自不同E-1起始以合成E-6a相同方式获得。
Figure PCTCN2022075635-appb-000117
6、中间体E-7a的合成
Figure PCTCN2022075635-appb-000118
向E-6a(100mg，0.32mmol)在EtOH(10mL)中的悬浮液中添加B-7b(86mg,0.42mmol)。将所得反应混合物在密封管中加热至100℃持续16h。将反应混合物冷却至室温并且在减压下浓缩。将残余物溶解于乙酸乙酯中并且用饱和NaHCO 3溶液洗涤。将有机层在真空下浓缩，并且使用乙酸乙酯和己烷的混合物使所得固体结晶，即得化合物E-7a(49mg,0.10mmol，32％)。ESI-MS(m/z)：479.18[M+H] +。
以下中间体可自不同E-6a至E-6d起始以合成E-7a相同方式获得。
Figure PCTCN2022075635-appb-000119
Figure PCTCN2022075635-appb-000120
7、中间体E-10a的合成
Figure PCTCN2022075635-appb-000121
中间体E-8a的合成
在惰性气氛下进行反应。将E-7a(146mg，0.3mmol)溶解于THF(2mL)和1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮(58.5μL，0.5mmol)中并且冷却至-20℃。然后逐滴添加异丙基溴化镁(0.3mL，0.9mmol)并且将反应混合物搅拌1h。添加6-氧代-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯酮(84mg，0.4mmol)并且将反应混合物在室温下搅拌12h。将反应用NH 4Cl饱和溶液淬灭，并且用DCM萃取。减压下除去溶剂并且将残余物溶解于DMF中。将粗产物通过色谱法使用乙腈/水纯化，得到产物E-8a(141mg,0.25mmol,82％)。ESI-MS(m/z)：573.26[M+H] +。
中间体E-9a的合成
将E-8a(57.2mg，0.1mmol)溶解于二噁烷(3mL)中，并且加入HCl的二噁烷溶液(73.9μL，4M)。将反应混合物在室温下搅拌4d。在减压下除去溶剂，得到产物E-9a。ESI-MS(m/z)：509.19[M+H] +。
中间体E-10a的合成
将E-9a(70mg，138μmol)溶解于DMF(1mL)中，添加DIPEA(93.6μL，555μmol)和TBTU(66.4mg，207μmol)并且将混合物在室温下搅拌15min。然后添加乙酸(12.4mg，207μmol)并且将反应混合物在室温下搅拌1h。将反应混合物通过色谱法(乙腈/水)纯化，得到产物E-10a(55mg,100.74μmol,73％)。ESI-MS(m/z)：551.20[M+H] +。
以下中间体可自不同E-7a至E-7h起始以E-10a相同合成方式获得。
Figure PCTCN2022075635-appb-000122
8、中间体F-7a的合成
Figure PCTCN2022075635-appb-000123
中间体F-2的合成
将F-1(530mg，2.27mmol)溶解于THF中。在室温下添加(R)-(+)-2-甲基-2-丙烷亚磺酰胺(413mg；3.41mmol)和Ti(OEt) 4(1.29g，5.68mmol)，并且将所得反应混合物加热至80℃持续5h。将反应混合物冷却至室温并且用冰水淬灭。将沉淀物溶解于乙酸乙酯中并且通过硅藻土过滤。将有机层在真空中浓缩。硅胶柱层析分离纯化(乙酸乙酯：正己烷＝1:10-1:4)，得到产物F-2(418mg,1.36mmol,60％)。ESI-MS(m/z)：307.97[M+H] +。
中间体F-3的合成
在-78℃下向F-2(3.50g，10.00mmol)在THF(50mL)和水(5mL)中的搅拌溶液中添加硼氢化钠(0.61g,18.00mmol)。允许将反应温热至室温并且通过TLC监测。将反应混合物用冰水淬灭，用乙酸乙酯萃取并且在真空中浓缩。硅胶柱层析分离纯化(乙酸乙酯/石油醚)，将所述非对映体混合物分离，得到F-3是主要产物(2.16g,7.00mmol,75％)。ESI-MS(m/z)：309.99[M+H] +。
中间体F-5的合成
将F-3(500mg,1.61mmol)溶解于1，4-二氧六环(15mL)中，随后加入联硼酸频那醇酯(1.60g,6.45mmol)、乙酸钾(632mg,6.45mmol)、Pd(dppf)Cl 2(943mg,1.29mmol)，在N 2保护下将反应混合液加热至100℃并持续12小时。反应结束后将反应液冷却至室温，浓缩除去溶剂，残留物加水(50mL)溶解并用乙酸乙酯萃取三次，合并有机相干燥后减压 浓缩除去溶剂。粗产物通过硅胶柱层析(DCM：MeOH＝30：1)纯化得F-5(357mg,1.00mmol,62％)。ESI-MS(m/z)：358.16[M+H] +。
中间体F-6的合成
将F-5(500mg,1.40mmol)溶解于1，4-二氧六环(15mL)和水(3mL)中，随后加入1-(2-溴苯基)-N，N-二甲基甲胺(360mg,1.68mmol)、碳酸铯(1369mg,4.2mmol)、Pd(dppf)Cl 2(205mg,0.28mmol)，在N 2保护下将反应混合液加热至100℃并持续6小时。反应结束后将反应液冷却至室温，减压浓缩除去有机溶剂，残留物加水50mL溶解并用乙酸乙酯萃取三次，合并有机相干燥后减压浓缩除去溶剂。粗产物通过硅胶柱层析分离纯化(DCM：MeOH＝25:1)，得F-6(362mg,0.99mmol,71％)。ESI-MS(m/z)：365.16[M+H] +。
中间体F-7a的合成
将F-6(1.70g，5.02mmol)溶解在1,4-二噁烷(10mL)中，搅拌并向溶液中添加溶解在二噁烷(10mL)中的4M HCl。通过TLC监测反应。完成后，将反应混合物在真空中浓缩，过滤并且用Et 2O洗涤以获得产物F-7a(1.16g,4.47mmol,89％)。ESI-MS(m/z)：261.13[M+H] +。将化合物作为HCl盐分离。
以下中间体以F-7a相同合成方式获得。
Figure PCTCN2022075635-appb-000124
9、中间体G-3a的合成
Figure PCTCN2022075635-appb-000125
中间体G-1的合成
将2-氨基-4-甲氧基苯甲酸甲酯(500mg,2.76mmol)溶解于N,N-二甲基甲酰胺(20mL)中,接着加入碘甲烷(588mg,4.14mmol)和无水碳酸铯(1.80g,5.52mmol)，体系在100℃下反应48h,LCMS监测原料无剩余。降温至室温,向反应液中加入水(50mL),乙酸乙酯萃取(50mL×3),合并有机相,饱和氯化钠洗涤(50mL×2),无水硫酸钠干燥,减压除去溶剂,残留物柱层析分离纯化(二氯甲烷：甲醇＝80:1-30:1)得到G-1(300mg,1.54mmol，56％)。ESI-MS(m/z):196.12[M+H] +。
中间体G-2的合成
将G-1(300mg,1.54mmol)溶解于冰乙酸(15mL)中，接着加入氰酸钾的水溶液 (250mg,3.08mmol，5mL)，体系在室温下反应24h,然后在100℃下继续反应4h,LCMS监测原料无剩余。降温至室温,向反应液中加入水(50mL)，析出大量固体，过滤，干燥得G-2(250mg,1.21mmol,79％)。ESI-MS(m/z):207.10[M+H] +。
中间体G-3a的合成：
将G-2(250mg,1.21mmol)溶解四氯化碳(20mL)中，接着加入溴素(233mg,1.45mmol)，体系在室温下搅拌反应24h，LCMS监测原料无剩余，向反应液中加入水(50mL)，二氯甲烷萃取(20mL×3)，合并有机相，饱和氯化钠洗涤(50mL×2)，无水硫酸钠干燥，减压除去溶剂，残留物柱层析分离纯化(二氯甲烷：甲醇＝50:1-20:1)得G-3a(300mg,1.05mmol,87％)。ESI-MS(m/z):284.98/286.98[M+H] +。
10、中间体G-3b的合成
Figure PCTCN2022075635-appb-000126
中间体G-3b-1的合成
将2-氨基-5-甲氧基苯甲酸甲酯(0.50g,2.76mmol)溶解于四氢呋喃(50mL)中，接着加入碳酸铯(1.80g,5.52mmol)，碘甲烷(0.59g,4.14mmol)。体系在65℃下反应3h，LCMS监测原料无剩余。反应液过滤，滤液减压除去溶剂，残留物柱层析分离纯化(正己烷：乙酸乙酯＝40:1-20:1)得到G-3b-1(0.21g，1.08mmol,产率39％)。ESI-MS(m/z):196.08[M+H] +。
中间体G-3b的合成
将G-3b-1(0.21g,1.08mmol)溶解于冰醋酸(10mL)中，接着加入氰酸钾的水溶液(0.17g,2.16mmol,2mL)。体系在室温下过夜反应。次日，体系在80℃下反应3h，LCMS监测原料无剩余。过滤，滤饼用水洗涤得到G-3b(0.16g,0.78mmol,产率72％)。ESI-MS(m/z):207.11[M+H] +。
11、中间体G-3c的合成
Figure PCTCN2022075635-appb-000127
中间体G-3c-1的合成
将2-氨基-4,5-二甲氧基苯甲酸甲酯(500mg,2.37mmol)溶解于二氯甲烷(20mL)中，接着加入乙醛(115mg,2.61mmol)和醋酸硼氢化钠(962mg,4.54mmol)，整个体系在室温下搅拌反应48h，TLC监测跟踪直至原料无剩余，向反应液中加入水(50mL)，二氯甲烷萃取(50mL×3)，合并有机相，饱和氯化钠洗涤(50mL×2)，无水硫酸钠干燥，减压除去溶 剂，残留物经柱层析分离纯化(正己烷:乙酸乙酯＝20:1-4:1)得到G-3c-1(500mg,2.09mmol,88％)。ESI-MS(m/z):240.10[M+H] +。
中间体G-3c的合成
将G-3c-1(500mg,2.09mmol)溶解于冰乙酸(15mL)中,接着加入氰酸钾水溶液(339mg,4.18mmol,5mL)，整个体系在室温下搅拌反应24h，然后在100℃下继续搅拌反应4h，TLC监测跟踪直至原料无剩余。降温至室温，向反应液中加入水(50mL)，析出大量固体，过滤，干燥得G-3c(300mg,1.19mmol,57％)。ESI-MS(m/z):251.12[M+H] +。
二、实施例
实施例1化合物1的合成
Figure PCTCN2022075635-appb-000128
向A-6b(94mg，0.39mmol)在EtOH(100mL)中的悬浮液中添加B-7a(103mg，0.50mmol)和DIPEA(126mg，0.97mmol)。将所得反应混合物在密封管中加热至100℃持续16h。将反应混合物冷却至室温并且在减压下浓缩。将残余物溶解于乙酸乙酯中并且用饱和NaHCO 3溶液洗涤得化合物1(49mg,0.12mmol，31％)。ESI-MS(m/z)：410.12[M+H] +。
以下化合物可自不同中间体起始以类似方式获得,
Figure PCTCN2022075635-appb-000129
Figure PCTCN2022075635-appb-000130
Figure PCTCN2022075635-appb-000131
Figure PCTCN2022075635-appb-000132
实施例2化合物7的合成
Figure PCTCN2022075635-appb-000133
将D-7a(272mg，0.586mmol)溶解于2-丙醇(0.5mL)中。添加5N HCl水溶液(586μL,2.928mmol)，且将所得混合物在50℃下搅拌1小时，直至观察到原料的完全转化为止。利用氨水使反应混合物碱化，过滤且通过碱性反相色谱纯化(乙腈：水＝1:5-2:5)，得到化合物7(128mg,0.32mmol,54％)。ESI-MS(m/z)：405.18[M+H] +。
以下化合物可自中间体D-7b至D-7e起始以合成化合物7相同方法获得。
Figure PCTCN2022075635-appb-000134
Figure PCTCN2022075635-appb-000135
实施例3化合物14的合成
Figure PCTCN2022075635-appb-000136
将E-7d(95mg，206μmol)、1-乙基-5-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2-二氢吡啶-2-酮(103mg，412μmol)、Pd(amphos) 2Cl 2(15mg，21μmol)和Na 2CO 3(44mg，412μmol)溶解于二噁烷(5mL)、水(0.2mL)和EtOH(0.2mL)的混合物中，在50℃下搅拌3h。将反应混合物通过硅藻土过滤，用水淬灭并且用DCM萃取。将合并的有机层经MgSO 4干燥，过滤并且在真空中除去溶剂。将粗产物通过硅胶色谱法纯化，得到化合物14(61mg,122μmol,59％)。ESI-MS(m/z)：505.24[M+H] +。
以下化合物可以从不同的中间体开始以合成化合物14相同的方法获得。
Figure PCTCN2022075635-appb-000137
Figure PCTCN2022075635-appb-000138
实施例4化合物15的合成
Figure PCTCN2022075635-appb-000139
将E-10a(10mg，18.18μmol)溶解于THF(1mL)中，再加入NaH(3mg，72.70μmol)。将反应混合物在室温下搅拌5d，然后将反应用水淬灭，用DCM萃取并且在减压下除去溶剂。将粗产物通过色谱法(乙腈/水)纯化，得到产物15(7mg,14μmol,79％)。ESI-MS(m/z)：515.22[M+H] +。
以下化合物可以中间体E-10b至E-10c开始以合成化合物15相同的方法获得。
Figure PCTCN2022075635-appb-000140
实施例5化合物37的合成
Figure PCTCN2022075635-appb-000141
在惰性气氛下进行反应。将E-7h(158mg，0.30mmol)溶解于超干THF(10mL)中，再加入1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮(60μL,0.50mmol)，并冷却至-20℃。然后逐滴加入异丙基溴化镁(0.3mL,0.90mmol)并且将反应混合物搅拌1h。添加N-乙酰基-4-哌啶酮(63mg,0.45mmol)并将反应液在室温下搅拌12h。将反应液用NH 4Cl(饱和)淬灭并用DCM萃取三次(50mL×3)，合并有机相，经无水硫酸钠干燥后在减压下除去溶剂。粗产物经色谱法(乙腈/水)纯化，得到化合物37(113mg,0.19mmol,64％)。ESI-MS(m/z)：590.27[M+H] +。
化合物44
化合物44以合成化合物37相同的方法获得，ESI-MS(m/z)：534.22[M+H] +。
实施例6化合物40的合成
Figure PCTCN2022075635-appb-000142
将C-6-2(50mg，0.21mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入B-7b(72mg，0.32mmol)、六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(124mg，0.28mmol)、1,8-二氮杂二环十一碳-7-烯(97mg，0.64mmol)，体系在室温下反应8h。LCMS监测原料无剩余，反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠 洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝30:1)，得到化合物40(30mg，0.074mmol,35％)。ESI-MS(m/z)：408.12[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.26(d,J＝7.8Hz,1H),7.74(s,1H),7.72-7.70(m,2H),7.61-7.56(m,2H),6.79(s,1H),5.64-5.61(m,1H),3.93(s,3H),3.86(s,3H),3.45(s,3H),1.59(d,J＝6.6Hz,3H)。
实施例7化合物45的合成
Figure PCTCN2022075635-appb-000143
化合物45的合成
将G-3b(50mg，0.24mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入B-7a(74mg，0.36mmol)、六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(140mg，0.31mmol)、1,8-二氮杂二环十一碳-7-烯(55mg，0.36mmol)，体系在室温下反应8h。LCMS监测原料无剩余，反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝25:1)，得到化合物45(37mg，0.094mmol,39％)。ESI-MS(m/z)：393.13[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.39(d,J＝7.8Hz,1H),7.83(d,J＝3.0Hz,1H),7.36-7.30(m,2H),6.83-6.80(m,2H),6.71(s,1H),5.56(s,2H),5.49-5.47(m,1H),3.85(s,3H),3.42(s,3H),1.53(d,J＝7.2Hz,3H)。
实施例8化合物46的合成
Figure PCTCN2022075635-appb-000144
化合物46的合成：
将G-3c(40mg,0.16mmol)溶解于N,N-二甲基甲酰胺(30mL)中,接着加入B-7a(50mg,0.24mmol),1,8-二氮杂二环十一碳-7-烯(73mg,0.48mmol),六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(93mg,0.21mmol),整个体系在室温下搅拌反应24h,TLC监测跟踪直至原料无剩余,向反应液中加入水(50mL),乙酸乙酯萃取(30mL×3),合并有机相,饱和氯化钠洗涤(50mL×2),无水硫酸钠干燥,减压除去溶剂,经柱层析分离纯化(二氯甲烷:甲醇＝60:1-15:1)，得到化合物46(40mg,0.092mmol,58％)。ESI-MS(m/z):437.20[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.18(d,J＝6.0Hz,1H),7.74(s,1H),6.83-6.80(m,3H),6.72(s,1H),5.57(s,2H),5.50-5.48(m,1H),4.14(q,J＝6.0Hz,2H),3.93(s,3H),3.86(s,3H),1.53(d,J＝6.0Hz,3H),1.16(t,J＝6.0Hz,3H)。
实施例9化合物47的合成
Figure PCTCN2022075635-appb-000145
中间体47-1的合成：
将C-6(100mg，0.45mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入碘代异丙烷(84mg，0.50mmol)、碳酸钾(124mg，0.90mmol)，体系在100℃下反应2h，LCMS监测原料无剩余。反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物柱层析分离纯化(二氯甲烷：甲醇＝80:1-40:1)，得到47-1(75mg，0.28mmol,63％)ESI-MS(m/z):264.98[M+H] +。
化合物47的合成：
将47-1(75mg，0.28mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入B-7b(96mg，0.42mmol)、六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(163mg，0.36mmol)、1,8-二氮杂二环十一碳-7-烯(130mg，0.84mmol)，体系在室温下反应8h。LCMS监测原料无剩余，反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝33:1)，得到化合物47(40mg，0.092mmol,33％)。ESI-MS(m/z)：436.14[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.25(d,J＝12Hz,1H),7.83(s,1H),7.75(s,1H),7.71(d,J＝6.0Hz,1H),7.61-7.57(m,2H),6.79(s,1H),5.64-5.61(m,1H),4.66-4.63(m,1H),3.90(s,3H),3.46(s,3H),1.59(d,J＝6.0Hz,3H),1.33-1.24(m,6H)。
实施例10化合物48的合成
Figure PCTCN2022075635-appb-000146
中间体48-1的合成
在50mL的反应瓶中依次加入N，N-二甲基甲酰胺(10mL)，C-6(50mg，0.23mmol)、(S)-3-羟基四氢呋喃对甲苯磺酸酯(56mg，0.23mmol)和碳酸铯(90mg，0.28mmol)。反应体系升温至100℃下反应2h。TLC监控反应完毕，反应液浓缩至干，残留物通过薄层层析纯化(二氯甲烷：甲醇＝50:1)，得到48-1(30mg，0.10mmol,45％)。ESI-MS(m/z)：293.12[M+H] +。
化合物48的合成
在50mL的反应瓶中依次加入N，N-二甲基甲酰胺(10mL)、48-1(25mg，0.086mmol)、B-7b(29mg,0.13mmol)、六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(53mg,0.12 mmol)和1,8-二氮杂二环十一碳-7-烯(41mg,0.27mmol)，室温搅拌过夜。TLC监控反应完毕，反应液浓缩至干，残渣通过薄层层析纯化(二氯甲烷：甲醇＝50:1)，得到48(5mg，0.011mmol,13％)。ESI-MS(m/z)：464.17[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.24(d,J＝7.8Hz,1H),7.79(s,1H),7.74(s,1H),7.71(d,J＝7.2Hz,1H),7.62-7.58(m,2H),6.82(s,1H),5.65-5.62(m,1H),5.10-5.08(m,1H),3.95(s,3H),3.92-3.89(m,2H),3.86-3.84(m,1H),3.82-3.78(m,1H),3.46(s,3H),2.25-2.19(m,1H),2.00-1.98(m,1H),1.60(d,J＝7.2Hz,3H).
实施例11化合物49的合成
Figure PCTCN2022075635-appb-000147
中间体49-1的合成
合成方法同化合物48-1，只是用(R)-3-羟基四氢呋喃对甲苯磺酸酯代替(S)-3-羟基四氢呋喃对甲苯磺酸酯，得到49-1，收率为72％，ESI-MS(m/z)：293.11[M+H] +。
化合物49的合成
合成方法同化合物48，只是用49-1代替48-1，得到49，收率为22％。ESI-MS(m/z)：464.20[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.23(d,J＝7.8Hz,1H),7.78(s,1H),7.74(s,1H),7.71(d,J＝7.2Hz,1H),7.61-7.57(m,2H),6.81(s,1H),5.65-5.60(m,1H),5.09-5.08(m,1H),3.94(s,3H),3.91-3.87(m,2H),3.84-3.82(m,1H),3.81-3.77(m,1H),3.45(s,3H),2.24-2.18(m,1H),2.00-1.98(m,1H),1.58(d,J＝7.2Hz,3H).
实施例12化合物50的合成
Figure PCTCN2022075635-appb-000148
中间体50-1的合成
合成方法同化合物48-1，只是用(R)-3-(甲苯磺酰氧基)吡咯烷-1-羧酸叔丁酯代替(S)-3-羟基四氢呋喃对甲苯磺酸酯，得到50-1，收率为80％，ESI-MS(m/z)：392.17[M+H] +。
化合物50的合成
合成方法同化合物48，得到化合物50，收率为18％。ESI-MS(m/z)：563.24[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.24-8.23(m,1H)，7.84(d,J＝9.0Hz,1H),7.73(s,1H),7.70(d,J＝7.2Hz,1H),7.61-7.56(m,2H),6.82(s,1H),5.64-5.59(m,1H),5.04-4.98(m,1H),3.93(s,3H),3.56-3.53(m,1H),3.45(s,3H),3.43-3.39(m,3H),2.08-2.05(m,2H),1.58(d,J＝6.6Hz,3H),1.41(d,J＝13.2Hz,9H).
实施例13化合物51的合成
Figure PCTCN2022075635-appb-000149
化合物51的合成
在50mL的反应瓶中依次加入二氯甲烷(5mL)，50(120mg，0.21mmol)和三氟乙酸(1mL)。室温搅拌反应2h。TLC监控反应完毕，减压浓缩除去溶剂，将残留物溶于二氯甲烷(30mL)中，用饱和的碳酸氢钠溶液洗涤有机相，有机相经无水硫酸钠干燥后除去溶剂得粗产物。粗产物经薄层层析色谱法纯化(二氯甲烷：甲醇＝20:1)，得到化合物51(80mg，0.17mmol,82％)。ESI-MS(m/z)：463.19[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.23(d,J＝7.8Hz,1H),7.84(s,1H),7.74-7.71(m,2H),7.62-7.57(m,2H),6.84(s,1H),5.65-5.60(m,1H),5.10-5.09(m,1H),3.95(s,3H),3.51-3.49(m,1H),3.48(s,3H),3.44-3.41(m,1H),3.40-3.35(m,2H),2.18-2.15(m,2H),1.91(s,1H),1.60(d,J＝7.2Hz,3H).
实施例14化合物52的合成
Figure PCTCN2022075635-appb-000150
在50mL的反应瓶中依次加入51(20mg，0.043mmol)、甲酸(1mL)和甲醛水溶液(2mL)。70℃搅拌反应6h。TLC监控反应完毕，将反应液倾入饱和碳酸氢钠溶液中，乙酸乙酯萃取水相(50mL×3)，合并有机相，经无水硫酸钠干燥后减压浓缩除去溶剂，残留物经薄层层析色谱法纯化(二氯甲烷：甲醇：三乙胺＝100：3：1)，得到化合物52(15mg，0.031mmol,73％)。ESI-MS(m/z)：477.20[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.31(d,J＝7.8Hz,1H),7.83(s,1H),7.76(s,1H),7.73(d,J＝7.2Hz,1H),7.62-7.57(m,2H),6.84(s,1H),5.67-5.62(m,1H),5.13-5.09(m,1H),3.96(s,3H),3.46(s,3H),3.12-3.08(m,2H),2.78-2.75(m,2H),2.50(s,3H),2.14-2.02(m,2H),1.60(d,J＝7.2Hz,3H).
实施例15化合物53的合成
Figure PCTCN2022075635-appb-000151
中间体53-1的合成：
将C-6(150mg，0.68mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入(S)-3-(甲苯磺酰氧基)吡咯烷-1-羧酸叔丁酯(253mg，0.75mmol)、碳酸铯(264mg， 0.82mmol)，体系在100℃下反应3h，LCMS监测原料无剩余。反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物柱层析分离纯化(二氯甲烷：甲醇＝50:1-25:1)，得到53-1(105mg，0.27mmol,40％)。ESI-MS(m/z):392.10[M+H] +
化合物53的合成：
将53-1(105mg，0.27mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入B-7b(91mg，0.41mmol)、六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(154mg，0.35mmol)、1,8-二氮杂二环十一碳-7-烯(122mg，0.81mmol)，体系在室温下反应8h。LCMS监测原料无剩余，反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝25:1)，得到化合物53(88mg，0.16mmol,59％)。ESI-MS(m/z)：563.22[M+H] +。
1H NMR(600MHz，DMSO-d 6)δ8.27(m,1H),7.83(s,1H),7.75-7.66(m,2H),7.61-7.53(m,2H),6.82(s,1H),5.62-5.61(m,1H),5.03-5.00(m,1H),3.93(s,3H),3.54-3.43(m,4H),3.41(s,3H),2.09-2.05(m,2H),1.56(d,J＝7.2Hz,3H),1.42-1.40(m,9H).
实施例16化合物54的合成
Figure PCTCN2022075635-appb-000152
将53(70mg，0.12mmol)溶解于二氯甲烷(15mL)中，接着加入三氟乙酸(2mL)，体系在室温下反应3h。LCMS监测原料无剩余，减压蒸除反应液溶剂，残留物加入水(5mL)，饱和碳酸氢钠水溶液调节pH为8-9，乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠洗涤(10mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝5:1)，得到化合物54(25mg，0.054mmol,45％)。ESI-MS(m/z)：463.13[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.32(d,J＝7.8Hz,1H),7.88(s,1H),7.75-7.72(m,2H),7.61-7.58(m,2H),6.81(s,1H),5.64-5.62(m,1H),5.03-5.02(m,1H),3.93(s,3H),3.45(s,3H),3.25-3.11(m,4H),2.10-2.08(m,3H),1.60(d,J＝7.2Hz,3H).
实施例17化合物55的合成
Figure PCTCN2022075635-appb-000153
将54(30mg，0.065mmol)溶解于甲酸(4mL)中，接着加入37％甲醛水溶液(2mL)，体系在70℃反应12h。LCMS监测原料无剩余，反应液用饱和碳酸氢钠水溶液调节pH为7-8，乙酸乙酯萃取(15mL×3)，合并有机相，饱和氯化钠洗涤(15mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇：三乙胺＝100:2.5:1)，得到化合物 55(18mg，0.038mmol,58％)。ESI-MS(m/z)：477.23[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.30(d,J＝7.8Hz,1H),7.75-7.72(m,3H),7.62-7.57(m,2H),6.81(s,1H),5.66-5.62(m,1H),5.04-5.03(m,1H),3.94(s,3H),3.46(s,3H),3.05(m,1H),2.84-2.80(m,2H),2.66(m,1H),2.42(s,3H),2.40-2.34(m,1H),1.88-1.86(m,1H),1.60(d,J＝7.2Hz,3H).
实施例18化合物56的合成
Figure PCTCN2022075635-appb-000154
中间体56-1的合成
将C-6(150mg，0.68mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入4-(甲苯磺酰氧基)哌啶-1-羧酸叔丁酯(264mg，0.74mmol)、碳酸钾(186mg，1.36mmol)，体系在100℃下反应3h，LCMS监测原料无剩余。反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物柱层析分离纯化(二氯甲烷：甲醇＝70:1-20:1)，得到56-1(120mg，0.30mmol,产率44％)。ESI-MS(m/z)：406.11[M+H] +。
中间体56-2的合成
将56-1(120mg，0.30mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入B-7b(100mg，0.45mmol)、六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(170mg，0.39mmol)、1,8-二氮杂二环十一碳-7-烯(135mg，0.90mmol)，体系在室温下反应8h。LCMS监测原料无剩余，反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝25:1)，得到56-2(70mg，0.12mmol,41％)。ESI-MS(m/z)：577.26[M+H] +。
中间体56-3的合成
将56-2(35mg，0.061mmol)溶解于二氯甲烷(15mL)中，接着加入三氟乙酸(2mL)，体系在室温下反应3h。LCMS监测原料无剩余，减压蒸除反应液溶剂，残留物加入水(5mL)，饱和碳酸氢钠水溶液调节pH为8-9，乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠洗涤(10mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝5:1)，得到56-3(23mg，0.048mmol,79％)。ESI-MS(m/z)：477.15[M+H] +。化合物56的合成
将56-3(23mg，0.048mmol)溶解于甲酸(4mL)中，接着加入37％甲醛水溶液(2mL)，体系在70℃反应12h。LCMS监测原料无剩余，反应液用饱和碳酸氢钠水溶液调节 pH为7-8，乙酸乙酯萃取(15mL×3)，合并有机相，饱和氯化钠洗涤(15mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇：三乙胺＝100:2.5:1)，得到化合物56(10mg，0.020mmol,42％)。ESI-MS(m/z)：491.17[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.34(d,J＝6.0Hz,1H),7.96(s,1H),7.76(s,1H),7.72(d,J＝12.0Hz,1H),7.62-7.57(m,2H),6.81(s,1H),5.63-5.60(m,1H),4.41-4.40(m,1H),3.95(s,3H),3.45(s,3H),3.05-2.91(m,4H),2.43(s,3H),1.99-1.97(m,2H),1.80-1.78(m,2H),1.59(d,J＝6.0Hz,3H).
实施例19化合物57的合成
Figure PCTCN2022075635-appb-000155
中间体57-1的合成：
将G-3a(300mg,1.05mmol)溶解于N,N-二甲基甲酰胺(30mL)中,接着加入B-7b(239mg,1.27mmol),1,8-二氮杂二环十一碳-7-烯(484mg,3.18mmol),六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(610mg,1.38mmol),整个体系在室温下搅拌反应24h,TLC监测跟踪直至原料无剩余,向反应液中加入水(50mL),乙酸乙酯萃取(30mL×3),合并有机相,饱和氯化钠洗涤(50mL×2),无水硫酸钠干燥,减压除去溶剂,残留物经柱层析分离纯化(二氯甲烷:甲醇＝60:1-15:1)，得到57-1(350mg,0.77mmol,73％)。ESI-MS(m/z)：456.10[M+H] +。
化合物57的合成：
将57-1(50mg,0.11mmol)溶解于二氧六环(10mL)和水(2mL)中,接着加入碳酸铯(72mg,0.22mmol),1-甲基-6-氧代-1,6-二氢吡啶-3-硼酸频那醇酯(40mg,0.17mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(4.4mg,0.006mmol),用氮气置换三次,使整个体系处于氮气的氛围下。体系在100℃下回流搅拌,反应3h,TLC监测原料无剩余。向反应液中加入水(50mL),乙酸乙酯萃取(50mL×3),合并有机相,饱和氯化钠洗涤(50mL×2),无水硫酸钠干燥,减压除去溶剂,经柱层析分离纯化(二氯甲烷:甲醇＝50:1-20:1)，得到化合物57(27mg,0.056mmol,51％)。ESI-MS(m/z)：485.21[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.39(d,J＝6.0Hz,1H),8.19(s,1H),7.91(s,1H),7.76(s,1H),7.73(d,J＝6.0Hz,1H),7.63-7.58(m,3H),6.83(s,1H),6.48(d,J＝12Hz,1H),5.63-5.59(m,1H),3.95(s,3H),3.52(s,3H),3.49(s,3H),1.58(d,J＝6.0Hz,3H).
实施例20化合物58的合成
Figure PCTCN2022075635-appb-000156
中间体58-1的合成：
将G-3a(300mg,1.05mmol)溶解于N,N-二甲基甲酰胺(30mL)中,接着加入B-7a(260mg,1.27mmol),1,8-二氮杂二环十一碳-7-烯(484mg,3.18mmol),六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(610mg,1.38mmol),整个体系在室温下搅拌反应24h,TLC监测跟踪直至原料无剩余,向反应液中加入水(50mL),乙酸乙酯萃取(30mL×3),合并有机相,饱和氯化钠洗涤(50mL×2),无水硫酸钠干燥,减压除去溶剂,残留物经柱层析分离纯化(二氯甲烷:甲醇＝60:1-15:1)，得到58-1(320mg,0.68mmol,65％)。ESI-MS(m/z)：471.10[M+H] +。
化合物58的合成：
将58-1(52mg,0.11mmol)溶解于二氧六环(10mL)和水(2mL)中，接着加入碳酸铯(72mg,0.22mmol)，1-甲基-6-氧代-1,6-二氢吡啶-3-硼酸频那醇酯(40mg,0.17mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(4.4mg,0.006mmol)，用氮气置换三次,使整个体系处于氮气的氛围下。体系在100℃下回流搅拌,反应3h，TLC监测原料无剩余。向反应液中加入水(100mL)，乙酸乙酯萃取(50mL×3)，合并有机相，饱和氯化钠洗涤(50mL×2)，无水硫酸钠干燥，减压除去溶剂，经柱层析分离纯化(二氯甲烷:甲醇＝50:1-20:1)，得到化合物58(31mg,0.062mmol，56％)。ESI-MS(m/z)：500.21[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.31(d,J＝6.0Hz,1H),8.21(s,1H),7.90(s,1H),7.63(d,J＝12Hz,1H),6.84-6.81(m,3H),6.71(s,1H),6.49(d,J＝6.0Hz,1H),5.56(s,2H),5.50-5.45(m,1H),3.96(s,3H),3.52(s,3H),3.50(s,3H),1.52(d,J＝6.0Hz,3H).
实施例21化合物59的合成
Figure PCTCN2022075635-appb-000157
化合物59的合成：
将57-1(50mg,0.11mmol)溶解于二氧六环(10mL)和水(2mL)中，接着加入碳酸铯(72mg,0.22mmol)、3-羟甲基苯硼酸(21mg,0.14mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(4.4mg,0.006mmol)，用氮气置换三次，使整个体系处于氮气的氛围下。体系在100℃下回流搅拌，反应3h，TLC监测原料无剩余。向反应液中加入水(100mL)，乙酸乙酯萃取(50mL×3)，合并有机相，饱和氯化钠洗涤(50mL×2)，无水硫酸钠干燥，减压除去溶剂，残留物经柱层析分离纯化(二氯甲烷:甲醇＝50:1-15:1)，得到化合物59(30mg,0.062mmol,56％)。ESI-MS(m/z)：484.22[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.46(d,J＝6.0Hz,1H),8.23(s,1H),7.75(s,1H),7.72(d,J＝6.0Hz,1H),7.59-7.57(m,2H),7.44-7.40(m,2H),7.37-7.32(m,2H),6.85(s,1H),5.63-5.59(m,1H),5.25(t,J＝6.0Hz,1H),4.58(d,J＝4Hz,2H),3.93(s,3H),3.51(s,3H),1.57(d,J＝6.0Hz,3H).
实施例22化合物60的合成
Figure PCTCN2022075635-appb-000158
将57-1(50mg，0.11mmol)溶解于二氧六环(10mL)和水(2mL)中，接着加入(4-氨基甲酰基苯基)硼酸(27mg，0.17mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(10mg，0.01mmol)和碳酸铯(107mg，0.33mmol)，氮气置换三次，体系在100℃下反应3h。LCMS监测原料无剩余，减压蒸除溶剂，残留物中加入水(5mL)，乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠洗涤(10mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝20:1)，得到化合物60(25mg，0.050mmol,46％)。ESI-MS(m/z)：497.16[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.47(d,J＝6.0Hz,1H),8.29(s,1H),8.03(s,1H),7.97-7.96(m,2H),7.75(s,1H),7.72(d,J＝6.0Hz,1H),7.63-7.57(m,4H),7.41(s,1H),6.87(s,1H),5.61-5.60(m,1H),3.95(s,3H),3.51(s,3H),1.56(d,J＝6.0Hz,3H).
实施例23化合物61的合成
Figure PCTCN2022075635-appb-000159
将57-1(50mg，0.11mmol)溶解于二氧六环(10mL)和水(2mL)中，接着加入(3-氨基甲酰基苯基)硼酸(27mg，0.17mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(10mg，0.01mmol)和碳酸铯(107mg，0.33mmol)，氮气置换三次，体系在100℃下反应3h。LCMS监测原料无剩余，减压蒸除溶剂，残留物中加入水(10mL)，乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠洗涤(10mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物经薄层层析纯化(二氯甲烷：甲醇＝33:1)，得到化合物61(30mg，0.060mmol,55％)。ESI-MS(m/z)：497.15[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.47(d,J＝6.0Hz,1H),8.28(s,1H),8.04-8.02(m,2H),7.88(d,J＝7.2Hz,1H),7.75(s,1H),7.72(d,J＝6.0Hz,1H),7.65(d,J＝6.0Hz,1H),7.59-7.54(m,3H),7.43(s,1H),6.87(s,1H),5.61-5.60(m,1H),3.94(s,3H),3.52(s,3H),1.56(d,J＝6.0Hz,3H).
实施例24化合物62的合成
Figure PCTCN2022075635-appb-000160
中间体62-1的合成：
将57-1(300mg,0.66mmol)溶解于二氧六环(10mL)和水(2mL)中，接着加入碳酸铯(420mg,1.29mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(263mg,0.85mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(29mg,0.04mmol)，用氮气置换三次，使整个体系处于氮气的氛围下。体系在100℃下回流搅拌，反应3h，TLC监测原料无剩余。向反应液中加入水(100mL)，乙酸乙酯萃取(50mL×3)，合并有机相，饱和氯化钠洗涤(50mL×2)，无水硫酸钠干燥，减压除去溶剂，残留物经柱层析分离纯化(二氯甲烷:甲醇＝50:1-20:1)，得到62-1(220mg,0.39mmol,60％)。ESI-MS(m/z)：559.31[M+H] +。
化合物62的合成：
将62-1(150mg,0.27mmol)溶解于2M盐酸/甲醇溶液(10mL)中，体系在室温条件下搅拌过夜，TLC监测原料无剩余。减压除去溶剂，直接用作下一步。将浓缩的粗品再次溶解于二氯甲烷(20mL)中，接着加入三乙胺(54mg,0.54mmol)和乙酰氯(25mg,0.32mmol)，体系在室温下搅拌反应24h，TLC监测原料无剩余。减压除去溶剂，经柱层析分离纯化(二氯甲烷:甲醇＝60:1-15:1)，得到化合物62(55mg,0.11mmol,41％)。ESI-MS(m/z)：501.20[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.40(d,J＝6.0Hz,1H),8.05(s,1H),7.76(s,1H),7.72(d,J＝6.0Hz,1H),7.61-7.57(m,2H),6.75(s,1H),5.87-5.85(m,1H),5.61-5.59(m,1H),4.16-4.10(m,2H),3.94(s,3H),3.66-3.61(m,2H),3.46(s,3H),2.08-2.06(m,2H),2.30(s,3H),1.57(d,J＝6.0Hz,3H).
实施例25化合物63的合成
Figure PCTCN2022075635-appb-000161
化合物63的合成：
将62-1(151mg,0.27mmol)溶解于2M盐酸/甲醇溶液(10mL)中，体系在室温条件下搅拌过夜，TLC监测原料无剩余。减压除去溶剂，直接用作下一步。将浓缩的粗品再次溶解于甲酸(20mL)中，然后加入甲醛水溶液(5mL)。体系在70℃下搅拌反应24h,TLC监测原料无剩余。减压除去溶剂，残留物经柱层析分离纯化(二氯甲烷:甲醇＝60:1-10:1)，得到化合物63(37mg,0.078mmol,29％)。ESI-MS(m/z)：473.25[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.40(d,J＝7.8Hz,1H),8.04(s,1H),7.75(s,1H),7.71(d,J＝7.2Hz,1H),7.60-7.57(m,2H),6.78(s,1H),5.81-5.77(m,1H),5.60-5.58(m,1H),3.92(s,3H),3.45(s,3H),3.05-3.00(m,2H),2.57-2.55(m,2H),2.49-2.46(m,2H),2.30(s,3H),1.56(d,J＝7.2Hz,3H).
实施例26化合物64的合成
Figure PCTCN2022075635-appb-000162
中间体64-1的合成
将C-6(300mg，1.35mmol)溶解于N，N-二甲基甲酰胺(30mL)中，接着加入溴乙酸乙酯(336mg，2.03mmol)、碳酸钾(373mg，2.70mmol)，体系在100℃下反应2h，LCMS监测原料无剩余。反应液中加入水(50mL)，乙酸乙酯萃取(40mL×3)，合并有机相，饱和氯化钠洗涤(40mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物柱层析分离纯化(二氯甲烷：甲醇＝70:1-50:1)，得到64-1(142mg,0.46mmol,34％)。ESI-MS(m/z)：309.07[M+H] +。
化合物64的合成
将64-1(142mg，0.46mmol)溶解于N，N-二甲基甲酰胺(30mL)中，接着加入B-7b(156mg，0.69mmol)、六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(265mg，0.60mmol)、1,8-二氮杂二环十一碳-7-烯(210mg，1.38mmol)，体系在室温下反应8h。LCMS监测原料无剩余，反应液中加入水(50mL)，乙酸乙酯萃取(40mL×3)，合并有机相，饱和氯化钠洗涤(40mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物柱层析分离纯化(二氯甲烷：甲醇＝80:1-50:1)，得到化合物64(90mg，0.19mmol,41％)。ESI-MS(m/z)：480.18[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.25(d,J＝7.8Hz,1H),7.76(s,1H),7.73(s,1H),7.71(d,J＝6.0Hz,1H),7.61-7.59(m,2H),6.83(s,1H),5.64-5.59(m,1H),4.84(s,2H),4.20-4.19(m,2H),3.96(s,3H),3.46(s,3H),1.58(d,J＝12.0Hz,3H),1.22(t,J＝6.0Hz,3H).
实施例27化合物65的合成
Figure PCTCN2022075635-appb-000163
将64(20mg，0.042mmol)溶解于四氢呋喃(10mL)中，冰浴下加入硼氢化锂(2mg，0.092mmol)，体系在室温下反应3h。LCMS监测原料无剩余，反应用水淬灭，之后加入水(10mL)，乙酸乙酯萃取(10mL×3)，合并有机相，经饱和氯化钠洗涤(10mL×2)，无水硫酸钠干燥后减压蒸除溶剂，残留物经薄层层析纯化(二氯甲烷：甲醇＝50:3)，得到化合物65(10mg，0.023mmol,54％)。ESI-MS(m/z)：438.12[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.30(d,J＝7.8Hz,1H),7.75-7.72(m,3H),7.61-7.60(m,2H),6.80(s,1H),5.65-5.60(m,1H),4.97(d,J＝6.0Hz,1H),4.09-4.07(m,2H),3.94(s,3H),3.80-3.79(m,2H),3.46(s,3H),1.59(d,J＝12.0Hz,3H).
实施例28化合物66的合成
Figure PCTCN2022075635-appb-000164
将C-6-2(70mg，0.30mmol)溶解于N，N-二甲基甲酰胺(15mL)中，接着加入B-7e(107mg，0.45mmol)、六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(170mg，0.39mmol)和1,8-二氮杂二环十一碳-7-烯(135mg，0.90mmol)，体系在室温下反应8h。LCMS监测原料无剩余，反应液中加入30mL水，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(30mL×2)，无水硫酸钠干燥。减压蒸除溶剂，残留物薄层层析纯化(二氯甲烷：甲醇＝50:1)，得到化合物66(40mg，0.095mmol,32％)。ESI-MS(m/z)：422.18[M+H] +。 1H NMR(600MHz，DMSO-d 6)δ8.26(d,J＝7.8Hz,1H),7.80(s,1H),7.59(s,1H),7.49-7.45(m,1H),7.28(d,J＝6.0Hz,1H),6.80(s,1H),5.78-5.76(m,1H),3.94(s,3H),3.89(s,3H),3.45(s,3H),2.04(t,J＝12Hz,3H),1.58(d,J＝6.0Hz,3H).
实施例29化合物67的合成
Figure PCTCN2022075635-appb-000165
将C-6-2(250mg,1.06mmol)溶解于N,N-二甲基甲酰胺(30mL)中，接着加入B-7f(263mg,1.27mmol)，1,8-二氮杂二环十一碳-7-烯(484mg,3.18mmol)和六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷(610mg,1.38mmol)，整个体系在室温下搅拌反应24h，TLC监测跟踪直至原料无剩余，向反应液中加入水(50mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(50mL×2)，无水硫酸钠干燥，减压除去溶剂，残留物经柱层析分离纯化(二氯甲烷:甲醇＝60:1-15:1)，得到化合物67(302mg,0.71mmol,67％)。ESI-MS(m/z)：426.17[M+H] +。 1HNMR(600MHz,DMSO-d 6)δ8.28(d,J＝7.8Hz,1H),7.78(s,1H),7.76-7.74(m,1H),7.68-7.66(m,1H),7.40-7.37(m,1H),6.79(s,1H),5.77-5.72(m,1H),3.93(s,3H),3.88(s,3H),3.44(s,3H),1.58(d,J＝7.2Hz,3H).
实施例30化合物68的合成
Figure PCTCN2022075635-appb-000166
将40(301mg,0.74mmol)溶解于甲苯(30mL)中，接着加入劳森试剂(599mg,1.48mmol)，整个体系回流搅拌反应3h，TLC监测跟踪直至原料无剩余，向反应液中加入水 (50mL)，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠洗涤(50mL×2)，无水硫酸钠干燥，减压除去溶剂，经柱层析分离纯化(二氯甲烷:甲醇＝50:1-15:1)，得到化合物68(156mg,0.37mmol,50％)。ESI-MS(m/z)：424.10[M+H] +。 1HNMR(600MHz,DMSO-d 6)δ8.58(d,J＝7.9Hz,1H),7.78(s,1H),7.76-7.74(m,2H),7.63-7.59(m,1H),6.97(s,1H),5.80-5.76(m,1H),4.07(s,3H),3.96(s,3H),3.90(s,3H),1.63(d,J＝7.2Hz,3H)。
实施例31化合物69的合成
Figure PCTCN2022075635-appb-000167
中间体69-1的合成：
将7-二甲氧基-2,4-喹唑啉二酮(140mg,0.63mmol)溶解于三氯氧磷(20mL)中，整个体系在105℃下搅拌反应8h，TLC监测跟踪直至原料无剩余。直接减压除去反应液中的溶剂，残留物经柱层析分离纯化(正己烷:乙酸乙酯＝20:1-4:1)，得到69-1(140mg，0.54mmol，86％)。ESI-MS(m/z):259.01[M+H] +。
中间体69-2的合成：
将69-1(140mg,0.54mmol)溶解于异丙醇(20mL)中，接着加入B-7b(123mg,0.65mmol)和N,N-二异丙基乙胺(279mg,2.16mmol)，整个体系在105℃下搅拌反应48h，TLC监测跟踪直至原料无剩余。反应完全后将反应体系降温至室温，向反应液中加入50mL水淬灭反应，随后用乙酸乙酯萃取(30mL×3)，合并有机相。有机相经饱和氯化钠洗涤(50mL×2)，无水硫酸钠干燥，减压除去溶剂，残留物经柱层析分离纯化(二氯甲烷:甲醇＝60:1-20:1),得到69-2(100mg,0.24mmol,产率45％)。ESI-MS(m/z):412.12[M+H] +。
化合物69的合成：
将69-2(100mg,0.24mmol)溶解于冰乙酸(20mL)中，整个体系在90℃下搅拌反应8h，TLC监测跟踪直至原料无剩余，反应完全后直接减压除去溶剂，残留物经柱层析分离纯化(二氯甲烷:甲醇＝60:1-15:1)，得到化合物69(60mg,0.15mmol,产率63％)。ESI-MS(m/z):394.13[M+H] +。 1HNMR(600MHz,DMSO-d 6)δ10.51(s,1H),8.26(d,J＝6.0Hz,1H),7.75(s,1H),7.73(d,J＝6.0Hz,1H),7.68(s,1H),7.63-7.58(m,2H),6.67(s,1H),5.65-5.61(m,1H),3.84(s,3H),3.81(s,3H),1.60(d,J＝6.0Hz,3H).
三、生物活性测定实验：
1.K-Ras G12D与hSOS1的结合分析
此测定法可用于检查化合物抑制SOS1与KRAS G12D之间的蛋白-蛋白相互作用的效 力。通过均相时间分辨荧光(HTRF)检测由抗GST-Europium(FRET供体)结合的GST-KRas G12D与抗-6His-XL665结合的His标记的hSOS1(FRET受体)的结合，测定化合物对K-Ras G12D与hSOS1的抑制作用。
试剂
缓冲液(5mM HEPES pH 7.4,150mM NaCl,10mM EDTA,1mM DTT,0.05％BSA pH 7.0,0.0025％IGEPAL以及100mM KF)；
GST-标签hK-RasG12D(市售)
His-标签hSOS1(市售)
Ras混合液
在使用前将GST-hK-RasG12D 10nM(最终浓度)以及抗GST-Europium 2nM(最终浓度)混合在实验缓冲液中并且在室温保持。
SOS混合液
在使用前将His-标签hSOS1 20nM(最终浓度)以及抗-6His-XL665 10nM(最终浓度)混合在实验缓冲液中并且在室温保持。
将待测化合物溶解在DMSO中，浓度为100倍的实验浓度。通过使用Hummingbird liquid handler或者Echo acoustic system取出50nL移入黑色微量检测板中。
所有的实验步骤均在20℃下完成。实验中，2.5μL的Ras混合液通过多点分配器(Multidrop dispenser)加入到检测板上所有孔中。在预孵育2分钟后，除了边缘孔外，其他待测孔均加入2.5μL的SOS混合液，边缘孔加入2.5μL的化合物对照溶液。孵育60分钟后，通过Pheraster的HTRF模块(激发光337nm,发射光1:620nm,发射光2:665nm)。
结果计算：
使用4参数逻辑模型计算和分析IC 50值。
化合物的SOS-1抑制活性：
根据以上方法测试实施例中的代表化合物，并发现它们抑制SOS-1的活性。化合物活性数据见下表。
Figure PCTCN2022075635-appb-000168
Figure PCTCN2022075635-appb-000169
以上数据说明本申请化合物对SOS-1均显示出良好的抑制活性。

Claims (20)

  1. 一种如式(I)所示化合物，或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其具有如下结构：
    Figure PCTCN2022075635-appb-100001
    其中，
    Figure PCTCN2022075635-appb-100002
    表示单键或双键，
    Figure PCTCN2022075635-appb-100003
    不同时为双键，
    Figure PCTCN2022075635-appb-100004
    不同时为双键；
    当
    Figure PCTCN2022075635-appb-100005
    为单键时，X选自C(R A)(R A)、NR A、O、S；当
    Figure PCTCN2022075635-appb-100006
    为双键时，X选自CR A、N；
    R A每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-10环烷基、-C(O)-3-10元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基C(O)-C 3-10环烷基、-C 1-6烷基C(O)-3-10元杂环基和5-10元杂芳基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、-C(O)-C 1-6烷基、-C(O)-C 3-10环烷基、-C(O)-3-10元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基C(O)-C 3-10环烷基、-C 1-6烷基C(O)-3-10元杂环基和5-10元杂芳基均任选地被一个或多个相同或不同的R a1取代；
    R a1每次出现各自独立地选自-OR c、-NR cR c、卤素、-CN、-C(O)R c、-C(O)OR c、-C(O)NR cR c、-S(O) 2R c、-S(O) 2NR cR c、-NHC(O)R c、-N(C 1-4烷基)C(O)R c、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c取代；
    R c每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
    当
    Figure PCTCN2022075635-appb-100007
    为单键时，Y选自C 1-6烷基；当
    Figure PCTCN2022075635-appb-100008
    为双键时，Y选自O、S；
    当
    Figure PCTCN2022075635-appb-100009
    为单键时，Z选自CH、N、O、S，当Z选自O、S时，R 2不存在；当
    Figure PCTCN2022075635-appb-100010
    为双键时，Z选自C和N，当Z选自N时，R 2不存在；
    当
    Figure PCTCN2022075635-appb-100011
    为双键时，R 1是O；当
    Figure PCTCN2022075635-appb-100012
    为单键时，R 1选自-O-R B、任选取代的C 2-4烷基、C 2-4烯基、C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基；
    其中，当
    Figure PCTCN2022075635-appb-100013
    为单键，且R 1选自-O-R B时，R B选自C 1-6烷基、C 3-10环烷基和3-10元杂环基，其中所述C 1-6烷基、C 3-10环烷基和3-10元杂环基任选地被一个或多个相同或不同的R b1取代；
    R b1每次出现各自独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基均任选地被一个或多个相同或不同的R c1取代；
    R c1每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
    或者，当
    Figure PCTCN2022075635-appb-100014
    为单键，且R 1选自C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基时，所述C 3-12碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R a2取代；
    R a2每次出现独立地选自-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-C 0-4烷基C(O)NR c2R c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-4烷基)C(O)R c2、-NHC(O)OR c2、氧代基、＝NH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c2取代；
    R c2每次出现独立地选自氢、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
    或者当
    Figure PCTCN2022075635-appb-100015
    为单键，且R 1选自C 2-4烷基和C 2-4烯基时，所述C 2-4烷基和C 2-4烯基任选地被一个或多个相同或不同的R b2取代；
    R b2每次出现独立地选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3和-C(O)-N(C 1-4烷基)-OR c3；
    R c3每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；
    R 2选自氢、C 1-6烷基、-O-C 1-4烷基、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基)(C 1-4烷基)和卤素；
    R 3选自氢、C 1-4烷基、C 1-4卤代烷基、-O-C 1-4烷基、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基)(C 1-4烷基)和卤素；
    环A选自C 4-12环烷基、4-12元杂环基、C 6-10芳基、5-12元杂芳基；
    R 4每次出现分别独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基、-CH＝CH-C 3-6环烷基、-CH＝CH-C 6-10芳基、-CH＝CH-5-10元杂芳基、-CH＝CH-3-6元杂环基、-CH＝CH-CH 2-C 3-6环烷基、-CH＝CH-CH 2-C 6-10芳基、-CH＝CH-CH 2-5-10元杂芳基、-CH＝CH-CH 2-3-6元杂环基、-SO 2-C 1-4烷基，其中C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基、-CH＝CH-C 3-6环烷基、-CH＝CH- C 6-10芳基、-CH＝CH-5-10元杂芳基、-CH＝CH-3-6元杂环基、-CH＝CH-CH 2-C 3-6环烷基、-CH＝CH-CH 2-C 6-10芳基、-CH＝CH-CH 2-5-10元杂芳基、-CH＝CH-CH 2-3-6元杂环基的基团，所述基团任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)、C 2-6烯基、C 2-6炔基的基团所取代；其中w＝0,1,2,3,4。
  2. 根据权利要求1所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中，当
    Figure PCTCN2022075635-appb-100016
    为单键，X选自C(R A)(R A)、NR A、O、S；其中，R A选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-8芳基、3-6元杂环基、-C(O)-C 1-6烷基、-C(O)-C 4-6环烷基、-C(O)-3-6元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基-C(O)-C 4-6环烷基、-C 1-6烷基-C(O)-3-6元杂环基和5-6元杂芳基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 6-8芳基、3-6元杂环基、-C(O)-C 1-6烷基、-C(O)-C 4-6环烷基、-C(O)-3-6元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基-C(O)-C 4- 6环烷基、-C 1-6烷基-C(O)-3-6元杂环基和5-6元杂芳基任选地被一个或多个相同或不同的R a1取代；
    R a1每次出现独立地选自-OR c、-NR cR c、卤素、-CN、-C(O)R c、-C(O)OR c、-C(O)NR cR c、-S(O) 2R c、-S(O) 2NR cR c、-NHC(O)R c、-N(C 1-4烷基)C(O)R c、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基任选地被一个或多个相同或不同的R c取代；
    R c每次出现各自独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基。
  3. 根据权利要求1～2中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中，
    Figure PCTCN2022075635-appb-100017
    为单键，X选自C(R A)(R A)、NR A、O、S；其中，R A选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-8芳基、3-6元杂环基、-C(O)-C 1-6烷基、-C(O)-C 4-6环烷基、-C(O)-3-6元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1-6烷基-C(O)-C 4-6环烷基、-C 1-6烷基-C(O)-3-6元杂环基和5-6元杂芳基；其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-8芳基、3-6元杂环基、-C(O)-C 1-6烷基、-C(O)-C 4-6环烷基、-C(O)-3-6元杂环基、-C 1-6烷基-C(O)-C 1-6烷基、-C 1- 6烷基-C(O)-C 4-6环烷基、-C 1-6烷基-C(O)-3-6元杂环基和5-6元杂芳基任选地被一个或多个相同或不同的R a1取代；
    R a1每次出现各自独立地选自-OR c、-NR cR c、卤素、-CN、-C(O)R c、-C(O)OR c、-C(O)NR cR c、-S(O) 2R c、-S(O) 2NR cR c、-NHC(O)R c、-N(C 1-4烷基)C(O)R c、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 4-6环烷基、C 6-10芳基、4-6元杂环基和5-6元杂芳基任选地被一个或多个相同或不同的R c取代；
    R c每次出现各自独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、环丁基、乙烯基、乙炔基、C 4-6环烷基、C 6芳基、5-6元杂环基和5-6元杂芳基。
  4. 根据权利要求1～3中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中，
    Figure PCTCN2022075635-appb-100018
    为单键，且R 1是-O-R B；
    其中，R B选自C 1-6烷基、C 3-10环烷基和3-10元杂环基，其中所述C 1-6烷基、C 3-10环烷基和3-10元杂环基任选地被一个或多个相同或不同的R b1取代；或者，R B选自C 1-4烷基、C 4-6环烷基和4-6元杂环基，所述C 1-4烷基、C 4-6环烷基和4-6元杂环基任选地被一个或多个相同或不同的R b1取代；或者，R B选自正丙基、异丙基、正丁基、异丁基、任选被一个或多个R b1取代的甲基、任选被一个或多个R b1取代的乙基、任选被一个或多个R b1取代的C 5-6环烷基、任选被一个或多个R b1取代的5-6元杂环基；
    R b1每次出现独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基，其中所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R c1取代；
    R c1每次出现各自独立地选自氢、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基。
  5. 根据权利要求1～4中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：R b1每次出现独立地选自-OR c1、-NR c1R c1、卤素、-CN、-C(O)R c1、-C(O)OR c1、-C(O)NR c1R c1、-S(O) 2R c1、-S(O) 2NR c1R c1、-NHC(O)R c1、-N(C 1-4烷基)C(O)R c1、氧代基、C 1-4烷基；
    R c1每次出现独立地选自氢、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；或者，R c1每次出现各自独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、环丁基。
  6. 根据权利要求1～3中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：
    Figure PCTCN2022075635-appb-100019
    为单键，且R 1选自C 3-10碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基，其中所述C 3-10碳环基、C 6-10芳基、3-12元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R a2取代；或者，
    Figure PCTCN2022075635-appb-100020
    为单键，且R 1选自C 4-9环烷基、C 4-9环烯基、C 6-10芳基、4-10元杂环基和5-10元杂芳基，所述C 4-9环烷基、C 4-9环烯基、C 6-10芳基、4-10元杂环基和5-10元杂芳基任选地被一个或多个相同或不同的R a2取代；或者，R 1为选自C 4单环烷基、C 5单环烷基、C 6单环烷基、C 7单环烷基、3元/4元螺环烷基、4元/3元螺环烷基、4元/4元螺环烷基、4元/5元螺环烷基、5元/4元螺环烷基、5元/5元螺环烷基、4元/6元螺环烷基、6元/4元螺环烷基、3元/4元稠环烷基、4元/3元稠环烷基、4元/4元稠环烷基、4元/5元稠环烷基、5元/4元稠环烷基、5元/5元稠环烷基、4元/6元稠环烷基、6元/4元稠环烷基、C 4单环烯基、C 5单环烯基、C 6单环烯基、C 7单环烯基、3元/4元螺环烯基、4元/3元螺环烯基、4元/4元螺环烯基、4元/5元螺环烯基、5元/4元螺环烯基、5元/5元螺环烯基、4元/6元螺环烯基、6元/4 元螺环烯基、3元/4元稠环烯基、4元/3元稠环烯基、4元/4元稠环烯基、4元/5元稠环烯基、5元/4元稠环烯基、5元/5元稠环烯基、4元/6元稠环烯基、6元/4元稠环烯基、4元单杂环基、5元单杂环基、6元单杂环基、7元单杂环基、3元/4元螺杂环基、4元/3元螺杂环基、4元/4元螺杂环基、4元/5元螺杂环基、5元/4元螺杂环基、5元/5元螺杂环基、4元/6元螺杂环基、6元/4元螺杂环基、3元/4元稠杂环基、4元/3元稠杂环基、4元/4元稠杂环基、4元/5元稠杂环基、5元/4元稠杂环基、5元/5元稠杂环基、4元/6元稠杂环基、6元/4元稠杂环基、5元/6元稠杂环基、C 6芳基、5元杂芳基、6元杂芳基的基团，所述基团任选被一个或多个相同或不同的R a2取代；R a2每次出现独立地选自C 1-6烷基、-OR c2、-NR c2R c2、卤素、-CN、-C(O)R c2、-C(O)OR c2、-OC(O)R c2、-S(O) 2R c2、-S(O) 2NR c2R c2、-NHC(O)R c2、-N(C 1-4烷基)-C(O)R c2、-NHC(O)OR c2、-C 0-4烷基-C(O)NR c2R c2、氧代基、＝NH，其中所述C 1- 6烷基任选被一个或多个相同或不同的R c2取代；
    R c2每次出现各自独立地选自氢、OH、C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基；或者，R c2每次出现各自独立地选自氢、OH、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、C 3-6环烷基、苯基、3-6元杂环基。
  7. 根据权利要求1～3中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：当
    Figure PCTCN2022075635-appb-100021
    为单键，且R 1选自C 2-4烷基和C 2-4烯基时，所述C 2-4烷基和C 2-4烯基任选地被一个或多个R b2取代；R b2每次出现独立地选自-C(O)R c3、-C(O)OR c3、-C(O)NR c3R c3、-C(O)NHOR c3和-C(O)N(C 1-4烷基)-OR c3；R c3每次出现独立地选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基和5-10元杂芳基。
  8. 根据权利要求1-7中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中，当
    Figure PCTCN2022075635-appb-100022
    为单键，R 1选自
    Figure PCTCN2022075635-appb-100023
    Figure PCTCN2022075635-appb-100024
    Figure PCTCN2022075635-appb-100025
  9. 根据权利要求1～8任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：R 2选自氢、C 1-4烷基、-O-C 1-4烷基和卤素；或者，R 2选自氢、-F、-Cl、-Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、-O-CH 3、-O-CH 2CH 3、-O-CH 2CH 2CH 3、-O-CHCH 3CH 3、-O-CH 2CHCH 3CH 3、-O-CH 2CH 2CH 2CH 3；当Z选自O、S时，R 2不存在；或者，R 2为-O-CH 3。
  10. 根据权利要求1～9中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：R 3选自氢、C 1-4烷基、-O-C 1-4烷基和卤素；或者，R 3选自氢、-F、-Cl、-Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基。
  11. 根据权利要求1～10中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：环A选自C 4-8的环烷基、4-8元杂环基、C 6-10芳基、5-10元杂芳基；或者，环A选自C 5-6的环烷基、5-6元杂环基、C 6-10芳基、5-6元杂芳基；或者，环A为苯基或噻吩基。
  12. 根据权利要求1～11中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：R 4每次出现独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基，其中C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、C 1-4烷基-NH 2、C 1-4烷基-NH-C 1-4烷基、C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)、C 2-6烯基、C 2-6炔基的基团所取代；w＝0,1,2,3,4；或者
    R 4每次出现独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基，其中C 3-6环烷基、C 6-10芳基、5-10元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6-10芳基、-O-5-10元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6-10芳基、-O-CH 2-5-10元杂芳基、-O-CH 2-3-6元杂环基任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、C 1-4烷基-NH 2、 C 1-4烷基-NH-C 1-4烷基、C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)的基团所取代；其中w＝0,1,2,3,4；或者，
    R 4每次出现分别独立地为选自氢、-NH 2、甲基、乙基、正丙基、异丙基、F、Cl、Br、CHF 2、CF 3、-O-CH 3、-O-CF 3、3元杂环基、4元杂环基、5元杂环基、6元杂环基、环丙基、环丁基、环戊基、环己基、C 6芳基、5元杂芳基、6元杂芳基，所述3元杂环基、4元杂环基、5元杂环基、6元杂环基、环丙基、环丁基、环戊基、环己基、C 6芳基、5元杂芳基、6元杂芳基任选被一个或多个相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、C 1-4烷基-NH 2、C 1-4烷基-NH-C 1-4烷基、C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)的基团所取代；其中w＝0,1,2,3,4；或者
    R 4每次出现独立地为选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、-O-C 1-4烷基、-O-C 1-4卤代烷基、C 3-6环烷基、C 6芳基、5-6元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6芳基、-O-5-6元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6芳基、-O-CH 2-5-6元杂芳基、-O-CH 2-3-6元杂环基，其中C 3-6环烷基、C 6芳基、5-6元杂芳基、3-6元杂环基、-O-C 3-6环烷基、-O-C 6芳基、-O-5-6元杂芳基、-O-3-6元杂环基、-O-CH 2-C 3-6环烷基、-O-CH 2-C 6芳基、-O-CH 2-5-6元杂芳基、-O-CH 2-3-6元杂环基任选被一个或多个(例如，1个、2个或3个)相同或不同的选自羟基、氧代基、C 1-6烷基、氨基、氰基、硝基、卤素、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)、C 2-6烯基、C 2-6炔基的基团所取代；其中w＝0,1,2,3,4；或者
    R 4每次出现独立地选自氢、-NH 2、C 1-4烷基、卤素、C 1-4卤代烷基、C 6芳基、3-6元杂环基，其中C 6芳基和3-6元杂环基任选被一个或多个(例如，1个、2个或3个)相同或不同的选自羟基、-C 1-4烷基-NH 2、-C 1-4烷基-NH-C 1-4烷基、-C 1-4烷基-N-(C 1-4烷基)(C 1-4烷基)的基团所取代；其中w＝0,1,2或3；或者
    R 4每次出现独立地选自-NH 2、-CF 3、-F、-CHF 2、-CF 2CH 3、
    Figure PCTCN2022075635-appb-100026
    且w＝0,1,2或3。
  13. 根据权利要求1～12中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中结构单元
    Figure PCTCN2022075635-appb-100027
    选自
    Figure PCTCN2022075635-appb-100028
    Figure PCTCN2022075635-appb-100029
  14. 根据权利要求1～13中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：所述化合物进一步具有如式(Ia)所示结构：
    Figure PCTCN2022075635-appb-100030
  15. 根据权利要求1～14中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：所述化合物进一步具有如式(Ⅱ)～式(X)所示结构：
    Figure PCTCN2022075635-appb-100031
  16. 根据权利要求1～15所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：所述化合物进一步具有如式(Ⅱa)～式(Xa)所示结构：
    Figure PCTCN2022075635-appb-100032
  17. 根据权利要求1中所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，其中：所述化合物选自：
    Figure PCTCN2022075635-appb-100033
    Figure PCTCN2022075635-appb-100034
    Figure PCTCN2022075635-appb-100035
    Figure PCTCN2022075635-appb-100036
    Figure PCTCN2022075635-appb-100037
  18. 一种药物组合物，其包含权利要求1～17中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐，以及药学上可接受的辅料。
  19. 根据权利要求1～17中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐或权利要求18所述的药物组合物在制备治疗由SOS1抑制剂介导的疾病的药物中的用途；优选地，所述由SOS1抑制剂介导的疾病为癌症或肿瘤。
  20. 根据权利要求1～17中任一项所述的化合物或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、同位素标记的类似物、前药或其药学上可接受的盐或权利要求18所述的药物组合物在制备治疗RAS突变导致的疾病的药物中的用途；优选地，所述RAS突变导致的疾病选自1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征(LEGIUS SYNDROME)和遗传性牙龈纤维瘤病。
PCT/CN2022/075635 2021-02-10 2022-02-09 一种具有抗肿瘤活性的化合物及其用途 WO2022171118A1 (zh)

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