WO2022258057A1 - Composés en tant qu'agents anticancéreux - Google Patents

Composés en tant qu'agents anticancéreux Download PDF

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WO2022258057A1
WO2022258057A1 PCT/CN2022/098201 CN2022098201W WO2022258057A1 WO 2022258057 A1 WO2022258057 A1 WO 2022258057A1 CN 2022098201 W CN2022098201 W CN 2022098201W WO 2022258057 A1 WO2022258057 A1 WO 2022258057A1
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alkyl
mmol
compound
alkylene group
methyl
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Ying Han
Dapeng Li
Huajun LONG
Zhiyu Yin
Jinghan WANG
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Jingrui Biopharma Co., Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention is directed to novel compounds which are used as inhibitors of pan KRAS :: SOS1, their synthesis and their use for treating diseases or conditions, such as cancer.
  • RAS is one of the most well-known oncogenes. In human beings, three RAS genes (HRAS, KRAS and NRAS) encode four highly homologous RAS proteins (HRAS, KRAS-4A, KRAS-4B and NRAS) . RAS proteins are small GTPases, they function as binary molecular switches that involved in transduction of extracellular growth and differentiation signaling.
  • RAS generally cycles between a GDP-bound “off” state and a GTP-bound “on” state. This cycle is regulated by several factors. Guanine nucleotide exchange factors (GEFs) , including SOS1 and SOS2 facilitate the exchange and formation of GTP-bound RAS. While, GTPase-activating proteins (GAPs) , for example, NF-1 promote the hydrolysis of GTP and therefore turn RAS back to GDP-bound inactivate state (Kessler et al, PNAS, 2019, 116 (32) : 15823–15829) .
  • GAPs GTPase-activating proteins
  • RAS initiates conformational changes in two specific regions Switch 1 and Switch 2, which allows engagement and activation of downstream effector proteins to initiate a cascade of intracellular signaling pathways.
  • These effectors include RAF–MEK–ERK and PI3K-AKT–mTOR pathways, both of which have crucial roles in regulating cell proliferation, differentiation, and survival (Cox et al., Nature Reviews Drug Discovery, 2014, 13: 828-851) .
  • RAS mutations have been identified in around 30%of human tumors. These mutations occur frequently as single-base missense mutations in codons 12, 13 or 61, resulting in stabilization of the activated GTP-bound RAS form and constitutive activation of RAS downstream signaling pathways.
  • KRAS is the most frequently mutated RAS in cancer, account for 85%of all RAS-driven cancers, followed by NRAS (12%) and HRAS (3%) .
  • KRAS mutation has been detected in around 95%of pancreatic ductal adenocarcinoma, 50%of colorectal adenocarcinoma and 30%of lung adenocarcinoma. The majority of KRAS mutations occur at residue 12, and the mutation type varied in different cancers.
  • SOS1 Son of Sevenless 1
  • the SOS1 protein consists of 1333 amino acids (150 kDa) .
  • SOS1 is a multi-domain protein with two tandem N-terminal histone domains (HD) followed by the Dbl homology domain (DH) , a Pleckstrin homology domain (PH) , a helical linker (HL) , RAS exchanger motif (REM) , CDC25 homology domain and a C-terminal proline rich domain (PR) .
  • SOS1 has two binding sites for RAS-family proteins; a catalytic site that binds GDP-bound RAS-family proteins to promote guanine nucleotide exchange and an allosteric site that binds GTP-bound RAS-family proteins which causes a further increase in the catalytic GEF function of SOS1 (Freedman et al., Proc.
  • SOS1 is critically involved in the activation of RAS-family protein signaling in cancer via mechanisms other than mutations in RAS-family proteins.
  • SOS1 interacts with the adaptor protein Grb2 and the resulting SOS1/Grb2 complex binds to activated/phosphorylated Receptor Tyrosine Kinases (e.g. EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL) (Pierre et al., Biochem. Pharmacol., 2011, 82 (9) : 1049-56) .
  • activated/phosphorylated Receptor Tyrosine Kinases e.g. EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, Trk
  • SOS1 is also recruited to other phosphorylated cell surface receptors such as the T cell Receptor (TCR) , B cell Receptor (BCR) and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275 (8) : 5966-75) .
  • TCR T cell Receptor
  • BCR B cell Receptor
  • monocyte colony-stimulating factor receptor SOS1 to promote RAS-family protein activation.
  • SOS1-activation of RAS-family proteins can also be mediated by the interaction of SOS1/Grb2 with the BCR-ABL oncoprotein commonly found in chronic myelogenous leukemia (Kardinal et al., 2001, Blood, 98:1773–81; Sini et al., Nat. Cell Biol., 2004, 6 (3) : 268-74) .
  • SOS1 mutations are found in embryonal rhabdomyosarcomas, sertoli cell testis tumors, granular cell tumors of the skin (Denayer et al., Genes Chromosomes Cancer, 2010, 49 (3) : 242-52) and lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature. 2014, 511 (7511) : 543-50) .
  • lung adenocarcinoma Cancer Genome Atlas Research Network., Nature. 2014, 511 (7511) : 543-50
  • bladder cancer Wanganabe et al., IUBMB Life., 2000, 49 (4) : 317-20
  • prostate cancer Tuofeeva et al., Int. J.
  • hereditary SOS1 mutations are implicated in the pathogenesis of RASopathies like e.g. Noonan syndrome (NS) , cardio-facio-cutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (Pierre et al., Biochem. Pharmacol., 2011, 82 (9) : 1049-56) .
  • SOS1 inhibitor compounds are be expected to consequently inhibit signaling in cells downstream of RAS-family proteins (e.g. ERK phosphorylation) .
  • SOS1 inhibitor compounds are be expected to deliver anti-cancer efficacy (e.g. inhibition of proliferation, survival, metastasis etc. ) .
  • High potency towards inhibition of SOS1 RAS-family protein binding (nanomolar level IC 50 values) and ERK phosphorylation in cells (nanomolar level IC 50 values) are desirable characteristics for a SOS1 inhibitor compound.
  • the present invention provides novel compounds, their analogues including stereoisomers, or pharmaceutically acceptable salts, which are useful as pan KRAS : : SOS1 inhibitors.
  • the present invention also provides processes and intermediates for making the compounds of the present invention.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one of the compounds of the present invention or stereoisomers thereof, or pharmaceutically acceptable salts thereof.
  • the compounds of the invention may be used in the treatment of diseases or conditions associated with KRAS activating mutations, or associated with or modulated by SOS1.
  • the compounds of the present invention may be used for the manufacture of a medicament for the treatment of diseases or conditions associated with KRAS activating mutations, or associated with or modulated by SOS1.
  • the present invention is directed to a method of treating a cancer comprising administering to a patient in need of such treatment a compound of the present invention as described above.
  • a cancer includes a lung cancer, a colorectal cancer and a pancreatic cancer.
  • the present application provides a compound of the formula I:
  • R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, CN, amino, C 3-6 cycloalkyl and C 1-6 alkoxy, in which the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, R 7 is independently selected from H and C 1-6 alkyl;
  • R 4 is selected from H and C 1-6 alkyl
  • X is selected from C, N and S;
  • R 5 is selected from H, C 1-6 alkyl, optionally substituted amino, C 1-6 alkoxy, SOR 6 , SO 2 R 6 , optionally substituted phenyl and optionally substituted pyridyl, in which R 6 is independently selected from H and C 1-6 alkyl;
  • Z 1 and Z 2 are independently selected from C and N;
  • R 8 is selected from the group consisting of halogen, C 1-6 alkyl, halogen substituted C 1- 6 alkyl and NH 2 ;
  • n denotes 1 or 2
  • connection site denotes a connection site.
  • R 1 and R 2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, n-pentyl, neopentyl, n-hexyl, sec hexyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 1 and R 2 are independently selected from methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl. In some embodiments of the first aspect, R 1 and R 2 are independently selected from methyl and tetrahydrofuranyl. In some embodiments of the first aspect, R 1 is tetrahydrofuranyl, and R 2 is C 1-6 alkyl. In some embodiments of the first aspect, R 1 is tetrahydrofuranyl, and R 2 is selected from methyl, ethyl, n-propyl and isopropyl. In some embodiments of the first aspect, R 1 is tetrahydrofuranyl, and R 2 is methyl.
  • R 1 and R 2 together form a C 3-12 alkylene group, wherein the C 3-12 alkylene group is optionally replaced by 1 oxygen atom.
  • R 1 and R 2 together form a C 3-8 alkylene group, wherein the C 3-8 alkylene group is optionally replaced by 1 oxygen atom.
  • R 1 and R 2 together form a C 5-12 alkylene group, wherein the C 5-12 alkylene group is replaced by 2 oxygen atoms. In some embodiments of the first aspect, R 1 and R 2 together form a C 5-8 alkylene group, wherein the C 5-8 alkylene group is replaced by 2 oxygen atoms. In some embodiments of the first aspect, R 1 and R 2 together form a C 5-6 alkylene group, wherein the C 5-6 alkylene group is replaced by 2 oxygen atoms.
  • R 1 and R 2 together form a C 8-12 alkylene group, wherein the C 8-12 alkylene group is replaced by 3 oxygen atoms.
  • R 1 and R 2 together form a C 3-8 alkylene group.
  • R 1 and R 2 together form a C 3-6 alkylene group.
  • R 1 and R 2 together form a C 3-4 alkylene group. In some embodiments of the first aspect, R 1 and R 2 together form a C 3 alkylene group. In some embodiments of the first aspect, R 1 and R 2 together form a C 3-12 alkylene group, wherein the C 3-12 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R 1 and R 2 together form a C 3-8 alkylene group, wherein the C 3-8 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R 1 and R 2 together form a C 3-6 alkylene group, wherein the C 3-6 alkylene group is replaced by one oxygen atom.
  • R 1 and R 2 together form a C 5 alkylene group, wherein the C 5 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R 1 and R 2 together form a In some embodiments of the first aspect, R 1 and R 2 together form a C 5- 12 alkylene group, wherein the C 5-12 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R 1 and R 2 together form a C 5-8 alkylene group, wherein the C 5-8 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other.
  • R 1 and R 2 together form a C 8 alkylene group, wherein the C 8 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R 1 and R 2 together form a In some embodiments of the first aspect, R 1 and R 2 together form a C 7-12 alkylene group, wherein the C 7-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other.
  • R 1 and R 2 together form a C 9-12 alkylene group, wherein the C 9-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R 1 and R 2 together form a C 10-12 alkylene group, wherein the C 10-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R 1 and R 2 together form a C 12 alkylene group, wherein the C 12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other.
  • R 1 and R 2 together form In some embodiments of the first aspect, R 1 and R 2 together form
  • R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, C 3-6 cycloalkyl and C 1-6 alkoxy, in which the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, R 7 is independently selected from H and C 1-6 alkyl.
  • R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, and C 3- 6 cycloalkyl, in which the C 1-6 alkyl is optionally substituted with –OH, -NR 7 R 7 or halogen, the phenyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, the pyridyl is optionally substituted with one or two C 1-6 alkyl, the pyrazolyl is optionally substituted with a C 1-6 alkyl, and R 7 is selected from H and C 1-6 alkyl.
  • R 3 is H.
  • R 3 is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, and R 7 is independently selected from H and C 1-6 alkyl. In some embodiments of the first aspect, R 3 is selected from methyl, ethyl and isopropyl, wherein the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, and R 7 is independently selected from H and C 1-6 alkyl. In some embodiments of the first aspect, R 3 is methyl.
  • R 3 is selected from a phenyl, wherein the phenyl is optionally substituted with a C 1-6 alkyl or one or two halogens selected from F, Cl and Br. In some embodiments of the first aspect, R 3 is selected from phenyl, wherein the phenyl is optionally substituted with a C 1-6 alkyl or one or two halogens selected from F and Cl. In some embodiments of the first aspect, R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with one or two C 1-6 alkyls.
  • R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with two C 1-6 alkyls. In some embodiments of the first aspect, R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with two C 1-3 alkyls. In some embodiments of the first aspect, R 3 is selected from a pyrazolyl, wherein the pyrazolyl is optionally substituted with a C 1-6 alkyl. In some embodiments of the first aspect, R 3 is selected from a pyrazolyl, wherein the pyrazolyl is optionally substituted with a C 1-3 alkyl. In some embodiments of the first aspect, R 3 is cyclopropyl. In some embodiments of the first aspect, R 3 is selected from H and methyl.
  • R 4 is selected from C 1-6 alkyl. In some embodiments of the first aspect, R 4 is selected from methyl, ethyl, n-propyl and isopropyl. In some embodiments of the first aspect, R 4 is methyl.
  • X is selected from C and S. In some embodiments of the first aspect, X is C. In some embodiments of the first aspect, X is S.
  • R 5 is selected from methyl, ethyl, n-propyl and isopropyl.
  • R 5 is methyl.
  • R 5 is selected from C 1-3 alkoxy.
  • R 5 is selected from SOR 6 , wherein R 6 is independently selected from H and C 1-6 alkyl.
  • R 5 is selected from SO 2 R 6 , wherein R 6 is independently selected from H and C 1-6 alkyl.
  • Z 1 is independently selected from C and N, and Z 2 is N. In some embodiments of the first aspect, Z 1 is C, and Z 2 is N. In some embodiments of the first aspect, Z 1 is N, and Z 2 is N.
  • R 8 is selected from the group consisting of halogen, C 1-6 alkyl, halogen substituted C 1-6 alkyl, NH 2 . In some embodiments of the first aspect, R 8 is selected from the group consisting of halogen, C 1-6 alkyl, halogen substituted C 1-6 alkyl, NH 2 . In some embodiments of the first aspect, R 8 is selected from the group consisting of F, Cl, Br, C 1-3 alkyl, halogen substituted C 1-3 alkyl, NH 2 . In some embodiments of the first aspect, R 8 is selected from the group consisting of F, CHF 2 , NH 2 , CF 3 and CF 2 CH 3 . In some embodiments of the first aspect, R 8 is NH 2 .
  • n denotes 1. In some embodiments of the first aspect, n denotes 2.
  • n denotes 2
  • one of R 8 is NH 2
  • the other R 8 is selected from the group consisting of F, CHF 2 , CF 3 and CF 2 CH 3 .
  • the compound is represented by formula I-1: wherein R 1 and R 2 together form a C 3-12 alkylene group, wherein the C 3-12 alkylene group is optionally replaced by 1-3 heteroatoms selected from O, S and N, wherein the group replaced by 1-3 heteroatoms is optionally substituted by a C 1-3 alkyl, p-methoxybenzyl, acetyl and oxygen.
  • R 1 and R 2 together form a C 3-8 alkylene group, wherein the C 3-8 alkylene group is optionally replaced by 1 heteroatom selected from O and S, or a C 5-12 alkylene group, wherein the C 5-12 alkylene group is replaced by 2 heteroatoms selected from O and S, wherein said 2 heteroatoms are not adjacent to each other.
  • R 1 and R 2 together form a C 3-5 alkylene group, wherein the C 3-5 alkylene group is optionally replaced by 1 heteroatom selected from O and S, or a C 5-8 alkylene group, wherein the C 5-8 alkylene group is replaced by 2 heteroatoms selected from O and S, wherein said 2 heteroatoms are not adjacent to each other.
  • R 1 and R 2 together form a C 3-5 alkylene group, wherein the C 3-5 alkylene group is optionally replaced by 1 oxygen atom, or a C 5-8 alkylene group, wherein the C 5-8 alkylene group is replaced by 2 oxygen atoms, wherein said 2 oxygen atoms are not adjacent to each other.
  • R 1 and R 2 together form a C 3-8 alkylene group. In some embodiments of the first aspect, R 1 and R 2 together form a C 3-6 alkylene group. In some embodiments of the first aspect, R 1 and R 2 together form a C 3-4 alkylene group. In some embodiments of the first aspect, R 1 and R 2 together form a C 3 alkylene group. In some embodiments of the first aspect, R 1 and R 2 together form a C 3-12 alkylene group, wherein the C 3-12 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R 1 and R 2 together form a C 3-8 alkylene group, wherein the C 3-8 alkylene group is replaced by one oxygen atom.
  • R 1 and R 2 together form a C 3-6 alkylene group, wherein the C 3-6 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R 1 and R 2 together form a C 5 alkylene group, wherein the C 5 alkylene group is replaced by one oxygen atom. In some embodiments of the first aspect, R 1 and R 2 together form a In some embodiments of the first aspect, R 1 and R 2 together form a C 5-12 alkylene group, wherein the C 5-12 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other.
  • R 1 and R 2 together form a C 5-8 alkylene group, wherein the C 5-8 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R 1 and R 2 together form a C 8 alkylene group, wherein the C 8 alkylene group is replaced by two oxygen atoms, wherein the two oxygen atoms are not adjacent to each other.
  • R 1 and R 2 together form a In some embodiments of the first aspect, R 1 and R 2 together form a In some embodiments of the first aspect, R 1 and R 2 together form a C 7-12 alkylene group, wherein the C 7-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R 1 and R 2 together form a C 9-12 alkylene group, wherein the C 9-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other.
  • R 1 and R 2 together form a C 10-12 alkylene group, wherein the C 10-12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other. In some embodiments of the first aspect, R 1 and R 2 together form a C 12 alkylene group, wherein the C 12 alkylene group is replaced by three oxygen atoms, wherein the three oxygen atoms are not adjacent to each other.
  • R 1 and R 2 together form In some embodiments of the first aspect, R 1 and R 2 together form
  • the compound is represented by formula I-2:
  • R 8 is selected from the group consisting of halogen, C 1-6 alkyl, halogen substituted C 1- 6 alkyl and optionally substituted NH 2 ; and n denotes 1 or 2. In some embodiments of the first aspect, R 8 is selected from the group consisting of halogen, C 1-6 alkyl, halogen substituted C 1-6 alkyl, NH 2 . In some embodiments of the first aspect, R 8 is selected from the group consisting of halogen, C 1-6 alkyl, halogen substituted C 1-6 alkyl, NH 2 .
  • R 8 is selected from the group consisting of F, Cl, Br, C 1-3 alkyl, halogen substituted C 1-3 alkyl, NH 2 . In some embodiments of the first aspect, R 8 is selected from the group consisting of F, CHF 2 , NH 2 , CF 3 and CF 2 CH 3 . In some embodiments of the first aspect, R 8 is NH 2 .
  • n denotes 1. In some embodiments of the first aspect, n denotes 2.
  • n denotes 2
  • one of R 8 is NH 2
  • the other R 8 is selected from the group consisting of F, CHF 2 , CF 3 and CF 2 CH 3 .
  • the compound is represented by the following formula I-3:
  • R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, CN, amino, C 3-6 cycloalkyl and C 1-6 alkoxy, in which the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, R 7 is independently selected from H and C 1-6 alkyl.
  • R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, C 3-6 cycloalkyl and C 1-6 alkoxy, in which the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, R 7 is independently selected from H and C 1-6 alkyl.
  • R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, and C 3- 6 cycloalkyl, in which the C 1-6 alkyl is optionally substituted with –OH, -NR 7 R 7 or halogen, the phenyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, the pyridyl is optionally substituted with one or two C 1-6 alkyl, the pyrazolyl is optionally substituted with a C 1-6 alkyl, and R 7 is selected from H and C 1-6 alkyl.
  • R 3 is H.
  • R 3 is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, and R 7 is independently selected from H and C 1-6 alkyl. In some embodiments of the first aspect, R 3 is selected from methyl, ethyl and isopropyl, wherein the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, and R 7 is independently selected from H and C 1-6 alkyl. In some embodiments of the first aspect, R 3 is methyl.
  • R 3 is selected from a phenyl, wherein the phenyl is optionally substituted with a C 1-6 alkyl or one or two halogens selected from F, Cl and Br. In some embodiments of the first aspect, R 3 is selected from phenyl, wherein the phenyl is optionally substituted with a C 1-6 alkyl or one or two halogens selected from F and Cl. In some embodiments of the first aspect, R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with one or two C 1-6 alkyls.
  • R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with two C 1-6 alkyls. In some embodiments of the first aspect, R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with two C 1-3 alkyls. In some embodiments of the first aspect, R 3 is selected from a pyrazolyl, wherein the pyrazolyl is optionally substituted with a C 1-6 alkyl. In some embodiments of the first aspect, R 3 is selected from a pyrazolyl, wherein the pyrazolyl is optionally substituted with a C 1-3 alkyl. In some embodiments of the first aspect, R 3 is cyclopropyl. In some embodiments of the first aspect, R 3 is selected from H and methyl.
  • the compound is represented by the following formula I-4: wherein R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, CN, amino, C 3-6 cycloalkyl and C 1-6 alkoxy, in which the C 1- 6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, R 7 is independently selected from H and C 1-6 alkyl.
  • R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, C 3-6 cycloalkyl and C 1-6 alkoxy, in which the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, each of the phenyl, the pyridyl, the amino and the pyrazolyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, R 7 is independently selected from H and C 1-6 alkyl.
  • R 3 is selected from H, C 1-6 alkyl, phenyl, pyridyl, pyrazolyl, and C 3- 6 cycloalkyl, in which the C 1-6 alkyl is optionally substituted with –OH, -NR 7 R 7 or halogen, the phenyl is optionally substituted with one or two C 1-6 alkyls or one or two halogens, the pyridyl is optionally substituted with one or two C 1-6 alkyl, the pyrazolyl is optionally substituted with a C 1-6 alkyl, and R 7 is selected from H and C 1-6 alkyl.
  • R 3 is H.
  • R 3 is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, and R 7 is independently selected from H and C 1-6 alkyl. In some embodiments of the first aspect, R 3 is selected from methyl, ethyl and isopropyl, wherein the C 1-6 alkyl is optionally substituted with -OH, -NR 7 R 7 or halogen, and R 7 is independently selected from H and C 1-6 alkyl. In some embodiments of the first aspect, R 3 is methyl.
  • R 3 is selected from a phenyl, wherein the phenyl is optionally substituted with a C 1-6 alkyl or one or two halogens selected from F, Cl and Br. In some embodiments of the first aspect, R 3 is selected from phenyl, wherein the phenyl is optionally substituted with a C 1-6 alkyl or one or two halogens selected from F and Cl. In some embodiments of the first aspect, R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with one or two C 1-6 alkyls.
  • R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with two C 1-6 alkyls. In some embodiments of the first aspect, R 3 is selected from a pyridyl, wherein the pyridyl is optionally substituted with two C 1-3 alkyls. In some embodiments of the first aspect, R 3 is selected from a pyrazolyl, wherein the pyrazolyl is optionally substituted with a C 1-6 alkyl. In some embodiments of the first aspect, R 3 is selected from a pyrazolyl, wherein the pyrazolyl is optionally substituted with a C 1-3 alkyl. In some embodiments of the first aspect, R 3 is cyclopropyl. In some embodiments of the first aspect, R 3 is selected from H and methyl.
  • connection site denotes a connection site
  • the compound is selected from:
  • a pharmaceutical composition comprising the compound of the present invention, a pharmaceutically acceptable salt thereof or stereoisomer thereof and a pharmaceutically acceptable excipient.
  • the disease or condition is a cancer.
  • the cancer is a lung cancer, a colorectal cancer or a pancreatic cancer.
  • a method of inhibiting a disease or condition associated with KRAS activating mutations which comprises administering to an individual the compound of the present invention, a pharmaceutically acceptable salt thereof or stereoisomer thereof.
  • the disease or condition is associated with KRAS activating mutations.
  • the disease or condition is a cancer. More preferably, the disease or condition is a lung cancer, a colorectal cancer or a pancreatic cancer.
  • the method disclosed here can be used to treat or delay progression of a cancer that has a KRAS mutation.
  • KRAS is a GTPase and KRAS mutations have been found in various human cancers, including but not limited to, pancreatic carcinomas, colon carcinomas, lung carcinomas, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia and breast cancer. Oncogenic forms of the KRAS gene are particularly prevalent in pancreatic cancer, colorectal cancer and lung cancer. KRAS has been reported to be mutated at several sites, but the vast majority of mutations occur at the Gly residue of codon 12 and codon 13.
  • KRAS mutation is detected in tissue or cell samples containing cancer cells from a subject.
  • the KRAS mutation is a somatic mutation.
  • the method is used to treat or delay progression of a cancer that has a KRAS G12C mutation.
  • the method is used to treat or delay progression of a cancer that has a KRAS G12V mutation.
  • the method is used to treat or delay progression of a cancer that has a KRAS G12D mutation.
  • references made in the singular may also include the plural.
  • “a” and “an” may refer to either one, or one or more.
  • PMB refers to 4-methoxybenzyl.
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
  • the indication of the number of members in groups that contain one or more heteroatom (s) relates to the total number of atoms of all the ring members or the total of all the ring and carbon chain members.
  • the indication of the number of carbon atoms in groups that consist of a combination of carbon chain and carbon ring structure relates to the total number of carbon atoms of all the carbon ring and carbon chain members.
  • a ring structure has at least three members.
  • aryl-C 1-6 alkyl means an aryl group which is bound to a C 1-6 alkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono-or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 6 alkyl denotes alkyl having 1 to 6 carbon atoms.
  • Example alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, isobutyl, t-butyl) , and pentyl (e.g., n-pentyl, isopentyl, neopentyl) .
  • Me methyl
  • Et ethyl
  • propyl e.g., n-propyl and isopropyl
  • butyl e.g., n-butyl, isobutyl, t-butyl
  • pentyl e.g., n-pentyl, isopentyl, neopentyl
  • alkyl also applies if alkyl is a part of another (combined) group such as for example C x-y alkylamino or C x-y alkyloxy.
  • alkylene can also be derived from alkyl.
  • Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl.
  • Corresponding groups are for example -CH 3 and -CH 2 -, -CH 2 CH 3 and -CH 2 CH 2 -or >CHCH 3 etc.
  • C 1-4 alkylene includes for example - (CH 2 ) -, - (CH 2 -CH 2 ) -, - (CH(CH 3 ) ) -, - (CH 2 -CH 2 -CH 2 ) -, - (C (CH 3 ) 2 ) -, - (CH (CH 2 CH 3 ) ) -, - (CH (CH 3 ) -CH 2 ) -, - (CH 2 -CH (CH 3 ) ) -, - (CH 2 -CH 2 -CH 2 -CH 2 ) -, - (CH 2 -CH 2 -CH (CH 3 ) ) -, - (CH (CH 3 ) -CH 2 -CH 2 ) -, - (CH 2 -CH 2 -CH 2 ) -, - (CH (CH 3 ) -CH 2 -CH 2 ) -, - (CH 2 -CH (CH 3 ) -,
  • alkylene examples include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1, 1-dimethylpropylene, 2, 2-dimethylpropylene, 1, 2-dimethylpropylene, 1, 3-dimethylpropylene, hexylene etc.
  • propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1, 1-dimethylethylene and 1, 2-dimethylethylene.
  • alkylene also applies if alkylene is part of another (combined) group such as for example in HO-C x-y alkyleneamino or H 2 N-C x-y alkyleneoxy.
  • Haloalkyl is derived from the previously defined alkyl by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl is to be further substituted, the substitutions may take place independently of one another, in the form of mono-or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.
  • haloalkylene unlike haloalkyl, is bivalent and requires two binding partners.
  • the second valency is formed by removing a hydrogen atom from a haloalkyl.
  • Corresponding groups are for example -CH 2 F and -CHF-, -CHFCH 2 F and -CHFCHF-or >CFCH 2 F etc.
  • Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
  • Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms in common. In spiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two rings together.
  • a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono-or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [4.3.0] nonyl (octahydroindenyl) , bicyclo [4.4.0] decyl (decahydronaphthyl) , bicyclo [2.2.1] heptyl (norbornyl) , bicyclo [4.1.0] heptyl (norcaranyl) , bicyclo [3.1.1] heptyl (pinanyl) , spiro [2.5] octyl, spiro [3.3] heptyl etc.
  • cycloalkyl also applies if cycloalkyl is part of another (combined) group as for example in C x-y cycloalkylamino, C x-y cycloalkyloxy or C x-y cycloalkylalkyl.
  • cycloalkylene can thus be derived from the previously defined cycloalkyl.
  • Cycloalkylene unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl.
  • Corresponding groups are for example:
  • cycloalkylene also applies if cycloalkylene is part of another (combined) group as for example in HO-C x-y cycloalkyleneamino or H 2 N-C x-y cycloalkyleneoxy.
  • alkoxy refers to an –O-alkyl group.
  • C 1-6 alkoxy (or alkyloxy) , is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkoxy groups.
  • Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , and t-butoxy.
  • substituted means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • the total number of C and N atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of C and N atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of C and N atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.
  • any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • a group is shown to be substituted with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.
  • R is selected independently from the definition of R.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituents are selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclo, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfon
  • a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form.
  • a free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers.
  • Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and configuration isomers.
  • the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 22 nd Edition, Allen, L.V. Jr., Ed.; Pharmaceutical Press, London, UK (2012) , the disclosure of which is hereby incorporated by reference.
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • Treating refers to administering at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein to a subject in recognized need thereof that has, for example, cancer.
  • terapéuticaally effective amount refers to an amount of at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein effective to "treat” as defined above, a disease or disorder in a subject.
  • cancer refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include but are not limited to squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung) , cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer) , pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lympho
  • Examples of cancer may include primary tumors of any of the above types of cancer or metastatic tumors at a second site derived from any of the above types of cancer. Included in this definition are benign and malignant cancers as well as dormant tumors or micrometastases.
  • the term “inhibitor” refers to biological or chemical substance that interferes with or otherwise reduces the physiological and/or biochemical action of another biological or chemical molecule. In some embodiments, the inhibitor or antagonist specifically binds to the other molecule.
  • a “subject, ” “patient” or “individual” includes a mammal, such as a human or other animal, and typically is human.
  • the subject e.g., patient, to whom the therapeutic agents and compositions are administered, is a mammal, typically a primate, such as a human.
  • the primate is a monkey or an ape.
  • the subject can be male or female and can be any suitable age, including infant, juvenile, adolescent, adult, and geriatric subjects.
  • the subject is a non-primate mammal, such as a rodent, a dog, a cat, a farm animal, such as a cow or a horse, etc.
  • the compounds in the present invention can be synthesized in a number of ways well to one skilled in the art of organic synthesis described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods are not limited as those described below.
  • the references cited here are incorporated by reference in their entirety.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 rd edition, John Wiley &Sons) . These groups are removed at certain stage of the compound synthesis using the methods that are apparent to those skilled in the art.
  • Step 4 (S) -2-Amino-4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzamide
  • Step 5 (S) -7-Methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-ol
  • Step 2 Methyl (S) -4-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzoate
  • Step 3 (S) -4-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzamide
  • Step 4 (S) -4-Methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzamide
  • Step 5 (S) -4-hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-2 (1H) -one
  • Step 6 4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-2 (1H) -one
  • Step 4 Methyl 5-bromo-6-methoxy-2- (methylamino) nicotinate
  • Step 5 Methyl 6-methoxy-2- (methylamino) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan -2-yl) nicotinate
  • Step 6 Methyl 5-hydroxy-6-methoxy-2- (methylamino) nicotinate
  • Step 7 Methyl 2- ( (tert-butoxycarbonyl) (methyl) amino) -5-hydroxy-6-methoxy nicotinate
  • Step 8 Methyl (S) -6-methoxy-2- (methylamino) -5- ( (tetrahydrofuran-3-yl) oxy) nicotinate
  • Step 9 Methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (methyl) amino) -6-methoxy-5 - ( (tetrahydrofuran-3-yl) oxy) nicotinate
  • Step 10 Methyl (S) -6-methoxy-2- (methyl (sulfamoyl) amino) -5- ( (tetrahydro furan-3-yl) oxy) nicotinate
  • Step 11 (S) -4-Hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) -1H-pyrido [2, 3-c] [1, 2, 6] thiadiazine 2, 2-dioxide
  • Step 12 4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-pyrido [2, 3-c] [1, 2, 6] thiadiazine 2, 2-dioxide
  • Step 4 Methyl (S) -4-methoxy-2- (sulfamoylamino) -5- ( (tetrahydrofuran-3-yl) oxy) benzoate
  • Step 6 (S) -4-Hydroxy-7-methoxy-1-methyl-6- ( (tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide
  • Step 7 4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-1-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine-2, 2-dioxide
  • Step 1 (S) -2-Bromo-N-isopropyl-5-methoxy-4- ( (tetrahydrofuran-3-yl) oxy) aniline
  • Step 2 Methyl (S) -2- (isopropylamino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate
  • Step 3 Methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (isopropyl) amino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate
  • Step 4 Methyl (S) -2- (isopropyl (sulfamoyl) amino) -4-methoxy-5- ( (tetrahydro furan-3 -yl) oxy) benzoate
  • Step 5 4- (4-Bromo-2- (2- (methylamino) ethoxy) -5-nitrophenoxy) butanoic acid
  • Step 6 4- ( ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -1-isopropyl -7-methoxy-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide
  • Step 2 1- (8-Nitroquinolin-6-yl) ethan-1-one
  • Step 3 (Z) -1- (8-Nitroquinolin-6-yl) ethan-1-one oxime
  • Step 5 N- ( (R) -1- (8-aminoquinolin-6-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine
  • Step 1 1- (4-Nitro-1H-indol-3-yl) ethan-1-one
  • Step 2 1- (4-Nitro-1H-indol-3-yl) ethan-1-one
  • Step 4 Tert-butyl (Z) - (3- (1- (hydroxyimino) ethyl) -1-methyl-1H-indol-4-yl) carbamate
  • Step 5 Tert-butyl (3- (1-aminoethyl) -1-methyl-1H-indol-4-yl) carbamate
  • Step 6 3- (1-Aminoethyl) -1-methyl-1H-indol-4-amine
  • Step 7 N- ( (R) -1- (4-amino-1-methyl-1H-indol-3-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine
  • Step 2 Tert-butyl (Z) - (5- (1- (hydroxyimino) ethyl) -4-methylthiazol-2-yl) carbamate
  • Step 3 Tert-butyl (5- (1-aminoethyl) -4-methylthiazol-2-yl) carbamate
  • Step 4 Tert-butyl (5- ( (R) -1- ( (7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -4-methylthiazol-2-yl) carbamate
  • Step 5 5- ( (R) -1- ( (7-Methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-yl) amino) ethyl) -4-methylthiazol-2-amine
  • Step 1 N- ( (R) -1- (6-aminopyridin-2-yl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine
  • Step 1 Methyl (S) -2- (cyclopropylamino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate
  • Step 2 Methyl (S) -2- ( (N- ( (benzyloxy) carbonyl) sulfamoyl) (cyclopropyl) amino) -4-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) benzoate
  • Step 3 Methyl (S) -2- (cyclopropyl (sulfamoyl) amino) -4-methoxy-5- ( (tetra hydrofuran-3-yl) oxy) benzoate
  • Step 4 (S) -1-cyclopropyl-4-hydroxy-7-methoxy-6- ( (tetrahydrofuran-3-yl) oxy) -1H-benzo [c] [1, 2, 6] thiadiazine 2, 2-dioxide
  • Step 5 N- ( (R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6a, 7, 9, 9a-tetrahydrofuro [3', 4': 5, 6] [1, 4] dioxino [2, 3-g] quinazolin-4-amine
  • Step 3 Methyl 4- (4-bromo-2- (2- ( (tert-butoxycarbonyl) (methyl) amino) ethoxy) -5-nitrophenoxy) butanoate
  • Step 4 4- (4-Bromo-2- (2- ( (tert-butoxycarbonyl) (methyl) amino) ethoxy) -5-nitro phenoxy) butanoic acid
  • Step 5 4- (4-Bromo-2- (2- (methylamino) ethoxy) -5-nitrophenoxy) butanoic acid
  • Step 7 Methyl 4-methyl-11-nitro-5-oxo-3, 4, 5, 6, 7, 8-hexahydro-2H-benzo [b] [1, 4] dioxa [7] azacycloundecine-12-carboxylate
  • Step 8 Methyl 11-amino-4-methyl-5-oxo-3, 4, 5, 6, 7, 8-hexahydro-2H-benzo [b] [1, 4] dioxa [7] azacycloundecine-12-carboxylate
  • Step 9 4-Hydroxy-2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] aza cycloundecino [3, 2-g] quinazolin-10 (11H) -one
  • Step 10 (R) -4- ( (1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] azacycloundecino [3, 2-g] quinazolin-10 (11H) -one
  • Step 4 Methyl 7-amino-3- (methoxymethyl) -2, 3-dihydrobenzo [b] [1, 4] dioxine-6-carboxylate
  • Step 5 7- (Methoxymethyl) -2-methyl-7, 8-dihydro- [1, 4] dioxino [2, 3-g] quinazolin-4-ol
  • Step 6 N- ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) -7- (methoxymethyl) -2-methyl-7, 8-dihydro- [1, 4] dioxino [2, 3-g] quinazolin-4-amine
  • Step 4 Methyl 7-amino-1, 3, 3a, 9a-tetrahydrobenzo [b] furo [3, 4-e] [1, 4] dioxine-6-carboxylate
  • Step 5 2-Methyl-6a, 7, 9, 9a-tetrahydrofuro [3', 4': 5, 6] [1, 4] dioxino [2, 3-g] quinazolin-4-ol
  • Step 6 N- ( (R) -1- (3-Amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6a, 7, 9, 9a -tetrahydrofuro [3', 4': 5, 6] [1, 4] dioxino [2, 3-g] quinazolin-4-amine
  • Step 1 (R) -4- ( (1- (3- (Difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 9-dimethyl-8, 9, 12, 13-tetrahydro-7H- [1, 4] dioxa [7] azacycloundecino [3, 2-g] quinazolin-10 (11H) -one
  • the KRAS G12D-SOS1 biochemical binding assay was carried out by Pharmaron Beijing Co., Ltd. (China) .
  • logIC50 same log units as X
  • Example # IC 50 Example # IC 50 Example 2 A Example 22-1 C Example 4 A Example 22-2 C Example 18-1 C Example 23 C Example 18-2 A Example 21-1 C Example 21-2 B
  • A means ⁇ 100 nM
  • B means >100 nM and ⁇ 1000 nM
  • C means >1000 nM
  • the pERK in-cell WB assay was tested in GP2D cell lines and carried out by Pharmaron Beijing Co., Ltd. (China) .
  • Example # IC 50 Example 2 C
  • Example 4 A
  • Example 18-2 B Example 21-1 C
  • A means ⁇ 1 uM
  • B means >1 uM and ⁇ 2 uM
  • C means >2 uM
  • the cell proliferation was carried out in H358 and GP2D cell lines by Pharmaron.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne les composés de formule I, leur utilisation en tant qu'inhibiteurs de pan KRAS : SOS1, leurs compositions pharmaceutiques et leur utilisation en tant que médicaments, en particulier en tant qu'agents pour le traitement de maladies oncologiques comprenant le cancer.
PCT/CN2022/098201 2021-06-11 2022-06-10 Composés en tant qu'agents anticancéreux WO2022258057A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009294A1 (fr) * 1994-09-19 1996-03-28 The Wellcome Foundation Limited Composes heteroaromatiques substitues et leur utilisation en medecine
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2021203768A1 (fr) * 2020-04-08 2021-10-14 江苏恒瑞医药股份有限公司 Dérivé pyrimido dicyclo, son procédé de préparation et son utilisation en médecine
CN114539245A (zh) * 2020-11-26 2022-05-27 上海翰森生物医药科技有限公司 含嘧啶并环类衍生物调节剂、其制备方法和应用
WO2022143533A1 (fr) * 2020-12-30 2022-07-07 成都百裕制药股份有限公司 Dérivé de quinazoline et son utilisation en médecine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009294A1 (fr) * 1994-09-19 1996-03-28 The Wellcome Foundation Limited Composes heteroaromatiques substitues et leur utilisation en medecine
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2021203768A1 (fr) * 2020-04-08 2021-10-14 江苏恒瑞医药股份有限公司 Dérivé pyrimido dicyclo, son procédé de préparation et son utilisation en médecine
CN114539245A (zh) * 2020-11-26 2022-05-27 上海翰森生物医药科技有限公司 含嘧啶并环类衍生物调节剂、其制备方法和应用
WO2022143533A1 (fr) * 2020-12-30 2022-07-07 成都百裕制药股份有限公司 Dérivé de quinazoline et son utilisation en médecine

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