WO2023217095A1 - Composé hétérocyclique, composition pharmaceutique et utilisation associée - Google Patents

Composé hétérocyclique, composition pharmaceutique et utilisation associée Download PDF

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Publication number
WO2023217095A1
WO2023217095A1 PCT/CN2023/092820 CN2023092820W WO2023217095A1 WO 2023217095 A1 WO2023217095 A1 WO 2023217095A1 CN 2023092820 W CN2023092820 W CN 2023092820W WO 2023217095 A1 WO2023217095 A1 WO 2023217095A1
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ring
membered
group
methyl
alkyl
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PCT/CN2023/092820
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Hu HE
Song Liu
Chongxun GE
Song Shi
Yaqi CUI
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Synrx Therapeutics (Hangzhou) Co., Ltd.
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Publication of WO2023217095A1 publication Critical patent/WO2023217095A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • C07D417/02—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
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the present invention relates to a heterocyclic compound, a pharmaceutical composition and a use thereof.
  • DNA double-strand breaks are the most cytotoxic lesions and must be repaired to preserve chromosomal integrity and maintain cell survival.
  • Cells employ three main mechanisms to repair DSBs: homologous recombination (HR) , classical nonhomologous end joining (NHEJ) and microhomology-mediated end-joining (MMEJ) . While both NHEJ and HR mediate faithful repair, MMEJ induces mutagenesis follow DSB religation. Thus, MMEJ is an error prone repair mechanism, causes genomic instability and leads to tumorigenesis (Gerarda van de Kamp et al., Frontiers in genetics. 2021, 12, 738230-738245) .
  • NHEJ and HR cells repair majorities of DSBs.
  • MMEJ is activated for DSB repair.
  • MMEJ acts on DSB ends with short-range overhang and uses microhomology with 2-20 bp on both sides of DSB for ligation (Anna Schrempf et al., Trends in cancer. 2021, 7 (2) , 98-111) .
  • the key enzyme mediating MMEJ is DNA polymerase theta (Pol ⁇ , encoded by POLQ) , which induces the DNA ends pairing via microhomology and conducts DNA elongation towards filling the gap (Mateos-Gomez P.A., et al., Nature (2015) ; 518: 254-57) .
  • Pol ⁇ DNA polymerase theta
  • POLQ DNA polymerase theta
  • cancer cells Unlike normal cells, cancer cells often harbor genetic mutations that impair NHEJ or HR to induce genetic instability. During the process, MMEJ is hyperactivated to repair spontaneous DSBs. It has been shown that the expression of Pol ⁇ is remarkably upregulated in multiple types of cancer, including HR-deficient cancers (Ceccaldi R., et al., Nature (2015) ; 518, 258-62; Mateos-Gomez PA et al., Nature (2015) ; 518: 254-57) . This cellular phenotype is important for cancer cell viability since cancer cells need MMEJ to repair DSBs for survival. Thus, targeting Pol ⁇ largely abolishes DSB repair in cancer cells with HR and/or NHEJ defects, and induces cancer cell apoptosis via synthetic lethality.
  • Pol ⁇ is a 2590-residue nuclear polypeptide with a N-terminal ATPase domain and a C-terminal DNA polymerase domain.
  • the C-terminal polymerase domain is essential for DNA elongation at DSBs during MMEJ (Harris P.V., et al., Mol Cell Biol. (1996) ; 16: 5764-5771; Jia Zhou et al., Nature cancer. 2021, 2 (6) : 598-610; Lemee et al., PNAS (2010) , 107 (30) , 13390-13395) .
  • targeting the C-terminal polymerase domain is able to suppress MMEJ and the growth of cancer cells with HR and/or NHEJ defects.
  • the present disclosure provides a heterocyclic compound, a pharmaceutical composition and a use thereof, the compound of the present disclosure shows a good inhibitory effect on Pol ⁇ , which can be used as Pol ⁇ inhibitor to treat cancers containing DNA repair defects, such as breast cancer, lung cancer, ovarian cancer, and other cancers.
  • the present disclosure provides a compound represented by formula I, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of the pharmaceutically acceptable salt thereof;
  • R X1 and R X2 are independently H, deuterium, halogen, hydroxyl or C 1 -C 6 alkyl; or R X1 and R X2 together with the atom to which they are attached form a 3-6 membered saturated carbocyclic ring, or 3-6 membered saturated heterocarbocyclic ring having 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
  • Y is N or CH
  • R 1 is 5-12 membered heteroaryl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 5-12 membered heteroaryl substituted by one or more R 1-1 having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 5-12 membered heterocycloalkenyl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 5-12 membered heterocycloalkenyl substituted by one or more R 1-2 having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 5-12 membered heterocycloalkyl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, or 5-12 membered heterocycloalkyl substituted by one or more R 1-3 having 1-5 heteroatoms independently selected from the group consisting of N, O, and S;
  • each of R 1-1 , R 1-2 and R 1-3 is independently CN, halogen, hydroxyl, deuterium, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1-1-1 , C 2 -C 6 alkenyl, -SO 2 R 1-1-2 , C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 1-1-3 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R 1-1-4 , -NR d R e , -C (O) R d , -C (O) OR d , -C (O) NR d R e , -SO 2 NR d R e , -P (O) R d R e , -NR d C (O) R e , -NR d C (O) OR e or -NR d
  • each of R 1-1-1 is independently deuterium, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 1-1-1-1 , 3-12 membered heterocycloalkyl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 3-12 membered heterocycloalkyl substituted by one or more R 1-1-1-2 having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, -NR d R e or halogen;
  • each of R 1-1-1-1 is independently deuterium or R a , R b and R c are independently H or C 1 -C 6 alkyl;
  • each of R 1-1-1-2 is independently C 1 -C 6 alkyl
  • each of R 1-1-2 is independently C 1 -C 6 alkyl
  • each of R 1-1-3 is independently deuterium, hydroxyl or halogen
  • each of R 1-1-4 is independently deuterium, hydroxyl, halogen, C 1 -C 6 alkoxy or C 1 -C 6 alkyl;
  • each of R d and R e is independently H or C 1 -C 6 alkyl
  • R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 3-1 or C 3 -C 6 cycloalkyl;
  • each of R 3-1 is independently deuterium or halogen
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or a 5-6 membered heteroaromatic ring substituted by one or more R 3-2 having 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
  • each of R 3-2 is independently deuterium, halogen or C 1 -C 6 alkyl
  • ring A is C 6 -C 10 aromatic ring or 5-12 membered heteroaromatic ring having 1-5 heteroatoms independently selected from the group consisting of N, O, and S;
  • each of R 4 is independently CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 4-1 , halogen, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 4-2 , -NR d R e , -C (O) R d , -C (O) OR d , -C (O) NR d R e , -SO 2 R d , -SO 2 NR d R e , -P (O) R d R e , -NR d C (O) R e , -NR d C (O) OR e or -NR d SO 2 R e ; or two adjacent R 4 together with the two atoms to which they are attached form a 5-6 membered carbocyclic ring or 5-6 membered heterocarbocyclic ring having 1-3 heteroatoms independently selected from the
  • R 4-1 and R 4-2 are independently deuterium, hydroxyl or halogen
  • n 0, 1, 2, 3, 4 or 5;
  • ring B is C 6 -C 10 aromatic ring or 5-12 membered heteroaromatic ring having 1-5 heteroatoms independently selected from the group consisting of N, O, and S;
  • each of R 5 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 5-1 , hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 5-2 , CN, -NR d R e , -C (O) R d , -C (O) OR d , -C (O) NR d R e , -SO 2 R d , -SO 2 NR d R e , -P (O) R d R e , -NR d C (O) R e , -NR d C (O) OR e or -NR d SO 2 R e ; or two adjacent R 5 together with the two atoms to which they are attached form a 5-6 membered carbocyclic ring or 5-6 membered heterocarbocycl
  • R 5-1 and R 5-2 are independently deuterium, hydroxyl or halogen
  • n 0, 1, 2, 3, 4 or 5.
  • some groups in the compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof can be defined as below, and the unmentioned groups are as described in any one of the other embodiments (referred to as "in an embodiment” ) ,
  • R X1 and R X2 are independently H, deuterium, halogen, hydroxyl or C 1 -C 6 alkyl; or R X1 and R X2 together with the atom to which they are attached form a 3-6 membered saturated carbocyclic ring, or 3-6 membered saturated heterocarbocyclic ring having 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
  • Y is N or CH;
  • R 1 is 5-12 membered heteroaryl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 5-12 membered heteroaryl substituted by one or more R 1-1 having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 5-12 membered heterocycloalkenyl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 5-12 membered heterocycloalkenyl substituted by one or more R 1-2 having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 5-12 membered heterocycloalkyl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, or 5-12 membered heterocycloalkyl substituted by one or more R 1-3 having 1-5 heteroatoms independently selected from the group consisting of N, O, and S;
  • each of R 1-1 , R 1-2 and R 1-3 is independently CN, halogen, hydroxyl, deuterium, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1-1-1 , C 2 -C 6 alkenyl, -SO 2 R 1-1-2 , C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 1-1-3 , -NR d R e , -C (O) R d , -C (O) OR d , -C (O) NR d R e , -SO 2 NR d R e , -P (O) R d R e , -NR d C (O) R e , -NR d C (O) OR e or -NR d SO 2 R e ;
  • each of R 1-1-1 is independently deuterium, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 1-1-1-1 , 3-12 membered heterocycloalkyl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, 3-12 membered heterocycloalkyl substituted by one or more R 1-1-1-2 having 1-5 heteroatoms independently selected from the group consisting of N, O, and S, -NR d R e or halogen;
  • each of R 1-1-1-1 is independently deuterium or R a , R b and R c are independently H or C 1 -C 6 alkyl;
  • each of R 1-1-1-2 is independently C 1 -C 6 alkyl
  • each of R 1-1-2 is independently C 1 -C 6 alkyl
  • each of R 1-1-3 is independently deuterium, hydroxyl or halogen
  • each of R d and R e is independently H or C 1 -C 6 alkyl
  • R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 3-1 or C 3 -C 6 cycloalkyl;
  • each of R 3-1 is independently deuterium or halogen
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or a 5-6 membered heteroaromatic ring substituted by one or more R 3-2 having 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
  • each of R 3-2 is independently deuterium, halogen or C 1 -C 6 alkyl
  • ring A is C 6 -C 10 aromatic ring or 5-12 membered heteroaromatic ring having 1-5 heteroatoms independently selected from the group consisting of N, O, and S;
  • each of R 4 is independently CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 4-1 , halogen, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 4-2 , -NR d R e , -C (O) R d , -C (O) OR d , -C (O) NR d R e , -SO 2 R d , -SO 2 NR d R e , -P (O) R d R e , -NR d C (O) R e , -NR d C (O) OR e or -NR d SO 2 R e ; or two adjacent R 4 together with the two atoms to which they are attached form a 5-6 membered carbocyclic ring or 5-6 membered heterocarbocyclic ring having 1-3 heteroatoms independently selected from the
  • R 4-1 and R 4-2 are independently deuterium, hydroxyl or halogen
  • n 0, 1, 2, 3, 4 or 5;
  • ring B is C 6 -C 10 aromatic ring or 5-12 membered heteroaromatic ring having 1-5 heteroatoms independently selected from the group consisting of N, O, and S;
  • each of R 5 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 5-1 , hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 5-2 , CN, -NR d R e , -C (O) R d , -C (O) OR d , -C (O) NR d R e , -SO 2 R d , -SO 2 NR d R e , -P (O) R d R e , -NR d C (O) R e , -NR d C (O) OR e or -NR d SO 2 R e ; or two adjacent R 5 together with the two atoms to which they are attached form a 5-6 membered carbocyclic ring or 5-6 membered heterocarbocycl
  • R 5-1 and R 5-2 are independently deuterium, hydroxyl or halogen
  • n 0, 1, 2, 3, 4 or 5.
  • each of the halogen is independently F, Cl, Br or I, e.g., F or Cl.
  • each of the C 1 -C 6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, e.g., methyl, ethyl or n-propyl.
  • each of the 5-12 membered heteroaryl is independently 5-6 or 9-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of N, O, and S, e.g., thiazolyl (e.g., ) , oxazolyl (e.g., ) , pyrazolyl (e.g., ) , imidazolyl (e.g., ) , isoxazolyl (e.g., ) , 1, 3, 4-oxadiazolyl (e.g., ) , 1, 2, 5-oxadiazolyl (e.g., ) , 1, 2, 4-oxadiazolyl (e.g., ) , 1, 2, 3-triazolyl (e.g., ) , 1, 2, 4-triazolyl (e.g., ) , tetrazolyl (e.g., ) , benzimidazolyl (e.g., thiazolyl
  • each of the 5-12 membered heteroaryl is independently 5-6 or 9-10 membered heteroaryl having 2-4 heteroatoms independently selected from the group consisting of N and O, more preferably, each of the 5-12 membered heteroaryl is oxazolyl (e.g., ) , pyrazolyl (e.g., ) , imidazolyl (e.g., ) , isoxazolyl (e.g., ) , 1, 3, 4-oxadiazolyl (e.g., ) , 1, 2, 5-oxadiazolyl (e.g., ) , 1, 2, 4-oxadiazolyl (e.g., ) , 1, 2, 3-triazolyl (e.g., ) , 1, 2, 4-triazolyl (e.g., ) , tetrazolyl (e.g., ) , benzimidazolyl (e.g., ) , indazolyl (
  • each of the 5-12 membered heteroaryl is independently thiazolyl (e.g., ) , pyrazolyl (e.g., ) , imidazolyl (e.g., ) , isoxazolyl (e.g., ) , 1, 3, 4-oxadiazolyl (e.g., ) , 1, 2, 5-oxadiazolyl (e.g., ) , 1, 2, 4-oxadiazolyl (e.g., ) , 1, 2, 3-triazolyl (e.g., ) , 1, 2, 4-triazolyl (e.g., ) , tetrazolyl (e.g., ) , benzimidazolyl (e.g., ) , indazolyl (e.g., , pyridopyrazolyl (e.g., ) , more preferably, each of the 5-12 membered heteroaryl
  • each of the 5-12 membered heterocycloalkenyl is independently 5-6 membered heterocycloalkenyl having 1-3 heteroatoms selected from N, e.g.,
  • each of the 5-12 membered heterocycloalkyl is independently 5-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from the group consisting of N, O, and S, e.g.,
  • the C 2 -C 6 alkenyl is vinyl, propyl, allyl or butenyl, e.g., vinyl.
  • each of the C 1 -C 6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, e.g., methoxy or ethoxy.
  • each of the 3-12 membered heterocycloalkyl is independently 5-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from the group consisting of N and O, e.g., Preferably, each of the 3-12 membered heterocycloalkyl is independently 5-membered heterocycloalkyl having 1-3 heteroatoms selected from O.
  • the C 3 -C 6 cycloalkyl is independently cyclopropyl, cyclobutanyl, cyclopentanyl or cyclohexyl.
  • each of the 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from the group consisting of N, O, and S is independently 5-6 membered heteroaromatic ring having 1-3 heteroatoms selected from N, e.g.,
  • the C 6 -C 10 aromatic ring is independently benzene ring or naphthalene ring, e.g., benzene ring.
  • the 5-12 membered heteroaromatic ring having 1-5 heteroatoms independently selected from the group consisting of N, O, and S is 5-6 membered heteroaromatic ring having 1-2 heteroatoms selected from N, e.g., pyridine ring (e.g., ) or pyrimidine ring (e.g., ) .
  • the 5-12 membered heteroaromatic ring having 1-5 heteroatoms independently selected from the group consisting of N, O, and S is pyridine ring (e.g., ) .
  • the 5-12 membered heteroaromatic ring having 1-5 heteroatoms independently selected from the group consisting of N, O, and S is 5-6 or 9-10 membered heteroaromatic ring having 1-2 heteroatoms selected from N, e.g., pyridine ring (e.g., ) , pyrimidine ring (e.g., ) or pyridopyrrole ring (e.g., ) .
  • the 5-6 membered carbocyclic ring when two adjacent R 4 together with the two atoms to which they are attached form a 5-6 membered carbocyclic ring, then the 5-6 membered carbocyclic ring includes but is not limited to
  • the 5-6 membered heterocarbocyclic ring having 1-3 heteroatoms independently selected from the group consisting of N, O, and S includes but is not limited to
  • X is CR X1 R X2 , and Y is N; or, X is NH or O, Y is CH; preferably, X is CR X1 R X2 , and Y is N.
  • R X1 and R X2 are independently H, deuterium or C 1 -C 6 alkyl.
  • R X1 and R X2 are independently H, deuterium or C 1 -C 6 alkyl.
  • each of R 1-1 , R 1-2 and R 1-3 is independently CN, halogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1-1-1 , C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, -C (O) OR d , -C (O) NR d R e or -SO 2 R 1- 1-2 , preferably, each of R 1-1 , R 1-2 and R 1-3 is independently CN, halogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1-1-1 , C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, -C (O) OR d , or -C (O) NR d R e .
  • each of R 1-1 , R 1-2 and R 1-3 is independently CN, halogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1-1-1 , C 2 -C 6 alkenyl or -SO 2 R 1-1-2 , preferably, each of R 1-1 , R 1-2 and R 1-3 is independently CN, halogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1-1-1 or C 2 -C 6 alkenyl.
  • each of R 1-1-1 is independently deuterium, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 1-1-1-1 , 3-12 membered heterocycloalkyl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S or 3-12 membered heterocycloalkyl substituted by one or more R 1-1-1-2 having 1-3 heteroatoms independently selected from the group consisting of N, O, and S or halogen, preferably, each of R 1-1-1 is independently deuterium, hydroxyl, 5-6 membered heterocycloalkyl having 1-3 heteroatoms selected from N and O or 5-6 membered heterocycloalkyl substituted by one or more R 1-1-1-2 having 1-3 heteroatoms selected from N and O, C 1 -C 6 alkoxy, or halogen.
  • each of R 1-1-1 is independently deuterium, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted by one or more R 1-1-1-1 , 3-12 membered heterocycloalkyl having 1-5 heteroatoms independently selected from the group consisting of N, O, and S or 3-12 membered heterocycloalkyl substituted by one or more R 1-1-1-2 having 1-3 heteroatoms independently selected from the group consisting of N, O, and S, preferably, each of R 1-1-1 is independently deuterium, hydroxyl, 5-membered heterocycloalkyl having 1-3 heteroatoms selected from O or 5-membered heterocycloalkyl substituted by one or more R 1-1-1-2 having 1-3 heteroatoms selected from O.
  • R 3 is C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more deuterium.
  • ring A is 5-6 membered heteroaromatic ring having 1-2 heteroatoms selected from N.
  • each of R 4 is independently CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 4-1 , -C (O) R d , hydroxyl or halogen, preferably, each of R 4 is independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more R 4-1 or halogen.
  • each of R 4 is independently CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more halogen or halogen, preferably, each of R 4 is independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogen.
  • each of R 4 is independently halogen, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more R 4- 1 .
  • each of R 4 is independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogen.
  • ring B is benzene ring or 5-6 or 9-10 membered heteroaromatic ring having 1-2 heteroatoms selected from N, preferably, ring B is benzene ring.
  • each of R 5 is independently halogen or C 1 -C 6 alkyl.
  • X is CH 2 , NH, CH (CH 3 ) or O.
  • R 1 is
  • R 1 is
  • ring A is pyridine ring, e.g., e.g.,
  • each of R 4 is CF 3 , CH 3 , Cl, CN, CD 3 , OH, CH 2 F, CH 2 OH, C (O) H, e.g., CF 3 , CH 3 , Cl or CN.
  • n is 2 or 3, preferably, m is 2.
  • ring B is benzene ring, pyrimidine ring, pyridine ring or pyrrolopyridine ring.
  • each of R 5 is F, Cl or CH 3 .
  • n 1, 2 or 3.
  • the compound represented by general formula I is:
  • the compound represented by formula I is a compound represented by formula II:
  • R 1 , R X1 , R X2 , R 3 , R 4 , R 5 , m, n, ring A and ring B are as defined in any one of the embodiments.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present disclosure also provides a use of the compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of Pol ⁇ inhibitors.
  • the present disclosure also provides a use of the compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a medicament for treating and/or preventing cancers, includes but is not limited to breast, lung, and ovarian cancers.
  • the present disclosure also provides a method for treating and/or preventing cancers in a subject in need thereof, comprising: administering an effective amount of the compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof to the subject.
  • the cancers are breast, lung, and ovarian cancers.
  • pharmaceutically acceptable refers to relatively non-toxic, safety and suitable for patients.
  • pharmaceutically acceptable salt refers to the salt obtained by the reaction of a compound with a pharmaceutically acceptable acid or base.
  • the alkali addition salt can be obtained by contacting the compound with a sufficient amount of pharmaceutically acceptable alkali in a suitable inert solvent.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of pharmaceutically acceptable acid in a suitable inert solvent.
  • solvate refers to a substance formed by the combination of a compound and a solvent. Solvates can be divided into stoichiometric solvates and non-stoichiometric solvates.
  • solvate of pharmaceutically acceptable salt refers to substances formed by the combination of compounds with pharmaceutically acceptable acids or bases and solvents.
  • the amount of solvent can be stoichiometric or non-stoichiometric.
  • halogen refers to F, Cl, Br or I.
  • alkyl refers to linear or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 1 -C 6 ) .
  • exemplary alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • alkoxy refers to the group -O-R A , and the definition of R A is the same as the term “alkyl” .
  • exemplary alkoxy includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, etc.
  • alkenyl refers to linear or branched, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (e.g., C 2 -C 6 ) , which has one or more (e.g., 1, 2 or 3) carbon-carbon sp 2 double bonds.
  • exemplary alkenyl includes but is not limited to vinyl, etc.
  • aromatic ring refers to a cyclic, unsaturated hydrocarbon ring having a specified number of carbon atoms (eg, C 6 -C 10 ) , which is a monocyclic or polycyclic.
  • exemplary aromatic ring includes but is not limited to benzene ring or naphthalene ring.
  • heteroaryl refers to an unsaturated monovalent group having a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5) , a specified number of ring atoms (e.g., 5-12 membered, 5-6 membered, or 8-10 membered) , and a specified heteroatom species (one or more independently selected from the group consisting of N, O, and S) , which is a monocyclic or polycyclic, which share two atoms and one bond between single rings, and which are aromatic in each ring.
  • a specified number of heteroatoms e.g., 1, 2, 3, 4 or 5
  • ring atoms e.g., 5-12 membered, 5-6 membered, or 8-10 membered
  • a specified heteroatom species one or more independently selected from the group consisting of N, O, and S
  • Heteroaryl is attached to the rest of the molecule through a carbon atom or a heteroatom; Heteroaryl is attached to the rest of the molecule through a ring with or without a heteroatom.
  • Exemplary heteroaryl includes but is not limited to etc.
  • heterocycloalkenyl refers to unsaturated monovalent group having a specified number of heteroatoms (eg, 1, 2, 3, 4 or 5) , a specified number of ring atoms (eg, 5-12 membered, 5-6 membered, or 8-10 membered) , and a specified heteroatom species (one or more independently selected from the group consisting of N, O, and S) , which is monocyclic or polycyclic, which is not aromatic, which has one or more (eg, 1, 2, or 3) carbon-carbon sp 2 double bonds.
  • Heterocycloalkenyl is attached to the rest of the molecule through a carbon atom or a heteroatom.
  • Exemplary heterocycloalkenyl includes but is not limited to etc.
  • heterocycloalkyl refers to saturated monovalent group having a specified number of heteroatoms (eg, 1, 2, 3, 4 or 5) , a specified number of ring atoms (eg, 5-12 membered, 5-6 membered, or 8-10 membered) , and a specified heteroatom species (one or more independently selected from the group consisting of N, O, and S) , which is monocyclic or polycyclic.
  • Heterocycloalkyl is attached to the rest of the molecule through a carbon atom or a heteroatom.
  • Exemplary heterocycloalkyl includes but is not limited to etc.
  • cycloalkyl refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (eg, C 3 -C 6 ) , which is monocyclic.
  • exemplary cycloalkyl includes but is not limited to
  • treating refers to eliminating the cause or alleviating the symptoms.
  • preventing refers to reducing the risk of developing a disease.
  • pharmaceutically acceptable carrier refers to all substances contained in pharmaceutical preparations except active pharmaceutical ingredients, which are generally divided into excipients and additives.
  • pharmaceutically acceptable carrier refers to all substances contained in pharmaceutical preparations except active pharmaceutical ingredients, which are generally divided into excipients and additives.
  • pharmaceutically acceptable carrier refers to all substances contained in pharmaceutical preparations except active pharmaceutical ingredients, which are generally divided into excipients and additives.
  • pharmaceutical exceptions Paul J sheskey, Bruno C Hancock, Gary P moss, David J Goldfarb, 2020, 9th Edition
  • the term "effective amount” refers to an amount administered to a patient that is sufficient to effectively treat the disease.
  • the effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by those skilled in the art.
  • the compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic chemistry.
  • General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence in order to give the desired compound or compounds. Examples of compounds of the present invention prepared by methods described in the general schemes are given in the preparations and examples section set out hereinafter. Preparation of homochiral examples may be carried out by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products by chiral preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically enriched products.
  • Preparation of compounds of Formula I and intermediates used in the preparation of compounds can be prepared using procedures shown in the following Examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula I can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature.
  • the phrase “dried and concentrated” generally refers to drying of a solution in an organic solvent over either sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (generally under reduced pressure and at a temperature suitable to the stability of the material being prepared) .
  • Column chromatography is performed with regular gravity or flash chromatography, or pre-packed silica gel cartridges using a medium pressure chromatography apparatus (Biotage Isolera One) , eluting with the solvent or solvent mixture indicated.
  • the final products are purified by preparative thin layer chromatography using 20 cm ⁇ 20 cm ⁇ 0.5 mm or 20 cm ⁇ 20 cm ⁇ 1 mm silica gel plates developed in a suitable solvent system.
  • HPLC high performance liquid chromatography
  • a reverse phase column Waters Sunfire C18, Waters Xbridge C18, or the like
  • a reverse phase column Waters Sunfire C18, Waters Xbridge C18, or the like
  • Chemical names are generated using ChemDraw Professional version 19.1.
  • Step 1 tert-butyl (2- ( (3-chloro-4-fluorophenyl) (methyl) amino) -2-oxoethyl) carbamate.
  • Step 1 (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -3-nitro-1H-1, 2, 4-triazole.
  • Step 2. 1- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -1H-1, 2, 4-triazol-3-amine.
  • Step 3 N- (1- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -1H-1, 2, 4-triazol-3-yl) -6-methyl-4- (trifluoromethyl) pyridin-2-amine.
  • reaction mixture was cooled to room temperature, then concentrated in vacuo.
  • the mixture was extracted with EtOAc (3 ⁇ 50 mL) .
  • the combined organic layers were washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo, the residue was purified by flash column chromatography on silica gel using a gradient of 0%-20%EtOAc in PE to afford the desired compound as yellow solid (1.44 g, 71.3%) .
  • Step 4 2- ( (1- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -1H-1, 2, 4-triazol-3-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N- (3-chloro-4-fluorophenyl) -N-methylacetamide.
  • Step 5 N- (3-chloro-4-fluorophenyl) -2- ( (1- (2-hydroxyethyl) -1H-1, 2, 4-triazol-3-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide.
  • Step 1-Step 4. Conducted in a similar manner to Example 1, steps 1-4, using 2-nitro-1H-imidazole.
  • Example 38 is prepared according to general synthetic Scheme III.
  • Step 1 N- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) thiazol-2-amine
  • Step 2 N- (3-chloro-4-fluorophenyl) -N-methyl-2- ( (6-methyl-4- (trifluoromethyl) pyridin-2- yl) (thiazol-2-yl) amino) acetamide 2, 2, 2-trifluoroacetate
  • Example 50 is prepared according to general synthetic Scheme IV.
  • Step 1 ethyl 2- ( (6-methyl-4- (trifluoromethyl) pyridin-2-yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-imidazol-2-yl) amino) acetate
  • Step 4 N- (3-chloro-4-fluorophenyl) -N- (methyl-d 3 ) -2- ( (6-methyl-4- (trifluoromethyl) pyridin-2- yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) amino) acetamide
  • Step 1 N- ( (1- (3-chloro-4-fluorophenyl) -1H-imidazol-2-yl) methyl) -6-methyl-4- (trifluoromethyl) - N- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) pyridin-2-amine
  • Step 1 1- (4-methoxybenzyl) -1H-tetrazol-5-amine.
  • Step 2 N- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) -6-methyl-4- (trifluoromethyl) pyridin-2-amine.
  • Step 3 N- (5-chloro-2, 4-difluorophenyl) -2- ( (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide.
  • reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) .
  • EtOAc 50 mL ⁇ 3
  • the combined organic layers were washed with brine (50 mL ⁇ 3) , dried over Na 2 SO 4 , filtered and evaporated.
  • Step 1 1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole-4-carbonitrile.
  • Step 3 N- (3-chloro-4-fluorophenyl) -2- ( (4-cyano-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol- 2-yl) amino) -N-methylacetamide.
  • Step 4 N- (3-chloro-4-fluorophenyl) -2- ( (5-cyano-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol- 2-yl) (3-cyano-6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide.
  • Step 5 N- (3-chloro-4-fluorophenyl) -2- ( (5-cyano-1H-imidazol-2-yl) (3-cyano-6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide.
  • Step 1 N- (3-chloro-4-fluorophenyl) -2- ( (5-cyano-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol- 2-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide.
  • Step 2 N- (3-chloro-4-fluorophenyl) -2- ( (5-cyano-1H-imidazol-2-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide.
  • Step 1 N- (3-chloro-4-fluorophenyl) -2- ( (1- (2-chloroethyl) -1H-imidazol-2-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide.
  • Step 2 N- (3-chloro-4-fluorophenyl) -N-methyl-8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) - 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrimidine-7-carboxamide.
  • Step 1 (3-chloro-4-fluorophenyl) (methyl) carbamic chloride.
  • Step 2. (2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole.
  • N,O-dimethylhydroxylamine hydrochloride (3.48 g, 35.685 mmol) , DIPEA (14.744 mL, 89.212 mmol) and HATU (16.96 g, 44.606 mmol) were added to a solution of 6-methyl-4- (trifluoromethyl) pyridine-2-carboxylic acid (6.1 g, 29.737 mmol) in DMF (60 mL) . The mixture was stirred at ambient temperature for 17 hours. The mixture was dissolved in DCM and washed with 1M HCl, dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 6 (6-methyl-4- (trifluoromethyl) pyridin-2-yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- imidazol-2-yl) methanone.
  • Step 7 (E) - (6-methyl-4- (trifluoromethyl) pyridin-2-yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- imidazol-2-yl) methanone oxime.
  • Step 8 (6-methyl-4- (trifluoromethyl) pyridin-2-yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- imidazol-2-yl) methanamine.
  • Step 1 methyl 5- ( (4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) amino) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazole-3-carboxylate.
  • Step 2 methyl 5- ( (2- ( (3-chloro-2, 4-difluorophenyl) (methyl) amino) -2-oxoethyl) (4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) amino) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazole-3- carboxylate.
  • Step 4.5 ( (2- ( (3-chloro-2, 4-difluorophenyl) (methyl) amino) -2-oxoethyl) (4-methyl-6- (trifluoromethyl) pyrimidin-2-yl) amino) -N, N-dimethyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4- triazole-3-carboxamide.
  • N- (3-chloro-2, 4-difluorophenyl) -2- [ (5-chloro-2H-1, 2, 3-triazol-4-yl) [4-methyl-6- (trifluoromethyl) pyrimidin-2-yl] amino] -N-methylacetamide (30 mg, 0.060 mmol) in DMF (2 mL) was added Cs 2 CO 3 (59.1 mg, 0.181 mmol) and CH 3 I (12.8 mg, 0.091 mmol) . The mixture was stirred at room temperature for 12 hours.
  • Step 3 N- (1- ( (2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-1, 2, 4-triazol-3-yl) -6-methyl-4- (trifluoromethyl) pyridin-2-amine
  • Step 4 N- (3-chloro-2, 4-difluorophenyl) -2- ( (1- ( (2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-1, 2, 4- triazol-3-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N- (methyl-d3) acetamide
  • Step 1 5-dibromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazole.
  • Step 3 6-methyl-4- (trifluoromethyl) -N- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -3-vinyl-1H-1, 2, 4- triazol-5-yl) pyridin-2-amine.
  • Step 4 N- (3-chloro-2, 4-difluorophenyl) -N-methyl-2- ( (6-methyl-4- (trifluoromethyl) pyridin-2-yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) -5-vinyl-1H-1, 2, 4-triazol-3-yl) amino) acetamide.
  • reaction solution was poured into water (10 mL) , extracted with ethyl acetate (60 mL ⁇ 3) .
  • the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • Step 5 N- (3-chloro-2, 4-difluorophenyl) -2- ( (5- (1, 2-dihydroxyethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazol-3-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) - N-methylacetamide.
  • Step 6 N- (3-chloro-2, 4-difluorophenyl) -2- ( (5- (1, 2-dihydroxyethyl) -1H-1, 2, 4-triazol-3-yl) (6- methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide.
  • N- (3-chloro-2, 4-difluorophenyl) -2- ( (5- (1, 2-dihydroxyethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazol-3-yl) (6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N-methylacetamide (120 mg, 0.138 mmol) in THF (4 mL) was added TBAF (0.041 mL, 0.138 mmol ) . Then the mixture was stirred at rt for 48 h. Then to the reaction solution was added water (10 mL) .
  • Step 1 4- (benzyloxy) -2-chloro-6- (trifluoromethyl) pyrimidine.
  • Step 2 4- (benzyloxy) -6- (trifluoromethyl) -N- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazol- 3-yl) pyrimidin-2-amine.
  • Step 3 2- ( (4- (benzyloxy) -6- (trifluoromethyl) pyrimidin-2-yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-1, 2, 4-triazol-3-yl) amino) -N- (3-chloro-2, 4-difluorophenyl) -N-methylacetamide.
  • Step 4 N- (3-chloro-2, 4-difluorophenyl) -2- ( (4-hydroxy-6- (trifluoromethyl) pyrimidin-2-yl) (1H- 1, 2, 4-triazol-3-yl) amino) -N-methylacetamide.
  • Step 1 N- (3-chloro-2, 4-difluorophenyl) -2- ( (4-chloro-6- (trifluoromethyl) pyrimidin-2-yl) (4H-1, 2, 4- triazol-3-yl) amino) -N-methylacetamide.
  • Step 1 2- ( (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) amino) -6- (trifluoromethyl) pyrimidine-4- carboxylic acid
  • Step 2 (2- ( (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) amino) -6- (trifluoromethyl) pyrimidin-4- yl) methanol
  • the crude compound was purified by prep-HPLC (SilaSep TM C18 silica flash cartridge, 10%-95%MeCN in H 2 O with 0.1%TFA) to give the desired compound N- (3-chloro-2, 4-difluorophenyl) -2- ( (4- (fluoromethyl) -6- (trifluoromethyl) pyrimidin-2-yl) (1H-tetrazol-5-yl) amino) -N-methylacetamide (10.9 mg, 30.28% yield) as white solid.
  • Step 2 4- (methyl-d 3 ) -6- (trifluoromethyl) -N- (2- ( (2- (trimethylsilyl) ethoxy) methyl) -2H-1, 2, 3-triazol- 4-yl) pyrimidin-2-amine
  • Step 3 N- (5-chloro-2, 4-difluorophenyl) -N- (methyl-d3) -2- ( (4- (methyl-d3) -6- (trifluoromethyl) pyrimidin-2-yl) (2- ( (2- (trimethylsilyl) ethoxy) methyl) -2H-1, 2, 3-triazol-4- yl) amino) acetamide
  • the crude compound was purified by prep-HPLC (SilaSep TM C18 silica flash cartridge, 25%-95%MeCN in H 2 O with 0.1%FA) to give the title compound N- (3-chloro-2, 4-difluorophenyl) -N- (methyl-d3) -2- ( (4- (methyl-d3) -6- (trifluoromethyl) pyrimidin-2-yl) (1H-1, 2, 3-triazol-4-yl) amino) acetamide (31.5 mg, 44.75%yield) as white solid.
  • Step 1 4- (trifluoromethyl) -6- ( (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazol-3- yl) amino) picolinaldehyde
  • Step 2 (4- (trifluoromethyl) -6- ( (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazol-3- yl) amino) pyridin-2-yl) methanol
  • Step 3 N- (3-chloro-2, 4-difluorophenyl) -2- ( (6- (hydroxymethyl) -4- (trifluoromethyl) pyridin-2-yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazol-3-yl) amino) -N-methylacetamide
  • Step 4 N- (3-chloro-2, 4-difluorophenyl) -2- ( (6- (fluoromethyl) -4- (trifluoromethyl) pyridin-2-yl) (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazol-3-yl) amino) -N-methylacetamide
  • Step 6.5- (2- ( (3-chloro-2, 4-difluorophenyl) (methyl) amino) -2-oxoethyl) (6-methyl-4- (trifluoromethyl) -5-vinylpyridin-2-yl) amino) -N, N-dimethyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H- 1, 2, 4-triazole-3-carboxamide
  • Step 7 5- ( (2- ( (3-chloro-2, 4-difluorophenyl) (methyl) amino) -2-oxoethyl) (5-formyl-6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N, N-dimethyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4- triazole-3-carboxamide
  • Step 8 5- ( (2- ( (3-chloro-2, 4-difluorophenyl) (methyl) amino) -2-oxoethyl) (5-formyl-6-methyl-4- (trifluoromethyl) pyridin-2-yl) amino) -N, N-dimethyl-1H-1, 2, 4-triazole-3-carboxamide
  • TR-FRET assay was used to measure the ability of compounds to inhibit the activity of Pol ⁇ in vitro.
  • N-His tagged Pol ⁇ protein (amino acid 1819-2590, Catalog#: S2201T-H01H Lot#: 220107-1, ICE Bioscience) expressed in Sf9 cells was purified and stored at -80°C in aliquots. Assay measurements were performed with 1 ⁇ buffer comprising 25mM Tris (PH7.5) , 0.5mM MgCl 2 , 12.5 mM NaCl, 0.01%Triton X-100, 0.01%BSA, 1mM DTT.
  • Test compounds were prepared by dilution in 100%DMSO to give the correct dose range for 10-point concentration response and appropriate volume (0.15 ⁇ L) dispense into 384 well micro assay plates (Greiner-784075) using a Labcyte Echo 665 acoustic dispenser. DMSO concentration was maintained at 1%by back filling with DMSO. Purified recombinant Pol ⁇ was diluted in assay buffer to a 3 ⁇ concentration (7.5nM) . 5 ⁇ L Pol ⁇ was dispensed into each well of the compound plate using a 8 channel manual pipette and pre-incubated at 25°C for 10min.
  • dsDNA substrate was annealed by the two oligos below.
  • SEQ NO. 1 5'-Biotin-GCGGCTGTCATAAG-3'
  • SEQ NO. 2 5'-CTCAGATTGCGTCTTATGACAGCCGCG-3'.

Abstract

L'invention concerne un composé hétérocyclique, une composition pharmaceutique et une utilisation associée. L'invention concerne un composé représenté par la formule I, un solvate de celui-ci, un sel pharmaceutiquement acceptable de celui-ci ou un solvate du sel pharmaceutiquement acceptable de celui-ci. Le composé présente un bon effet inhibiteur sur Polθ, pouvant être utilisé en tant qu'inhibiteur de Polθ pour traiter des cancers contenant des défauts de réparation d'ADN, tels que des cancers du sein, du poumon et de l'ovaire.
PCT/CN2023/092820 2022-05-09 2023-05-08 Composé hétérocyclique, composition pharmaceutique et utilisation associée WO2023217095A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011112263A1 (fr) * 2010-03-11 2011-09-15 New York University Composés amido à titre de modulateurs rorγt et leurs utilisations
WO2013063214A1 (fr) * 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
WO2014052563A2 (fr) * 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2014052566A1 (fr) * 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2017099237A1 (fr) * 2015-12-11 2017-06-15 帝人ファーマ株式会社 Dérivé d'aminoazole
WO2019166824A1 (fr) * 2018-03-01 2019-09-06 Karus Therapeutics Limited Dérivés d'oxadiazolylthiophène à utiliser en tant qu'inhibiteurs de l'histone désacétylase
WO2020264437A1 (fr) * 2019-06-27 2020-12-30 The George Washington University Macrophages activés par hdac6, compositions et utilisations associées
WO2022026548A1 (fr) * 2020-07-29 2022-02-03 Ideaya Biosciences, Inc. Dérivés acétamido-amino et acétamido-soufre utilisés en tant qu'inhibiteurs de l'adn polymérase thêta

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011112263A1 (fr) * 2010-03-11 2011-09-15 New York University Composés amido à titre de modulateurs rorγt et leurs utilisations
WO2013063214A1 (fr) * 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
WO2014052563A2 (fr) * 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2014052566A1 (fr) * 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2017099237A1 (fr) * 2015-12-11 2017-06-15 帝人ファーマ株式会社 Dérivé d'aminoazole
WO2019166824A1 (fr) * 2018-03-01 2019-09-06 Karus Therapeutics Limited Dérivés d'oxadiazolylthiophène à utiliser en tant qu'inhibiteurs de l'histone désacétylase
WO2020264437A1 (fr) * 2019-06-27 2020-12-30 The George Washington University Macrophages activés par hdac6, compositions et utilisations associées
WO2022026548A1 (fr) * 2020-07-29 2022-02-03 Ideaya Biosciences, Inc. Dérivés acétamido-amino et acétamido-soufre utilisés en tant qu'inhibiteurs de l'adn polymérase thêta

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