WO2023185831A1 - Composé contenant un cycle thiazole - Google Patents

Composé contenant un cycle thiazole Download PDF

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Publication number
WO2023185831A1
WO2023185831A1 PCT/CN2023/084374 CN2023084374W WO2023185831A1 WO 2023185831 A1 WO2023185831 A1 WO 2023185831A1 CN 2023084374 W CN2023084374 W CN 2023084374W WO 2023185831 A1 WO2023185831 A1 WO 2023185831A1
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alkyl
alternatively
ring
membered
alkynyl
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PCT/CN2023/084374
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English (en)
Chinese (zh)
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张寅生
刘保民
黄雨
计磊
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正大天晴药业集团股份有限公司
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Publication of WO2023185831A1 publication Critical patent/WO2023185831A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • 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

Definitions

  • the present application relates to compounds containing thiazole rings, their preparation methods, pharmaceutical compositions containing the compounds, and their use in the treatment of cancer and other diseases.
  • DNA damage response plays an important role in maintaining cellular genome stability and organism survival.
  • DNA double-strand breaks (DSBs) are the most serious form of DNA damage.
  • Homologous recombination repair is one of the important mechanisms involved in the repair of DSBs damage in vivo, in which the recombinant protein RAD51 is the core factor in repairing DNA double-strand breaks (DSBs) through homologous recombination.
  • RAD51 is a eukaryotic gene.
  • the protein encoded by this gene is a member of the RAD51 protein family, which helps repair DNA double-strand breaks.
  • RAD51 is a 339-amino acid protein that plays an important role in DNA homologous recombination during double-strand break (DSB) repair.
  • RAD51 catalyzes strand transfer between the broken sequence and its unbroken homolog to allow resynthesis of the damaged region.
  • AID activation-induced cytidine deaminase
  • AID activation-induced cytidine deaminase
  • RAD51 RAD51 to repair DNA damage caused by cytosine deaminase.
  • RAD51 has low or no expression in normal tissues, but is overexpressed in a variety of human cancer cells, such as breast cancer, non-small cell lung cancer, prostate cancer, etc., and is associated with tumor metastasis and progression.
  • RAD51 highly expressed RAD51 promotes homologous recombination repair in cancer cells, thereby inducing resistance of cancer cells to radiotherapy and chemotherapy that can cause DNA damage. It has been reported in the literature that RAD51 inhibitors can enhance the sensitivity of cancer cells to chemotherapy and radiotherapy. Related research results support the use of RAD51 as an anti-tumor drug target to develop small molecule RAD51 inhibitors to enhance the lethality of chemotherapy or radiotherapy to cancer cells.
  • MCTs Monocarboxylate transporters
  • MCT1 is a high-affinity lactate transporter that efficiently imports and exports lactate.
  • Cancer cell metabolism requires lactate transport to support their high proliferation rate.
  • MCTs are frequently upregulated in cancer, leading to poor prognosis and increased mortality.
  • Inhibiting MCT results in downstream reductions in several proteins important for cell cycle regulation, including RAD51, which may explain the effects seen in homologous recombination analyses. Effects seen in group analyses.
  • MCT-mediated lactate transport is critical for cancer cell survival and tumorigenesis, making it an attractive target for cancer therapy and drug development.
  • R 1 is selected from 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-15 membered heterocyclyl, phenyl, 3-10 membered cycloalkyl, C 2-10 alkenyl or C 2- 10 alkynyl;
  • the 3-10-membered heterocycloalkyl or 5-6-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-15-membered heterocyclyl, phenyl or 3-10-membered cycloalkyl is optionally substituted by one or more R c ;
  • the C 2-10 alkenyl or C 2-10 alkynyl group is optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1-3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
  • R a is selected from deuterated C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -C 1-3 alkyl-CON(C 1-6 alkyl) 2 , the deuterated C 1-6 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl is optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1- 3 alkyl) 2 substituted;
  • R b is selected from halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl or halo C 1-6 alkyl;
  • R c is selected from C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, oxo, halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1-3 alkyl) Or -N(C 1-3 alkyl) 2 , the C 2-10 alkenyl or C 2-10 alkynyl group is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2. -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
  • R d and R e are independently selected from H, halogen, CN or C 1-6 alkyl;
  • L is selected from bond or NR f ;
  • R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl Cycloalkyl is optionally substituted with one or more OH, OC 1-3 alkyl, halogen, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
  • X 1 and X 2 are independently selected from NR g or O;
  • Y is selected from CH 2 , N or O;
  • R f and R g are independently selected from H or C 1-3 alkyl
  • R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl Cycloalkyl is optionally substituted with one or more OH, OC 1-3 alkyl, halogen, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
  • R 4 and R 5 are each independently selected from H, OH, halogen, CN, NH 2 , C 1-6 alkyl or C 1-6 alkoxy substitution.
  • R 1 is selected from 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-13 membered heterocyclyl, phenyl, 3-8 membered cycloalkyl, C 2 -8 alkenyl or C 2-8 alkynyl;
  • the 3-8-membered heterocycloalkyl or 5-6-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-13-membered heterocyclyl, phenyl or 3-8-membered cycloalkyl is optionally substituted by one or more R c ;
  • the C 2-8 alkenyl or C 2-8 alkynyl group is optionally substituted by one or more halogens or OH.
  • R 1 is selected from 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-11 membered heterocyclyl, phenyl, 4-6 membered cycloalkyl, C 3 -6 alkenyl or C 3-6 alkynyl;
  • the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-11 membered heterocyclyl, phenyl or 4-6 membered cycloalkyl is optionally substituted by one or more R c .
  • the R 1 is selected from 5-membered heteroaryl, 8-membered heterocyclyl, 10-membered heterocyclyl, 11-membered heterocyclyl or C 4-5 alkynyl;
  • the 5-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl is optionally substituted by one or more R c .
  • R1 is selected from the group consisting of 5-membered heteroaryl, 8-membered heterocyclyl containing a fused ring, 10-membered heterocyclyl containing a fused ring and a spiro ring, 10-membered heterocyclyl containing a fused ring and a spiro ring, 11-membered heterocyclyl or C 4-5 alkynyl;
  • the 5-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl is optionally substituted by one or more R c .
  • the heteroatom of the above-mentioned heterocycloalkyl, heteroaryl or heterocyclyl group is selected from nitrogen, oxygen or sulfur; alternatively, the heteroatom of the heterocyclyl group is selected from nitrogen or oxygen.
  • the number of heteroatoms may be selected from 1, 2, 3, 4, 5 or 6, or the number of heteroatoms may be selected from 2, 3 or 4, or the number of heteroatoms may be selected from 2 or 3 .
  • the heterocyclyl group contains at least 2 heteroatoms, selected from nitrogen or oxygen; in some specific embodiments, the heteroatoms of the heterocyclyl group are 2 nitrogen atoms, or 3 nitrogen atoms , or 2 nitrogen atoms and 1 oxygen atom.
  • the heterocyclyl group can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heterocyclyl group is selected from bicyclic or tricyclic rings. Furthermore, the bicyclic or tricyclic rings may be connected through fused rings, bridged rings or spiro rings. In some embodiments, the heterocyclyl group is selected from a bicyclic ring or a tricyclic ring, the bicyclic ring is connected through a fused ring, and the tricyclic ring is connected through a spiro ring and a fused ring.
  • the heterocyclyl group is selected from bicyclic or tricyclic rings, in which the ring directly connected to the NH site is an aromatic ring or a heteroaromatic ring.
  • the heterocyclyl group is selected from a bicyclic or tricyclic ring, and one of the bicyclic or tricyclic rings is selected from a heteroaromatic ring or an aromatic ring; optionally, one of the bicyclic or tricyclic rings is selected from a heteroaromatic ring or an aromatic ring.
  • the ring is selected from heteroaromatic rings; further, optionally, the bicyclic or tricyclic ring is directly connected to the NH position.
  • the attached ring is a heteroaromatic ring.
  • the heterocyclyl group is selected from the group consisting of a 5-membered ring fused to a 5-membered ring, a 3-membered spiro 6-membered ring fused to a 5-membered ring, or a 3-membered spiro 5-membered ring fused to a 5-membered ring.
  • R1 is selected from pyrazolyl, imidazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, Hydrogen-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2- b]pyrazol] base, 6',7'-dihydrospiro[cyclopropane-1,4'-pyrazolo[5,1-c][1,4]oxazine] base, 4'H,6 'H-spiro[cyclopropan-1,5'-pyrrolo[1,2-b]pyrazol]yl, pent-3-yn-2-yl or but-2-yn-1-yl,
  • the pyrazolyl, imidazolyl or triazolyl group is substituted by one or more R a , optionally substituted by one or more R b ;
  • the R1 is selected from
  • the R1 is selected from
  • R a is selected from deuterated C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -C 1-3 alkyl-CON(C 1-3 alkyl) 2.
  • the deuterated C 1-4 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl groups are optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 substitution.
  • R a is selected from deuterated C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkyl-CON(C 1-3 alkyl) 2.
  • the C 2-6 alkenyl or C 2-6 alkynyl group is optionally replaced by one or more halogens, OH, OC 1-2 alkyl, CN, NH 2 , -NH (C 1-2 alkyl ) or -N(C 1-2 alkyl) 2 replace.
  • R a is selected from deuterated C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -CH 2 CON(C 1-2 alkyl) 2 , the C 2-4 alkenyl or C 2-4 alkynyl is optionally substituted with one or more fluorine, chlorine, bromine or OH.
  • R a is selected from deuterated methyl, vinyl, propenyl, ethynyl, propynyl, -CH 2 CON(CH 3 ) 2 , said vinyl, propenyl, ethynyl, or propynyl.
  • Alkynyl groups are optionally substituted with one or more fluorine or OH.
  • R a is selected from optionally modified by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1 -3 alkyl) 2 substituted In some embodiments, R is selected from optionally substituted with one or more halogens, OH, CN, or NH
  • Ra is selected from deuterated methyl
  • R b is selected from halogen, OH, CN, NH 2 , C 1-3 alkyl, C 3-4 cycloalkyl, or haloC 1-3 alkyl;
  • R b is selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 3-4 cycloalkyl, or haloC 1-3 alkyl.
  • R b is selected from fluorine, chlorine, methyl, cyclopropyl, or -CHF 2 .
  • R c is selected from C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-8 alkenyl or C 2-8 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
  • R c is selected from C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-6 alkenyl or C 2-6 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
  • R c is selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-4 alkenyl or C 2-4 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
  • R c is selected from C 2-4 alkenyl, C 2-4 alkynyl, halogen, OH, CN or NH 2 , the C 2-4 alkenyl, C 2-4 alkynyl is optionally replaced by one or more halogen, OH, CN or NH 2 substitution.
  • R c is selected from Halogen, OH, CN or NH 2 .
  • R c is selected from Fluorine, chlorine or bromine. In some embodiments, R c is selected from Or fluorine.
  • R d and R e are each independently selected from hydrogen, halogen, CN, or C 1-3 alkyl.
  • R d and R e are each independently selected from hydrogen, fluorine, chlorine, CN, or methyl. In some embodiments, R d and Re are hydrogen.
  • the R1 is selected from The definitions of R a , R b or R c are independently as described above.
  • the R1 is selected from
  • L is selected from bond or NH. In some embodiments, L is selected from bonds.
  • R 2 is selected from C 1-3 alkyl, C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, said C 1-3 alkyl, C 3-5 cycloalkyl Or 3-5 membered heterocycloalkyl optionally substituted by one or more OH, halogen, CN, NH2 or C1-3 alkoxy group.
  • R2 is selected from C 1-3 alkyl, C 3-5 cycloalkyl, or 4-membered heterocycloalkyl, said C 1-3 alkyl, C 3-5 cycloalkyl, or 4-membered heterocycloalkyl
  • a membered heterocycloalkyl group is optionally substituted with one or more OH, halogen, CN or NH .
  • R is selected from ethyl, cyclopropyl, dicyclopentyl, or 4-membered heterocycloalkyl, optionally Substituted by one or more fluorine, chlorine or bromine.
  • R is selected from ethyl, cyclopropyl, bicyclopentyl, or a 4-membered heterocycloalkyl containing 1 heteroatom selected from N or O.
  • Pentyl or 4-membered heterocycloalkyl is optionally substituted with one or more fluorine, chlorine or bromine.
  • R is selected from ethyl, dicyclopentyl, oxetanyl, or cyclopropyl optionally substituted with one or more fluorine.
  • R is selected from ethyl
  • R is selected from C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, which is optionally replaced by a Or multiple OH, halogen, CN or NH substitutions. In some embodiments, R is selected from C 3-5 cycloalkyl, which is optionally substituted with one or more OH, halogen, CN , or NH . In some embodiments, R2 is selected from C3-4 cycloalkyl. In some embodiments, R is selected from
  • X 1 and X 2 are each independently selected from NH or O. In some embodiments, X1 is selected from NH and X2 is selected from O.
  • Y is selected from CH2 or O. In some embodiments, Y is selected from CH2 .
  • R f and R g are each independently selected from H or methyl. In some embodiments, Rf and Rg are H.
  • R 3 is selected from C 1-4 alkyl, C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, said C 1-4 alkyl, C 3-5 cycloalkyl Or 3-5 membered heterocycloalkyl optionally substituted by one or more OH, halogen, CN, NH2 or C1-3 alkoxy group.
  • R 3 is selected from C 1-4 alkyl, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl, said C 1-4 alkyl, C 3-4 cycloalkyl Or 3-4 membered heterocycloalkyl optionally substituted with one or more OH, halogen, CN or NH .
  • R3 is selected from C 1-4 alkyl, C 3-4 cycloalkyl, or 3-4 membered heterocycloalkyl.
  • R 3 is selected from C 1-4 alkyl. In some embodiments, R3 is selected from C3-4 alkyl.
  • R3 is selected from isopropyl.
  • R 4 and R 5 are each independently selected from hydrogen, OH, halogen, CN, NH 2 , C 1-3 alkyl, or C 1-3 alkoxy.
  • R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-3 alkyl, or C 1-3 alkoxy.
  • R 4 and R 5 are each independently selected from hydrogen.
  • structural fragments Selected from Further, the structure fragment Selected from
  • structural fragments Selected from In some embodiments, structural fragments Selected from In some embodiments, structural fragments Selected from
  • R1 is selected from pyrazolyl, imidazolyl, or triazolyl substituted with one or more Ra , optionally with one or Multiple R b substitutions.
  • the R1 is selected from pyrazolyl substituted with one or more Ra , optionally substituted with one or more Rb .
  • Ra is selected from deuterated C 1-3 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, which C 2-6 alkenyl or C 2-6 alkynyl is optionally Ground is substituted by one or more halogen, OH, OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl) 2 .
  • Ra is selected from deuterated C 1-3 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, which C 2-4 alkenyl or C 2-4 alkynyl is optionally Ground is substituted by one or more fluorine, chlorine, bromine or OH.
  • R is selected from deuterated methyl, vinyl, propenyl, or propynyl optionally substituted with one or more fluorine or OH.
  • Ra is selected from deuterated methyl or C 2-4 alkynyl optionally substituted with one or more fluorine or OH.
  • R is selected from deuterated methyl or propynyl, which is optionally substituted with one or more fluorine or OH.
  • Ra is selected from deuterated methyl
  • R is selected from C 2-6 alkenyl or C 2-6 alkynyl, which is optionally replaced by one or more halogen, OH , OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl) 2 substitution.
  • R is selected from C 2-4 alkenyl or C 2-4 alkynyl, which is optionally replaced by one or more fluorine, chlorine , bromine or OH substitution.
  • R is selected from vinyl, propenyl, or propynyl, which is optionally substituted with one or more fluorine or OH.
  • Ra is selected from
  • the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkenes base, C 2-6 alkynyl or deuterated C 1-3 alkyl, when it is substituted by two R a , one R a is selected from C 2-6 alkenyl or C 2-6 alkynyl, the other R a is selected from deuterated C 1-3 alkyl, the C 2-6 alkenyl or C 2-6 alkynyl is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 substitution.
  • the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkenes base or C 2-6 alkynyl, when it is substituted by two R a , one R a is selected from C 2-6 alkenyl or C 2-6 alkynyl, and the other R a is selected from deuterated C 1-3 Alkyl, the C 2-6 alkenyl or C 2-6 alkynyl is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl ) or N(C 1-3 alkyl) 2 substitution.
  • the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkynes group, when it is substituted by two R a , one R a is selected from C 2-6 alkynyl group, and the other R a is selected from deuterated C 1-3 alkyl group, the C 2-6 alkynyl group is optionally Substituted by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 .
  • the above-mentioned pyrazolyl, imidazolyl or triazolyl group is substituted by one or two R a , optionally substituted by one or more R b , when it is substituted by one R a , the R a Selected from C 2-6 alkynyl, when it is substituted by two R a , one R a is selected from C 2-6 alkynyl, and the other R a is selected from deuterated C 1-3 alkyl, the C 2 -6 Alkynyl is optionally substituted with one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 .
  • the above heterocyclyl group is substituted by one or two R c , and when substituted by one R c , R c is selected from C 2-4 alkenyl, or C 2-4 alkynyl; when substituted by two R c , one R c is selected from C 2-4 alkenyl or C 2-4 alkynyl, the other R c is selected from halogen, OH, CN or NH 2 ; the C 2-4 alkenyl or C 2-4 alkynyl is optionally replaced by a or more selected from halogen, OH, CN or NH substitution .
  • the above-mentioned heterocyclyl group is optionally substituted by one or two R c .
  • R c is selected from When replaced by two R c , one of which is selected from The other R c is selected from halogen.
  • the compound of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of compounds of Formula IA or Formula I-A', its stereoisomer or its pharmaceutically acceptable salt. of salt,
  • R 1 , L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as defined in this application.
  • structural fragments and is defined as described in this application.
  • the compound of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of a compound of Formula II, its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as described in this application;
  • R' is selected from hydrogen, halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
  • R 6 is each independently selected from C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, halogen, OH, CN, NH 2 , C 3-6 cycloalkyl, OC 1-3 alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
  • Ring A is selected from 5-6 membered heteroaryl or 8-15 membered heterocyclyl
  • n is selected from 0, 1, 2, 3 or 4.
  • the compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of a compound of formula III, its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R c are as described in this application;
  • Ring B is selected from absence, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl;
  • Ring C is selected from 5-6 membered heterocycloalkyl
  • Ring D is selected from 5-6 membered heteroaryl
  • n is selected from 0, 1, 2, 3 or 4.
  • the R' is selected from hydrogen, halogen, OH, OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl ) 2 ;
  • R' is selected from hydrogen, fluorine, chlorine, bromine or OH;
  • R' is selected from hydrogen, fluorine, bromine or OH;
  • R' is selected from hydrogen, fluorine or OH.
  • each R 6 is independently selected from C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, halogen, OH, CN, NH 2 , C 3- 4 cycloalkyl, OC 1-3 alkyl, -NH (C 1-3 alkyl) or -N (C 1-3 alkyl) 2 ; or, R 6 is each independently selected from C 1-3 alkyl , deuterated C 1-3 alkyl, halo C 1-3 alkyl, halogen or C 3-4 cycloalkyl; or, R 6 is each independently selected from methyl, deuterated methyl, halomethyl , fluorine, chlorine, bromine or cyclopropyl; alternatively, R 6 is each independently selected from methyl, -CD 3 , -CHF 2 , fluorine, chlorine or cyclopropyl.
  • the ring A is selected from 5-membered heteroaryl, 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl;
  • Ring A is selected from the group consisting of a 5-membered heteroaryl group, an 8-membered heterocyclyl group containing a fused ring, a 10-membered heterocyclyl group containing a fused ring and a spiro ring, and an 11-membered heterocyclyl group containing a fused ring and a spiro ring. ;
  • Ring A is selected from 5-membered heteroaryl
  • Ring A is selected from 5-membered nitrogen-containing heteroaryl
  • Ring A is selected from pyrazolyl, imidazolyl or triazolyl;
  • Ring A is selected from pyrazole.
  • Ring B is selected from Absence or C 3-4 cycloalkyl; or Ring B is selected from Absence or cyclopropyl.
  • the ring C is selected from pyrrolidinyl or morpholinyl.
  • Ring D is selected from 5-membered heteroaryl; or Ring D is selected from pyrazolyl or triazolyl.
  • Ring B is absent
  • Ring C is pyrrolidinyl
  • Ring D is selected from pyrazolyl or triazolyl.
  • the ring B is cyclopropyl
  • ring C is selected from pyrrolidinyl or morpholinyl
  • ring D is pyrazolyl
  • structural fragments and is defined as described in this application.
  • n is selected from 0, 1, 2, or 3; alternatively, m is selected from 0 or 1.
  • n is selected from 0, 1, 2, or 3.
  • the compound of Formula I, Formula IA or Formula II, its stereoisomer or its pharmaceutically acceptable salt described in the present application is selected from the group consisting of the compound of Formula II-A, its stereoisomer or its pharmaceutically acceptable salt. acceptable salt,
  • R', ring A, m, L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R 6 are as defined in this application.
  • the compound of Formula I, Formula IA or Formula III, its stereoisomer or its pharmaceutically acceptable salt described in the present application is selected from the group consisting of the compound of Formula III-A, its stereoisomer or its pharmaceutically acceptable salt. acceptable salt,
  • ring B, ring C, ring D, n, L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R c are as described in this application.
  • the compounds of Formula I, or Formula II, their stereoisomers, or pharmaceutically acceptable salts thereof described in the present application are selected from the group consisting of compounds of Formula IV, their stereoisomers, or their pharmaceutically acceptable salts ,
  • R', m, L, R 2 , R 3 , R 4 , R 5 and R 6 are as described in this application.
  • the compounds of Formula I, Formula IA, Formula II, Formula II-A or Formula IV, their stereoisomers or their pharmaceutically acceptable salts described in the present application are selected from the group consisting of compounds of Formula IV-A, their Stereoisomers or pharmaceutically acceptable salts thereof,
  • R', m, L, R 2 , R 3 , R 4 , R 5 and R 6 are as described in this application.
  • the compounds of Formula I or Formula III, their stereoisomers, or pharmaceutically acceptable salts thereof described in the present application are selected from the group consisting of compounds of Formula V, their stereoisomers, or their pharmaceutically acceptable salts,
  • n, L, R 2 , R 3 , R 4 , R 5 and R c are as described in this application.
  • the compounds of Formula I, Formula IA, Formula III, Formula III-A or V, their stereoisomers or their pharmaceutically acceptable salts described in the present application are selected from the group consisting of compounds of Formula VA, their stereoisomers body or a pharmaceutically acceptable salt thereof,
  • n, L, R 2 , R 3 , R 4 , R 5 and R c are as described in this application.
  • substituent ranges are disclosed in the specific embodiments and/or claims for any particular L, X1 , X2 , Y, R1 , R2 , R3 , R4 or R5 substituent, It is understood that one or more substituents may be deleted from this range and the remaining substituent ranges shall also be considered embodiments of the present application.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • the present application relates to a method for treating cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases in mammals, comprising administering a therapeutically effective amount of the above compounds, their stereoisomers, to mammals in need of such treatment, preferably humans. body or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of medicines for preventing or treating cancer, autoimmune diseases, immune deficiencies or neurodegenerative diseases. uses in.
  • the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in preventing or treating cancer, autoimmune diseases, immune deficiencies or neurodegenerative diseases.
  • the present application relates to the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases.
  • the cancer is selected from lymphoma, leukemia, or solid tumors.
  • the solid tumor is selected from lung cancer, breast cancer, and the like.
  • the present application relates to a method of treating a mammal with a disease mediated by RAD51 and/or MCT, comprising administering a therapeutically effective amount of the above compound, a stereoisomer thereof or a mammal in need of the treatment, preferably a human.
  • Pharmaceutically acceptable salts, or pharmaceutical compositions thereof are provided.
  • the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of drugs for preventing or treating diseases mediated by RAD51 and/or MCT.
  • the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in preventing or treating diseases mediated by RAD51 and/or MCT.
  • the present application relates to the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating RAD51 and/or MCT-mediated diseases.
  • the above-mentioned RAD51 and/or MCT-mediated diseases are selected from cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases.
  • the cancer is selected from lymphoma, leukemia, or solid tumors.
  • the solid tumor is selected from lung cancer, breast cancer, and the like.
  • the compound of the present application has at least one of the following effects: improved or excellent inhibitory activity on Daudi cells; compared with WI38-VA13 cells, it has selective inhibitory activity on Daudi cells; improved or excellent in vivo efficacy; in vitro various
  • the liver microsomal metabolism of species for example, rats, dogs, monkeys, mice and humans
  • mice or rats, dogs
  • Generation kinetic data (such as AUC, C max or t 1/2 , etc.).
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • the term "optionally” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and absence of the stated event or circumstance.
  • the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), or poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
  • One or more in this article refers to an integer ranging from one to ten. For example, “one or more” refers to one, two, three, four, five, six, seven, eight, nine or ten; or “one or more” refers to one, two , three, four, five or six; alternatively, "one or more” means one, two or three.
  • C mn as used herein means that the part has an integer number of carbon atoms in the given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • any variable e.g., R
  • its definition in each instance is independent. So, for example, if a group is replaced by 2 R's, there are separate options for each R.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • substituents bond When a substituent's bond is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • structural unit Indicates that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbyl group having the general formula C n H 2n+1 .
  • the alkyl group may be straight chain or branched.
  • C 1 -6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl refers to an alkyl group containing 1 to 5 carbon atoms
  • C 1 - 4 alkyl referring to an alkyl group containing 1 to 4 carbon atoms
  • C 1 - 3 Alkyl refers to an alkyl group containing 1 to 3 carbon atoms.
  • alkyl portion ie, alkyl of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.
  • alkoxy refers to -O-alkyl
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond.
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring (eg, a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring).
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl etc.
  • heterocyclyl refers to a partially unsaturated (but not fully unsaturated heteroaromatic) non-aromatic ring.
  • the "heterocyclyl” may be a single ring or a polycyclic ring (including but not limited to bicyclic or tricyclic rings).
  • the heterocycle is generally a 3- to 15-membered ring (e.g., 3-membered, 4-membered 1, 5, 6, or 7-membered rings).
  • Non-limiting examples of heterocyclyl include, but are not limited to, dihydrofuryl, dihydropyrrolyl, 2H-pyranyl, wait.
  • the term "monocyclic” refers to a cyclic group containing one ring, which may be fully saturated, partially saturated or aromatic.
  • the monocyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example.
  • bicyclic refers to a cyclic group containing two rings, which may be fully saturated, partially saturated, or aromatic.
  • the bicyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example.
  • the bicyclic ring may be a fused ring, a bridged ring or a spiro ring.
  • tricyclic refers to a cyclic group containing three rings, which may be fully saturated, partially saturated, or aromatic.
  • the tricyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example. Any two adjacent single rings in the three rings may be fused rings, bridged rings or spiro rings.
  • fused ring refers to a polycyclic compound formed by the fusion of two or more carbocyclic or heterocyclic rings with two atoms in common, including fully saturated, partially saturated and aromatic. Unless otherwise indicated, the fused ring has 5 to 20 members, preferably 6 to 14 members, and more preferably 9 to 14 members. Non-limiting examples of fused rings include, but are not limited to, naphthalene, anthracene, phenanthrene, wait.
  • bridged ring refers to a fully saturated or partially unsaturated polycyclic system in which two rings share three or more atoms, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the bridged ring is 5-14 yuan, preferably 6-14 yuan, more preferably 6-10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, more preferably bicyclic.
  • one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of N, O, S(O) n (where n is 0, 1 or 2) ), the remaining ring atoms are carbon atoms.
  • spiro ring refers to a fully saturated or partially unsaturated polycyclic system in which a single carbon atom (called a spiro atom) is shared between single rings, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the spiro ring is 5 to 20 members, preferably 6 to 14 members, more preferably 9 to 14 members.
  • the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of N, O, S(O) n (where n is 0, 1 or 2) ), the remaining ring atoms are carbon atoms.
  • heterocycloalkyl refers to a fully saturated cyclic group.
  • the “heterocycloalkyl” may be a single ring or a polycyclic ring (including but not limited to bicyclic or tricyclic rings).
  • the heterocycle is generally a 3- to 10-membered ring (e.g., 3-membered, 4-membered 1, 5, 6, or 7-membered rings).
  • 3-membered heterocycloalkyl include, but are not limited to, oxirane, ethylene sulfide, and aziridyl.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane.
  • Examples of cyclyl, thibutylcyclyl, and 5-membered heterocycloalkyl include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, and thiazolidine 1, 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxeptanyl, and thiopanyl. Preference is given to monocyclic heterocycloalkyl groups with 5 or 6 ring atoms.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetralin, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, such as 1, 2 or 3 ring atoms selected from N, O, S Ring atoms, the remaining ring atoms are C, and it has at least one aromatic ring.
  • Preferred heteroaryl groups have a single 5 to 8 membered ring (eg 4, 5, 6, 7 or 8 membered ring) or contain 6 to 14, especially 6 to 10 (or 9) rings Multiple fused rings of atoms.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • hetero refers to heteroatoms including, for example, oxygen (O), nitrogen (N), or sulfur (S).
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • treating means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, particularly when such disease A mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. .
  • composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
  • solvate refers to a compound formed by combining a compound of the invention with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include water, ethanol, acetic acid, etc.
  • Solvates include stoichiometric solvates and non-stoichiometric solvates.
  • hydrate refers to a solvate including a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of water.
  • the compounds of the present invention may also be prepared as prodrugs, such as pharmaceutically acceptable prodrugs. Since prodrugs are known to enhance numerous desirable properties of drugs (eg, solubility, bioavailability, preparation, etc.), the compounds of the invention can be delivered in the form of prodrugs. Accordingly, the present invention is intended to encompass prodrugs of the presently claimed compounds, methods of delivery thereof, and compositions containing the prodrugs.
  • prodrug is intended to include any covalently bound carrier that releases the active parent drug of the invention in vivo when such prodrug is administered to a mammalian subject.
  • the prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a manner that the modification is cleaved to the parent compound during routine manipulation or in vivo.
  • the term "individual” includes humans and animals, for example, mammals (such as primates, cattle, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep and birds, etc.).
  • the term "active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • mammals include mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); domestic animals, such as cattle, horses, sheep, goats, pigs; , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens.
  • Valence tautomers include tautomers by reorganization of some of the bonding electrons. Exemplary tautomers are shown below But not limited to this.
  • the present application also includes compounds of the present application that are the same as those described herein, but are isotopically labeled in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled compounds of the present application can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
  • substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability (such as increased in vivo half-life or reduced dosage requirements) and, therefore, in certain situations
  • deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • Exemplary deuterated compounds are shown below But not limited to this.
  • Stereoisomers of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • the stereoisomers respectively include, but are not limited to ( represents a five-membered heteroaryl group).
  • compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients.
  • they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • dosages of 0.01 to 200 mg/kg body weight are administered per day, in single or divided doses.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application.
  • the compound of Formula I of the present application can be prepared by those skilled in the field of organic synthesis through the following route:
  • R 1 , L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as defined in this application.
  • Boc represents tert-butoxycarbonyl
  • DMSO dimethyl sulfoxide
  • TBS represents tert-butyldimethylsilyl
  • BrettPhos Pd G3 represents methane sulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy Palladium(II) (2'-amino-1,1'-biphenyl-2-yl)(2'-amino-1,1'-biphenyl-2-yl)
  • Lawson's reagent represents 2,4-bis(p-methoxyphenyl)-1,3-dithiodiphosphatane-2,4 sulfide
  • TBSO represents tert-butyldimethylsiloxy.
  • intermediate 1-2 (220g), 2-methyl-tetrahydrofuran (1300mL), sodium carbonate (96g) and Lawson's reagent (202g) to the single-neck bottle respectively, and raise the temperature to 80°C for 3 hours.
  • the reaction solution was cooled to room temperature, poured into water (1L), extracted with ethyl acetate (1L ⁇ 2), the organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain intermediate 1-3 (260g). It was used directly in the next reaction without further purification.
  • intermediate 2-7 (6.8g) and 1,4-dioxane (10mL) in sequence, add dropwise 4M dioxane hydrochloride solution (60.0mL) under stirring, complete the addition, and stir at room temperature. 4h.
  • Pour the reaction solution into ice water (100 mL), add sodium bicarbonate to adjust the pH to neutral, extract with ethyl acetate (50 mL ⁇ 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane:methanol 50:1) to obtain intermediate 2-8 (4.6g).
  • intermediate 4-2 (12g), benzyl bromide (12.3g), potassium carbonate (21.3g) and acetonitrile (75mL) in sequence, and stir and react at room temperature for 1 hour.
  • intermediate 4-5 (3.87g), intermediate 1-A (3g), sodium carbonate (2.73g), and 1,1'-bis(diphenylphosphino)ferrocene dichloride in sequence.
  • Palladium (II) (0.63g), 1,4-dioxane (50mL) and water (5mL) were reacted at 100°C for 12 hours under a nitrogen atmosphere.
  • intermediate 8-2 (0.37g), tetrahydrofuran (10mL) and tetrabutylammonium fluoride (0.56g) in sequence, and stir and react at room temperature for 1 hour.
  • the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL).
  • the organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • intermediate 9-4 (0.15g), tetrahydrofuran (5mL) and tetrabutylammonium fluoride tetrahydrofuran solution (1M, 1.12mL, 1.12mmol) in sequence, and stir the reaction solution at room temperature for 1 hour.
  • intermediate 14-1 (3.9g), phthalic anhydride (3.37g) and acetic acid (40mL) in sequence, and mix under nitrogen protection. The mixture was heated to 120°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered with suction. The filter cake was washed with methyl tert-butyl ether (100 mL). The solid was collected and dried to obtain intermediate 14-2 (5.57g).
  • 1 H-NMR 500MHz, DMSO-d 6 ) ⁇ 14.20-13.81(m,1H),8.04(s,2H),7.97(s,2H).MS(ESI)m/z: 309.85[MH] - .
  • intermediate 14-2 (5.57g), potassium carbonate (2.73g) and N,N-dimethylformamide (45mL) in sequence; the resulting mixture is stirred in an ice water bath and cooled to 5°C.
  • Methyl iodide (2.55g) was added dropwise, and after the addition was completed, the reaction was stirred at room temperature overnight.
  • the reaction solution was poured into water (50 mL) and stirred vigorously for 10 minutes, filtered with suction, and the filter cake was washed with water (50 mL). The solid was collected and dried to obtain intermediate 14-3 (1.14 g).
  • intermediate 14-3 (0.6g), ethanol (20mL) and hydrazine hydrate (0.463g) in sequence, heat the reaction solution to 70°C and stir for 1.5 hours. At the end of the reaction, the reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated to dryness. Add methyl tert-butyl ether (10 mL) to the residue, stir vigorously for 10 minutes, filter with suction, and concentrate the filtrate to obtain intermediate 14-4. (0.33g).
  • 1 H-NMR 500MHz, DMSO-d 6 ) ⁇ 4.95 (s, 2H), 3.52 (s, 3H).
  • intermediate 15-2 (1g) and tetrahydrofuran (40mL) in sequence.
  • the reaction solution is stirred and cooled to -75°C.
  • n-butyllithium (2.54g, 2.54mL) is added dropwise to it. Keep it until the dropwise addition is completed.
  • Temperature reaction 1h. Add iodine (1.341g) to it. After adding, keep the temperature and stir for 10 seconds. min, then transferred to room temperature and stirred for 1 h.
  • intermediate 15-4 (0.5g), copper iodide (0.080g), bistriphenylphosphorus palladium dichloride (0.148g) and trifluoroacetic acid (1.708g, 2.352mL) in sequence , N,N-dimethylformamide (10mL), then bubble nitrogen into the mixture for five minutes, add tert-butyldimethyl (2-propynyloxy)silane (0.719g), and put in the microwave
  • the reactor was heated to 80°C for 2 hours. After the reaction is completed, pour the reaction solution into 100 mL of saturated sodium chloride solution, extract with ethyl acetate, combine the organic phases, and concentrate under reduced pressure. The residue was separated and purified using a silica gel column to obtain an intermediate (0.42g). MS(ESI)m/z: 280.23[M+H] + .
  • intermediate 16-1 (4.0g), potassium tert-butoxide (2.06g), and N,N-dimethylformamide (30mL) in sequence.
  • the mixture is cooled to 0°C and stirred under nitrogen protection.
  • the reaction was carried out for 10 minutes, and difluorobromomethyltrimethylsilane (4.06g) was added dropwise. After the dropwise addition was completed, the reaction solution was stirred and reacted at 0°C for 1 hour. After the reaction is completed, pour the reaction solution into water (200 mL), add ethyl acetate (100 mL), and extract.
  • intermediate 16-4 (320 mg), tetrahydrofuran (10 mL) and tetrabutylammonium fluoride (0.56 g) were added in sequence, and the mixture was stirred and reacted at room temperature for 30 minutes. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain intermediate 2-L (0.12g).
  • intermediate 1-B (0.15g), tert-butanol (5mL), cesium carbonate (0.334g), intermediate 2-I (0.036g) and BrettPhos Pd G3 (0.026g), nitrogen gas Replaced three times, the mixture was heated to 85°C for 12 hours under nitrogen protection.
  • the compounds of the present disclosure have improved or excellent inhibitory activity on Daudi cells; and compared with WI38-VA13 cells, they have selective inhibitory activity on Daudi cells.
  • the sample was added to an acetonitrile solution containing an internal standard and subjected to protein precipitation to prepare a supernatant, which was diluted and used for LC/MS/MS measurement.
  • test results show that the test compound of the present disclosure has stable metabolism in vitro (for example, the remaining amount is relatively large in 60 minutes), and the remaining amount in 60 minutes in the metabolism of human and/or mouse liver microparticles exceeds 50%.
  • ICR mice weighing 18 to 22 g, were randomly divided into groups of 9 after adapting for 3 to 5 days, and the test compound solution was orally administered at a dose of 10 mg/kg.
  • Blood collection time points are 15min, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 24h. Blood is collected from the orbit to prepare plasma samples to be tested.
  • Noncompartmental models were used to fit pharmacokinetic parameters.
  • test results show that the compounds of the present disclosure show good properties in pharmacokinetic tests, including but not limited to advantages in bioavailability, AUC, C max , t 1/2 , T max and other aspects.

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Abstract

La présente invention concerne un composé contenant un cycle thiazole, et spécifiquement un composé de formule I, son procédé de préparation, une composition pharmaceutique le comprenant et son utilisation dans le traitement de maladies telles que le cancer.
PCT/CN2023/084374 2022-03-29 2023-03-28 Composé contenant un cycle thiazole WO2023185831A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021164746A1 (fr) * 2020-02-19 2021-08-26 江苏先声药业有限公司 Composé aryle substitué
CN114072390A (zh) * 2019-03-12 2022-02-18 赛泰尔治疗公司 Rad51 抑制剂
CN115677684A (zh) * 2021-07-21 2023-02-03 先声药业有限公司 取代芳基或杂芳基类化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114072390A (zh) * 2019-03-12 2022-02-18 赛泰尔治疗公司 Rad51 抑制剂
WO2021164746A1 (fr) * 2020-02-19 2021-08-26 江苏先声药业有限公司 Composé aryle substitué
CN115677684A (zh) * 2021-07-21 2023-02-03 先声药业有限公司 取代芳基或杂芳基类化合物

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