WO2022143533A1 - Dérivé de quinazoline et son utilisation en médecine - Google Patents
Dérivé de quinazoline et son utilisation en médecine Download PDFInfo
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- WO2022143533A1 WO2022143533A1 PCT/CN2021/141677 CN2021141677W WO2022143533A1 WO 2022143533 A1 WO2022143533 A1 WO 2022143533A1 CN 2021141677 W CN2021141677 W CN 2021141677W WO 2022143533 A1 WO2022143533 A1 WO 2022143533A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- ethyl
- pharmaceutically acceptable
- quinazolin
- mixture
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 8
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract 2
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- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 claims abstract description 27
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 claims abstract description 27
- 101150100839 Sos1 gene Proteins 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
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- 239000013078 crystal Substances 0.000 claims description 32
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- 239000000651 prodrug Substances 0.000 claims description 30
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- 239000002904 solvent Substances 0.000 claims description 26
- 239000002207 metabolite Substances 0.000 claims description 25
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
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- -1 neobutyl Chemical group 0.000 description 64
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- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
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- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
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Classifications
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
-
- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Definitions
- the invention belongs to the field of medicinal chemistry, and particularly relates to quinazoline derivatives and their application in medicine.
- SOS1 is a guanine nucleotide exchange factor (GEF) that interacts with RAS proteins to convert GDP to GTP, or from an inactive state to an active state to signal cell proliferation.
- GEF guanine nucleotide exchange factor
- the RAS gene (including KRAS, NRAS, and HRAS) is the most frequently mutated oncogene and is present in approximately 30% of cancers.
- the RAS superprotein family belongs to the small GTPase protein family, which acts as a hydrolase to bind and hydrolyze GTP to form GDP.
- RAS protein When RAS protein binds to GDP, it is inactive, but it separates slowly after binding; SOS1 can catalyze the dissociation of GDP, so that RAS protein can be activated by binding to GTP, and through multiple downstream signaling pathways such as MAPK, PI3K and Ral-GEFs Promote cell survival, proliferation and cytokine release, etc. (Liu et al., 2019). Published data suggest that SOS1 is critical for KRAS mutations to initiate cancer (Jeng et al., 2012). Inhibition of SOS1 levels reduced the proliferation rate and survival of KRAS-mutated tumor cells.
- SOS1 is involved in the activation of RAS family protein signaling in cancer through mechanisms other than RAS mutations.
- SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1/Grb2 complex binds to activated/phosphorylated receptor tyrosine kinases.
- SOS1 is localized on the cell membrane, close to RAS family proteins, enabling SOS1 to promote RAS family protein activation.
- SOS1 Abnormal SOS1 is also associated with cancer. SOS1 mutations are found in embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, and lung adenocarcinoma. Meanwhile, SOS1 overexpression has also been reported in bladder cancer and prostate cancer.
- One of the objectives of one or more embodiments of the present application is to provide novel quinazoline derivatives or their stereoisomers, tautomers, mesomers, racemates, enantiomers, Diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the above, are useful for inhibiting SOS1.
- One or more embodiments of the present application provide compounds of general formula (I) or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers thereof Isomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof:
- X is -(OCR 2 R 3 CR 4 R 5 ) x -, wherein the O end is connected to Z, and the C end is connected to O; x is 0, 1 or 2;
- Y is -(OCR 6 R 7 CR 8 R 9 ) y -, wherein the O end is connected to Z, and the C end is connected to O; y is 0, 1 or 2;
- Z is -(CR 10 R 11 ) z -; z is 0, 1, 2, 3, 4 or 5;
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 cycloalkyl or C 1-6 heterocycloalkyl;
- any set of carbon atoms to which each R 2 and R 3 , each R 4 and R 5 , each R 6 and R 7 , each R 8 and R 9 , each R 10 and R 11 is attached to form C 1 -6 cycloalkyl or C 1-6 heterocycloalkyl, said C 1-6 heterocycloalkyl containing 1 or 2 oxygen atoms;
- the two carbon atoms to which the R 2 or R 3 and R 4 or R 5 are attached or the two carbon atoms to which R 6 or R 7 and R 8 or R 9 are attached form a C 1-6 cycloalkane or C 1-6 heterocycloalkyl, the C 1-6 heterocycloalkyl contains 1 or 2 oxygen atoms;
- Each R 1 is the same or different, and each independently is halogen, amino, C 1-6 alkyl, C 1-6 cycloalkyl, wherein said C 1-6 alkyl and C 1-6 cycloalkyl are optional is substituted with one or more substituents selected from hydroxy and halogen;
- n 1, 2 or 3.
- x is 0, y is 0, z is 2, x is 0, y is 0, z is 3, x is 0, y is 0, z is 4, x is 0, y is 0, z is 5, x is 1, y is 1, z is 2, x is 0, y is 1, z is 2, x is 1, y is 0, z is 2, x is 1, y is 2 , z is 2, or x is 2, y is 1, and z is 2.
- each of said R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 is independently H or C 1-6 alkane base.
- One or more embodiments of the present application provide compounds or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or the same thereof A mixture, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof:
- One or more embodiments of the present application provide compounds or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or the same thereof A mixture, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof:
- One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the manufacture of a medicament for the treatment or prevention of cancer or tumor.
- the cancer or tumor is embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.
- One or more embodiments of the present application provide compounds described herein or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers thereof Conforms, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or the use of the compositions described herein in the preparation of SOS1 inhibitors.
- One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or use of a composition described herein in the manufacture of a composition for the treatment or prevention of a disease associated with SOS1.
- One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a medicament.
- One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of cancer or tumor.
- the cancer or tumor is embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.
- One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a SOS1 inhibitor.
- One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of a disease associated with SOS1.
- One or more embodiments of the present application provide a method of treating or preventing cancer or tumor comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, mesomer thereof , racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application .
- the cancer or tumor is embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.
- One or more embodiments of the present application provide a method of treating or preventing a disease associated with SOS1, comprising administering to a subject in need thereof a compound of the present application, or a stereoisomer, tautomer, endogenous isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or the combination.
- One or more embodiments of the present application provide methods of inhibiting SOS1, comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, meso, racemic isomers, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application.
- the disease associated with SOS1 is cancer or tumor.
- the disease associated with SOS1 is embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
- isotopes of carbon include 12 C, 13 C
- Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably an alkyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched chain isomers thereof; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.
- Alkoxy refers to a group formed by substituting at least one carbon atom in an alkyl group with an oxygen atom.
- Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy.
- the definition of alkyl is the same as the definition of "alkyl" described above.
- Alkenyl means a straight chain consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds Chain or branched unsaturated aliphatic hydrocarbon groups, preferably alkenyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms.
- Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-yl Alken-3-yl.
- the alkenyl group may be optionally further substituted with one or more substituents.
- Alkynyl means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms.
- Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
- the alkynyl group may optionally be further substituted with one or more substituents.
- Aryl means a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (eg, 5, 6, 7, 8) , 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be a bridged ring or a spiro ring, non-limiting implementation Examples include phenyl, naphthyl. The aryl group may optionally be further substituted with one or more substituents.
- Heteroaryl refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states.
- N, S can be oxidized into various oxidation states.
- Heteroaryl groups can be attached to heteroatoms or carbon atoms, and heteroaryl groups can be bridged or spirocyclic, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.
- Carbocyclyl or “carbocycle” refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for “aryl”; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) (membered) tricyclic ring system, which can be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclo
- Heterocyclyl or “heterocycle” refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle, and when it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl” above; when When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (eg 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (eg 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
- 1- to 10-membered eg 3, 4, 5, 6, 7, 8, 9, 10-membered
- 4- to 12-membered eg 7, 8, 9, 10, 11, 12 membered
- bicyclic ring or 10 to 15 membere
- Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of “heterocyclyl” or “heterocycle” can be oxidized to various oxidation states; “heterocyclyl” or A “heterocycle” can be attached to a heteroatom or a carbon atom; a “heterocyclyl” or “heterocycle” can be a bridged ring or a spirocyclic ring.
- heterocyclyl or “heterocycle” include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azazelyl, diazepine, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl
- Cycloalkyl refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more
- the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms.
- Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl and the like. When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.
- Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
- heterocycloalkyl can be oxidized to various oxidation states; “heterocycloalkyl” can be attached to a heteroatom or carbon atom; “heterocycloalkyl” Alkyl” can be bridged or spiro.
- heterocycloalkyl include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxetanyl Oxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
- Halogens include F, Cl, Br and I.
- “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
- “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
- Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
- Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
- Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
- a “prodrug” refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound.
- the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
- the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
- Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components.
- a co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
- Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;
- Compound 12-2 1 H NMR (400MHz, DMSO-d6) ⁇ 7.55(s,1H), 7.50-7.38(m,1H), 7.32-7.15(m,2H), 6.20-5.96(m,3H) ,4.94–4.73(m,1H),3.99(dh,2H),3.08(s,1H),2.51(s,3H),1.89–1.61(m,2H),1.56–1.35(m,5H),1.24 (dd, 6H).
- the serially diluted test compounds were added to a 384-well cell culture plate (Corning, CLS3830-50EA), and duplicate wells were set up. An equal volume of culture medium was added to the positive control group, and an equal volume of DMSO was added to the negative control group, and centrifuged at 1000 rpm for 1 minute at room temperature. NCI-H358 cells (ATCC, CRL-5807) were inoculated into 384 culture plates containing compounds, an equal volume of cells was added to the negative control group, and an equal volume of culture medium was added to the positive control group.
- the luminescence value was read with an Envision multifunctional enzyme labeler (Perkin Elmer, Envision 2104).
- the IC50 50% inhibitory concentration of the compound was obtained using the XLFIT software with the following nonlinear fit equation:
- Inhibition rate (%) 100 ⁇ (mean value of negative control-compound reading)/(mean value of negative control-mean value of positive control)
- the measured IC 50 is shown in Table 1 (A means the measured IC 50 ⁇ 0.5 ⁇ M; B means the measured IC 50 is between 0.5 ⁇ M and 1 ⁇ M; C means IC50s were measured between 1 ⁇ M and 10 ⁇ M.
- 1X buffer preparation (prepared and used now): Hepes: 5 mM; NaCl: 150 mM; EDTA: 10 mM; Igepal: 0.0025%; KF: 100 mM; DTT: 1 mM; BSA: 0.05%.
- KRAS(G12C)+MAb Anti GST-Eu cryptate+MAb Anti 6HIS-XL665 4X working solution preparation: KRAS(G12C), MAb Anti GST-Eu cryptate and MAb Anti 6HIS-XL665 (400ng/uL) were prepared with 1X buffer The final concentration of KRAS(G12C) protein was 80nM, the final concentration of MAb Anti GST-Eu cryptate was 1ng/uL, and the final concentration of MAb Anti 6HIS-XL665 (400ng/uL) was 8ng/uL.
- Reading excitation at 320 nm, emission at 615 nm, 665 nm.
- the measured IC 50 is shown in Table 2 (A means the measured IC 50 ⁇ 0.2 ⁇ M; B means the measured IC 50 is between 0.2 ⁇ M and 0.5 ⁇ M between; C indicates the measured IC50 between 0.5 ⁇ M and 1 ⁇ M.
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Abstract
L'invention concerne un dérivé de quinazoline de formule (I), une composition pharmaceutique contenant le dérivé et son utilisation en médecine, en particulier son utilisation en tant qu'inhibiteur de SOS1 et son utilisation dans la préparation d'un médicament pour le traitement ou la prévention de maladies associées à SOS1.
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WO2022258057A1 (fr) * | 2021-06-11 | 2022-12-15 | Jingrui Biopharma Co., Ltd. | Composés en tant qu'agents anticancéreux |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997013760A1 (fr) * | 1995-10-11 | 1997-04-17 | Glaxo Group Limited | Composes condenses tricycliques et compositions pharmaceutiques les contenant |
CN1534026A (zh) * | 2002-03-28 | 2004-10-06 | �Ϳ���ҽҩ��˾ | 新型作为酪氨酸激酶抑制剂的稠合的喹唑啉衍生物 |
CN110167928A (zh) * | 2016-12-22 | 2019-08-23 | 勃林格殷格翰国际有限公司 | 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物 |
WO2021203768A1 (fr) * | 2020-04-08 | 2021-10-14 | 江苏恒瑞医药股份有限公司 | Dérivé pyrimido dicyclo, son procédé de préparation et son utilisation en médecine |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997013760A1 (fr) * | 1995-10-11 | 1997-04-17 | Glaxo Group Limited | Composes condenses tricycliques et compositions pharmaceutiques les contenant |
CN1534026A (zh) * | 2002-03-28 | 2004-10-06 | �Ϳ���ҽҩ��˾ | 新型作为酪氨酸激酶抑制剂的稠合的喹唑啉衍生物 |
CN110167928A (zh) * | 2016-12-22 | 2019-08-23 | 勃林格殷格翰国际有限公司 | 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物 |
WO2021203768A1 (fr) * | 2020-04-08 | 2021-10-14 | 江苏恒瑞医药股份有限公司 | Dérivé pyrimido dicyclo, son procédé de préparation et son utilisation en médecine |
Non-Patent Citations (1)
Title |
---|
HILLIG, ROMAN C. ET AL.: "Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction", PNAS, vol. 116, no. 7, 25 January 2019 (2019-01-25), XP055841142 * |
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WO2022258057A1 (fr) * | 2021-06-11 | 2022-12-15 | Jingrui Biopharma Co., Ltd. | Composés en tant qu'agents anticancéreux |
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