WO2021180181A1 - 嘧啶并杂环类化合物及其应用 - Google Patents
嘧啶并杂环类化合物及其应用 Download PDFInfo
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- WO2021180181A1 WO2021180181A1 PCT/CN2021/080278 CN2021080278W WO2021180181A1 WO 2021180181 A1 WO2021180181 A1 WO 2021180181A1 CN 2021080278 W CN2021080278 W CN 2021080278W WO 2021180181 A1 WO2021180181 A1 WO 2021180181A1
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- LQUPKVMEAATBSL-UHFFFAOYSA-L zinc;2,3,4-trichlorophenolate Chemical compound [Zn+2].[O-]C1=CC=C(Cl)C(Cl)=C1Cl.[O-]C1=CC=C(Cl)C(Cl)=C1Cl LQUPKVMEAATBSL-UHFFFAOYSA-L 0.000 description 1
Images
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
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
- C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D419/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to a class of pyrimidoheterocyclic compounds, in particular to a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.
- RAS oncogene mutations are the most common activating mutations in human cancers, occurring in 30% of human tumors.
- the RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), of which 85% of RAS-driven cancers are caused by mutations in the KRAS subtype.
- KRAS mutations are common in solid tumors, such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS mutant tumors, 80% of oncogenic mutations occur at codon 12.
- the most common mutations include: p.G12D (41%), p.G12V (28%) and p.G12C (14%).
- KRAS The full name of the KRAS gene is Kirsten rat sarcoma viraloncogene homolog (Kristen rat sarcoma virus oncogene homolog).
- KRAS plays a pivotal role in the signal regulation of cell growth.
- the upstream cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4, after receiving external signals, will pass through the RAS protein to transfer the signal. Pass it downstream.
- the KRAS protein When the KRAS protein is not activated, it binds closely to GDP (guanine nucleotide diphosphate).
- guanine nucleotide exchange factors such as SOS1
- GTP guanine nucleotide triphosphate
- KRAS gene After being activated by guanine nucleotide exchange factors such as SOS1, it binds to GTP (guanine nucleotide triphosphate) and becomes a state of kinase activity.
- GTP guanine nucleotide triphosphate
- KRAS gene After the mutation of KRAS gene, it can independently transmit growth and proliferation signals to downstream pathways independently of the upstream growth factor receptor signal, resulting in uncontrolled cell growth and tumor progression. At the same time, whether the KRAS gene has mutations is also one of the prognosis of tumors. Important indicators.
- KRAS is the first oncogene to be discovered, it has long been regarded as an un-drugable target.
- Amgen and Mirati Therapeutics successively announced the clinical research results of KRAS small molecule inhibitors AMG510 and MRTX849, which for the first time clinically confirmed the effectiveness of KRAS inhibitors in the treatment of tumors.
- Both AMG 510 and MRTX849 are irreversible small-part inhibitors, which inhibit KRAS activity by forming irreversible covalent bonds with the cysteine residues of the KRAS G12C mutant protein.
- the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from O and N;
- R 1 is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, and the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2, 3, 4 or 5 Ra replace;
- R 2 When T 1 is selected from O, R 2 does not exist;
- R 3 is selected from a C 1-3 alkyl group, the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R c ;
- R 4 is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
- R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted with 1, 2 or 3 F;
- R 8 is selected from H and CH 3 ;
- R a is independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl ,
- the C 1-3 alkyl group, C 1-3 alkoxy group, C 2-3 alkynyl group and C 2-3 alkenyl group are optionally substituted with 1, 2 or 3 F;
- R b is independently selected from F, Cl, Br, I, OH and NH 2 ;
- R c are each independently selected from 4-8 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 R;
- R d are independently selected from F, Cl, Br, I, OH, NH 2 and CN;
- R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy and -C 1-3 alkyl-O-CO-C 1-3 alkane Amino; provided that when R 1 is selected from naphthyl, the naphthyl is optionally substituted by F, Cl, Br, OH, NH 2 , CF 3 , CH 2 CH 3 and -C ⁇ CH, and R 5 , R 6 and R 7 are each independently selected from H.
- each R a is independently selected from F, OH, NH 2, CH 3, CF 3, CH 2 CH 3 and -C ⁇ CH, other variables are as defined in the present invention.
- R 1 is selected from phenyl, naphthyl, indolyl and indazolyl, and the phenyl, naphthyl, indolyl and indazolyl are optionally selected by 1, 2 or 3 R a is substituted, and other variables are as defined in the present invention.
- R 1 is selected from Other variables are as defined in the present invention.
- R 2 is selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally selected from 1, 2 or 3 R b substitutions, and other variables are as defined in the present invention.
- R 2 is selected from H and CH 3 , and other variables are as defined in the present invention.
- each R above is independently selected from H, F, Cl, Br, OH, CN, CH 3 , CH 2 CH 3 , CH 2 CF 3 , OCH 3 , OCF 3 and Other variables are as defined in the present invention.
- the above-mentioned R c is selected from tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl, and the tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl are optionally selected by 1, 2 Or 3 R substitutions, and other variables are as defined in the present invention.
- R c is selected from Other variables are as defined in the present invention.
- R c is selected from Other variables are as defined in the present invention.
- R 3 is selected from CH 3 , and the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- R 4 is selected from H and CH 3 , and the CH 3 is optionally substituted with 1, 2 or 3 R d , and other variables are as defined in the present invention.
- R 4 is selected from H, CH 3 and CH 2 CN, and other variables are as defined in the present invention.
- the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from O and N;
- R 1 is selected phenyl, naphthyl, and indazolyl, said phenyl, naphthyl and indazolyl optionally substituted 3, 4 or 5 substituents R a;
- R 2 When T 1 is selected from O, R 2 does not exist;
- R 3 is selected from a C 1-3 alkyl group, the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R c ;
- R 4 is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
- R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- R 8 is selected from H and CH 3 ;
- R a is independently selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CF 3 and OCH 3 ;
- R b is independently selected from F, Cl, Br, I, OH and NH 2 ;
- R c is independently selected from tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl, the tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl are substituted with 1, 2 or 3 R;
- R d are independently selected from F, Cl, Br, I, OH, NH 2 and CN;
- R is each independently selected from H, F, Cl, Br, and CH 3 .
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- R 4 is selected from C 1-3 alkyl group, said C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R d ;
- T 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R d are as defined in the present invention.
- the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
- R 1 is selected from phenyl, naphthyl and The phenyl, naphthyl and Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
- R 1 is selected from Other variables are as defined in the present invention.
- R 2 is selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally selected from 1, 2 or 3 R b substitutions, and other variables are as defined in the present invention.
- R 2 is selected from H and CH 3 , and other variables are as defined in the present invention.
- R c is selected from Other variables are as defined in the present invention.
- R c is selected from Other variables are as defined in the present invention.
- R 3 is selected from CH 3 , and the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- R 4 is selected from H and CH 3 , and the CH 3 is optionally substituted with 1, 2 or 3 Rd , and other variables are as defined in the present invention.
- R 4 is selected from H, CH 3 and CH 2 CN, and other variables are as defined in the present invention.
- the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from O and N;
- R 1 is selected phenyl, naphthyl, and indazolyl, said phenyl, naphthyl and indazolyl optionally substituted 3, 4 or 5 substituents R a;
- R 2 When T 1 is selected from O, R 2 does not exist;
- R 3 is selected from a C 1-3 alkyl group, the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R c ;
- R 4 is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
- R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- R 8 is selected from H and CH 3 ;
- R a is independently selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CF 3 and OCH 3 ;
- R b is independently selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
- R c are each independently selected from tetrahydropyrrolyl, which is substituted with 1, 2 or 3 R;
- R d are independently selected from F, Cl, Br, I, OH, NH 2 and CN;
- R is each independently selected from F, Cl, Br, and CH 3 .
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- T 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the present invention.
- the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
- R 1 is selected from phenyl, naphthyl and The phenyl, naphthyl and Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
- R 1 is selected from Other variables are as defined in the present invention.
- R 2 is selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally selected from 1, 2 or 3 R b substitutions, and other variables are as defined in the present invention.
- R 2 is selected from H and CH 3 , and other variables are as defined in the present invention.
- R c is selected from Other variables are as defined in the present invention.
- R 3 is selected from CH 3 , and the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- R 4 is selected from CH 3 , and the CH 3 is optionally substituted with 1, 2 or 3 R d , and other variables are as defined in the present invention.
- R 4 is selected from CH 2 CN, and other variables are as defined in the present invention.
- the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
- T 1 is selected from O and N;
- R 1 is selected phenyl and naphthyl, said phenyl and naphthyl optionally substituted with 1, 2 or 3 R a;
- R 2 When T 1 is selected from O, R 2 does not exist;
- R 3 is selected from a C 1-3 alkyl group, the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R c ;
- R 4 is selected from C 1-3 alkyl group, said C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R d ;
- R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- R a is independently selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 and OCH 3 ;
- R b is independently selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
- R c are each independently selected from tetrahydropyrrolyl, which is substituted with 1, 2 or 3 R;
- R d are independently selected from F, Cl, Br, I, OH, NH 2 and CN;
- R is independently selected from F, Cl, Br and CH 3 ;
- the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
- R 1 is selected naphthyl group, a naphthyl group optionally substituted with 1, 2 or 3 R a, the other variables are as defined in the present invention.
- R 1 is selected from Other variables are as defined in the present invention.
- R 2 is selected from CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally selected from 1, 2 or 3 R b substitutions, other variables are as defined in the present invention.
- R 2 is selected from CH 3 , and other variables are as defined in the present invention.
- R c is selected from Other variables are as defined in the present invention.
- R 3 is selected from CH 3 , and the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- R 4 is selected from CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 R d , and other variables are as defined in the present invention.
- R 4 is selected from CH 2 CN, and other variables are as defined in the present invention.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R 1 is selected phenyl and naphthyl, said phenyl and naphthyl optionally substituted with 1, 2 or 3 R a;
- R 3 is selected from a C 1-3 alkyl group, the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R c ;
- R 4 is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
- R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
- R a and R b are each independently selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
- R c are each independently selected from tetrahydropyrrolyl, which is substituted with 1, 2 or 3 R;
- R d are independently selected from F, Cl, Br, I, OH, NH 2 and CN;
- R is independently selected from F, Cl, Br and CH 3 ;
- the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
- R 1 is selected from naphthyl, and other variables are as defined in the present invention.
- R 1 is selected from Other variables are as defined in the present invention.
- R 2 is selected from CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally selected from 1, 2 or 3 R b substitutions, other variables are as defined in the present invention.
- R 2 is selected from CH 3 , and other variables are as defined in the present invention.
- R c is selected from Other variables are as defined in the present invention.
- R 3 is selected from CH 3 , and the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- R 4 is selected from CH 3 , and the CH 3 is optionally substituted by 1, 2 or 3 R d , and other variables are as defined in the present invention.
- R 4 is selected from CH 2 CN, and other variables are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- R 1 , R 5 , and R c are as defined in the present invention.
- R 4 is selected from C 1-3 alkyl group, said C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R d ;
- R d are independently selected from F, Cl, Br, I, OH, NH 2 and CN;
- the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R are as defined in the present invention.
- the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating diseases related to KRASG12C mutant protein.
- the compound of the present invention has good cell proliferation inhibitory activity on KRASG12C mutant MIA-PA-CA-2 cell line and NCI-H358 cell. It has good stability of liver microsomes, hepatocytes, plasma and whole blood, good PK properties, and significant anti-tumor effect.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
- the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
- the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
- the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterium can be substituted for hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent.
- the substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable.
- Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
- any variable such as R
- its definition in each case is independent.
- the group can optionally be substituted with up to two Rs, and R has independent options in each case.
- combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
- Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
- any one or more sites of the group can be connected to other groups through chemical bonds.
- the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
- the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Express.
- the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
- the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
- wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key Or straight dashed key like represent represent
- the term “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refers to one of the isomers or pairs of
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
- the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
- optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
- the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
- the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
- C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
- the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
- C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
- C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
- the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
- Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and so on.
- C 2-3 alkenyl is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and a carbon-carbon double bond It can be located in any position of the group.
- the C 2-3 alkenyl groups include C 2 and C 3 alkenyl group; a C 2- 3 alkenyl group may be a monovalent, divalent or polyvalent. Examples of C 2-3 alkenyl include, but are not limited to, vinyl, propenyl, and the like.
- C 2-3 alkynyl is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, and a carbon-carbon triple bond It can be located in any position of the group. It can be univalent, bivalent, or multivalent.
- the C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl include, but are not limited to, ethynyl, propynyl, and the like.
- C 6-10 aromatic ring and “C 6-10 aryl” in the present invention can be used interchangeably, and the term “C 6-10 aromatic ring” or “C 6-10 aryl” means A cyclic hydrocarbon group with a conjugated ⁇ -electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
- 5-10 membered heteroaryl ring and “5-10 membered heteroaryl group” can be used interchangeably in the present invention.
- the term “5-10 membered heteroaryl group” means a ring consisting of 5 to 10 A cyclic group composed of atoms with a conjugated ⁇ -electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, where each ring is aromatic.
- the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
- the 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
- the 5-10 membered heteroaryl groups include 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups and the like.
- Examples of the 5-10 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazoly
- the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms.
- heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
- a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
- the 4-8 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
- 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidin
- C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1- 12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is from n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, a nucleophilic substitution reaction).
- representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyld
- hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
- Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
- alkyl groups such as methyl, ethyl, and tert-butyl
- acyl groups such as alkanoyl groups (such as acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- the single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
- the light source is CuK ⁇ radiation
- the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
- the solvent used in the present invention is commercially available.
- Figure 1 shows the changes in tumor volume with different doses over time.
- Figure 2 shows the changes in animal body weights of different doses over time.
- reaction solution was poured into a saturated aqueous ammonium chloride solution (80 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated.
- the compound methyl acetate (5.55g, 74.98mmol, 5.96mL, 5eq) was dissolved in tetrahydrofuran (50mL), the temperature was reduced to -78°C under nitrogen protection, and sodium hexamethyldisilazide (1M, 74.98mL, 5eq) was added to the reaction solution. After stirring at -78°C for 1 hr, compound 1-3 (5 g, 15.00 mmol, 1 eq) was slowly added dropwise to the reaction solution, and stirring was continued at this temperature for 1 hr.
- reaction solution was poured into a saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated to obtain compound 1-4, which was directly used in the next reaction.
- LCMS m/z 376.1 [M+1] + .
- the reaction was quenched by adding saturated ammonium chloride solution (10 mL), water (10 mL) was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure to obtain a crude product.
- reaction system was cooled to -78°C with a dry ice acetone bath, and a solution of compound 2-2 (1.08 g, 5.68 mmol, 1.1 eq) in tetrahydrofuran (6 mL) was added dropwise thereto.
- the reaction was stirred for 30 minutes, then slowly raised to room temperature and stirred for 30 minutes.
- the reaction was quenched by adding water (30 mL), and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 2).
- the combined organic phase was dried over sodium sulfate, filtered to remove the desiccant, and the filtrate was decompressed to remove the solvent to obtain a crude product.
- reaction solution was concentrated in vacuo, and the residue was adjusted to pH ⁇ 3-4 with 2M hydrochloric acid, and then extracted with ethyl acetate (30 mL ⁇ 3).
- the combined organic phase was concentrated under vacuum to obtain the crude product.
- reaction solution was poured into 700mL of water, filtered, and the filter cake was washed with water (100mL ⁇ 3 times); the resulting filter cake was dissolved with 300mL ethyl acetate and then separated, the organic phase was added with 50.00g anhydrous sulfuric acid After the sodium was dried, it was filtered, and the filtrate was rotary evaporated under reduced pressure at 45°C to obtain compound 4-4.
- reaction solution was poured into 100 mL of saturated ammonium chloride solution, combined with 1 g batch, and separated, the organic phase was added with 3.00 g of anhydrous sodium sulfate and dried, filtered, and the filtrate was subjected to reduced pressure rotary evaporation at 45°C.
- n-butyllithium (2M, 7.50mL, 1.9eq) was added dropwise to it, and after the reaction continued for 30 minutes, the temperature was lowered to -70 ⁇ -65°C, and then compound 4-6 (2.75g, 9.87mmol, 1 eq) was dissolved in tetrahydrofuran (27 mL) and added dropwise to it, and the reaction was continued for 0.5 hr. After the reaction solution was poured into 50 mL of saturated ammonium chloride solution for quenching, the organic phase was dried by adding 1.50 g of anhydrous sodium sulfate and filtered, and the filtrate was subjected to reduced pressure rotary evaporation at 45°C.
- the white solid obtained was extracted by adding 10 mL of water and 10 mL of ethyl acetate for liquid separation.
- the organic phase was washed once with 10 mL of saturated brine, and then dried by adding 0.50 g of anhydrous sodium sulfate, and then filtered
- the filtrate was subjected to vacuum rotary evaporation at 45°C.
- N,N-dimethylformamide (5mL), compound 5-5 (0.33g, 569.94 ⁇ mol, 1eq) into a clean reaction flask prepared in advance, start stirring, and then add N,N-diisopropyl Ethylethylamine (368.29mg, 2.85mmol, 496.35 ⁇ L, 5eq), compound 5-5a (143mg, 1.14mmol, 2.00eq, 2HCl) were added to it, the temperature was raised to 100°C, and the reaction was carried out for 1hr.
- reaction solution was poured into 20 mL of saturated amine chloride solution, it was added to 10 mL of ethyl acetate solution for liquid separation, the organic phase was added with anhydrous sodium sulfate and dried, filtered, and the filtrate was subjected to reduced pressure rotary evaporation at 45°C.
- N,N-dimethylformamide (6mL), compound 5-9 (150mg, 193.18 ⁇ mol, 80% mass content, 1eq) into the pre-prepared reaction flask, start stirring, and then reduce the temperature to 0 ⁇ 5°C, then sequentially add 2-fluoroacrylic acid (26.10mg, 289.78 ⁇ mol, 3.08 ⁇ L, 1.5eq), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea Hexafluorophosphate (110.18mg, 289.78 ⁇ mol, 1.5eq) and N,N-diisopropylethylamine (74.90mg, 579.55 ⁇ mol, 100.94 ⁇ L, 3eq) were added to it and reacted for 0.5hr.
- 2-fluoroacrylic acid 26.10mg, 289.78 ⁇ mol, 3.08 ⁇ L, 1.5eq
- Compound 7A was obtained (chiral column peak time: 1.263 min).
- 2,2,6,6-Tetramethylpiperidine (31.31g, 221.65mmol, 37.63mL, 3eq) was added to anhydrous tetrahydrofuran (300mL), the temperature was reduced to -5°C, and n-butyllithium (2.5 M, 94.57mL, 3.2eq), react at -5 ⁇ 0°C for 15min, cool to -60°C, add compound 8-2 (27g, 73.88mmol, 1eq) in tetrahydrofuran (60mL) solution, react at -60°C for 0.5hr, Quickly add N,N-dimethylformamide (108.00g, 1.48mol, 113.69mL, 20eq), and react at -60°C for 10min.
- reaction solution was washed with saturated ammonium chloride (20 mL x 2), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and used in the next step without purification to obtain compound 9-4.
- reaction system was cooled to -60°C, and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphonium salt (114.77mg, 301.85 ⁇ mol, 1.2eq), the reaction system was reacted at -60°C for 10 minutes, then compound 9-5 (0.14 g, 251.54 ⁇ mol, 1 eq) was added, and the reaction was continued for 1 hour.
- the reaction solution was diluted with dichloromethane (10 mL), washed with saturated ammonium chloride (10 mL x 2) solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the method of separation and purification using HPLC column is ⁇ (Column: Phenomenex luna C18 80*40mm*3 ⁇ m; Mobile phase: [H 2 O(0.04%HCl)-ACN]; Acetonitrile%: 20%-32%, 7min ] ⁇ , the chiral separation method according to SFC after lyophilization is ⁇ (Column: DAICEL CHIRALCEL OD (250mm*30mm, 10 ⁇ m); Mobile phase: [0.1%NH 3 H 2 O MEOH]; MeOH%: 60%- 60%, 9min) ⁇ .
- dichloromethane (5mL) to a dry reaction flask, then add compound 14-4 (260mg, 291.15 ⁇ mol, 1eq) to start stirring, then add trifluoroacetic acid (2.77g, 24.31mmol, 1.8mL, 83.50eq) ), the reaction system was stirred at 20°C for 2 hours.
- Dichloromethane (20mL) solution was added to the reaction solution to dilute the reaction solution, and then water (20mL) was added for separation.
- reaction solution was poured into a saturated aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine (5 mL), anhydrous sodium sulfate was added, dried and filtered, and the filtrate was concentrated under reduced pressure Get crude product.
- reaction solution was diluted by adding ethyl acetate (5mL), washed with saturated ammonium chloride (10mL x 2) solution and saturated brine (10mL), and anhydrous sulfuric acid was added After sodium drying and filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was not purified and was directly used in the next step to obtain compound 17-5.
- LCMS m/z 848.3 [M+H] + .
- LCMS m/z 593.3[M+H] + .
- compound 20-3 (20mg, 34.33 ⁇ mol) was dissolved in anhydrous dichloromethane (2mL), and diisopropylethylamine (13.31mg, 102.99 ⁇ mol, 17.94 ⁇ L) and acryloyl chloride ( 4.66mg, 51.49 ⁇ mol, 4.20 ⁇ L), the reaction solution was stirred at this temperature for 16 hours.
- Mutation KRAS G12C test compound on the MIA-PA-CA-2 cell proliferation inhibition IC 50 was selected from the MIA-PA-CA-2 cell proliferation inhibition IC 50.
- the main reagents used in this study include CellTiter-Glo (Promega, catalog number: G7573).
- the main instrument used in this research is PerkinElmer EnVision multi-function microplate reader.
- Adherent cells are trypsinized to form a cell suspension, and the cell suspension is counted for use.
- *F Day0 is the reading value of the original cell number test hole without drug treatment
- F Con is the fluorescence reading of the Con group after 72 hours of incubation.
- F Cpd is the fluorescence reading of each compound well after 72 hours of incubation.
- the experimental results show that the compound of the present invention has a good cell proliferation inhibitory activity on the KRASG12C mutant MIA-PA-CA-2 cell line.
- the main reagents used in this study included RPMI-1640 medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
- CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
- the NCI-H358 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences.
- the main instrument used in this research is the Nivo multi-label analyzer (PerkinElmer).
- Plant NCI-H358 cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 4000 NCI-H358 cells.
- the cell plate was placed in a carbon dioxide incubator for overnight culture.
- the compound to be tested is diluted 5 times with a discharge gun to the 9th concentration, that is, diluted from 2mM to 5.12nM, and a double-well experiment is set up.
- the concentration of the compound transferred to the cell plate ranges from 10 ⁇ M to 0.0256 nM.
- the cell plate was placed in a carbon dioxide incubator for 5 days. Another cell plate is prepared, and the signal value is read as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis.
- Add 25 ⁇ L of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Use multi-marker analyzer to read.
- the IC 50 value can be obtained by four-parameter curve fitting ("log(inhibitor) vs. GraphPad Prism" response--Variable slope” mode).
- Table 2 provides the inhibitory activity of the compounds of the present invention on the proliferation of NCI-H358 cells.
- the test substance is 1 ⁇ M
- the final concentration of the reference substance is 3 ⁇ M
- the final concentration of hepatocytes is 0.5 ⁇ 106cells/mL
- the final concentration of total organic solvents is 0.96%
- the final concentration of DMSO is 0.1 %.
- the incubation plate was taken out, and 25 ⁇ L of the mixture of the compound and the control compound and the cells were taken out and added to the sample plate containing 125 ⁇ L of stop solution (acetonitrile solution containing 200 ng/mL tolbutamide and Rabenol).
- stop solution acetonitrile solution containing 200 ng/mL tolbutamide and Rabenol.
- For Blank sample plates add 25 ⁇ L of incubation medium without hepatocytes directly. All sample plates were sealed and shaken on a plate shaker at 600 rpm for 10 minutes, and then centrifuged at 3220 ⁇ g for 20 minutes. The supernatant of the test substance and the reference substance was diluted with ultrapure water in a ratio of 1:3. All samples were mixed and analyzed by LC/MS/MS method.
- T60 incubation plate and NCF60 incubation plate were prepared two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate, respectively. Add 445 ⁇ L of microsomal working solution (liver microsomal protein concentration of 0.56 mg/mL) to the T60 incubation plate and NCF60 incubation plate respectively, and then place the above incubation plate in a 37°C water bath for pre-incubation for about 10 minutes.
- microsomal working solution liver microsomal protein concentration of 0.56 mg/mL
- the final concentration of the compound, testosterone, diclofenac and propafenone in the reaction is 1 ⁇ M
- the concentration of liver microsomes is 0.5mg/mL
- the final concentration of DMSO and acetonitrile in the reaction system They are 0.01% (v/v) and 0.99% (v/v), respectively.
- stop solution containing 200ng/mL tolbutamide and 200ng/mL labetalol
- Acetonitrile solution After incubating for an appropriate time (such as 5, 15, 30, 45, and 60 minutes), add 180 ⁇ L of stop solution (containing 200ng/mL tolbutamide and 200ng/mL labetalol to the sample wells of each stop plate). Acetonitrile solution), and then take out 60 ⁇ L sample from the T60 incubation plate to stop the reaction. All sample plates were shaken and centrifuged at 3220 ⁇ g for 20 minutes, and then 80 ⁇ L of supernatant was diluted into 240 ⁇ L of pure water from each well for liquid chromatography tandem mass spectrometry analysis, and liquid chromatography tandem mass spectrometry analysis of all samples.
- the final incubation concentration of the compound and the control compound bisacodyl, enalapril maleate, procaine and propensin was 2 ⁇ M, and the final organic phase content was 2.0%.
- take out the corresponding incubation plate and add 400 ⁇ L of acetonitrile solution containing 200 ng/mL tolbutamide and Rabenol to each corresponding sample well to precipitate the protein.
- centrifuge at 3220 ⁇ g for 20 minutes. Take 50 ⁇ L of supernatant and add 100 ⁇ L of ultrapure water to dilute, mix all samples and analyze by LC/MS/MS method.
- the compound of the present invention has good stability in human and mouse plasma.
- the purpose of the experiment to evaluate the stability of the test compound in the whole blood of CD-1 mice, SD rats, beagle dogs, and cynomolgus monkeys.
- test compound was mixed with a 5% dimethyl sulfoxide/95% (10% hydroxypropyl- ⁇ -cyclodextrin) solution, vortexed and sonicated to prepare a 1 mg/mL clear solution, which was filtered through a microporous membrane for use .
- Male SD rats aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously or orally. Collect whole blood for a certain period of time, prepare plasma, analyze drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software (Pharsight, USA) to calculate pharmacokinetic parameters.
- Table 8 The experimental results are shown in Table 8:
- PK studies show that the compound of the present invention is Rats have high unbound plasma exposure and good oral bioavailability.
- test compound was mixed with a 5% dimethyl sulfoxide/95% (10% hydroxypropyl- ⁇ -cyclodextrin) solution, vortexed and sonicated to prepare a 1 mg/mL clear solution, which was filtered through a microporous membrane for use .
- Male CD mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously or orally. Collect whole blood for a certain period of time, prepare plasma, analyze drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software (Pharsight, USA) to calculate pharmacokinetic parameters.
- Table 9 The experimental results are shown in Table 9:
- PK studies show that the compound of the present invention is Rats have high unbound plasma exposure and good oral bioavailability.
- Cell culture Human pancreatic cancer Mia PaCa-2 cells (ATCC-CRL-1420) are cultured in a monolayer in vitro, and the culture conditions are DMEM medium with 10% fetal bovine serum, 2.5% horse serum, and 37°C 5% carbon dioxide incubator. . Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and resuspended in an appropriate amount of PBS. Matrigel is added 1:1 to obtain a cell suspension with a cell density of 25x 106 cells/mL.
- PO oral administration
- QD once a day
- the tumor diameter was measured with vernier calipers twice a week.
- TGI time of tumor growth rate
- T/C relative tumor growth rate
- Relative tumor proliferation rate T/C(%) TRTV/CRTV ⁇ 100% (TRTV: treatment group RTV; CRTV: negative control group RTV).
- RTV relative tumor volume
- TGI (%) reflects the tumor growth inhibition rate.
- TGI(%) [(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor volume at the end of treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)] ⁇ 100%.
- the compound of the present invention has a significant anti-tumor effect, and the weight of each dose group of mice is stable, and there is no obvious intolerance.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
化合物编号 | IC 50(nM) |
1 | 5.21 |
8B的盐酸盐 | 2.7 |
9B | 6.98 |
12 | 1.30 |
16 | 2.22 |
17 | 0.44 |
18B | 3.29 |
化合物 | NCI-H358IC 50(nM) |
1 | 68.2 |
2 | 19.0 |
4B的盐酸盐 | 27.0 |
5B | 12.9 |
6A | <4.6 |
8B的盐酸盐 | <4.6 |
9B | 5.5 |
10 | 70 |
11 | 6.7 |
12 | 2.5 |
13 | 32.6 |
15 | 9.2 |
16 | 1.7 |
17 | 0.6 |
18B | 4.7 |
化合物 | 给药量 | 肿瘤体积均值 | T/C | TGI |
溶媒 | N/A | 2016.29mm 3 | N/A | N/A |
8B | 10mg/kg | 745.84mm 3 | 36.99% | 66.89% |
8B | 30mg/kg | 227.15mm 3 | 11.28% | 94.23% |
17 | 10mg/kg | 249.87mm 3 | 12.39% | 93.06% |
17 | 30mg/kg | 124.14mm 3 | 6.16% | 99.64% |
Claims (22)
- 式(III)所示化合物或其药学上可接受的盐,其中,T 1选自O和N;R 1选自C 6-10芳基和5-10元杂芳基,所述C 6-10芳基和5-10元杂芳基任选被1、2、3、4或5个R a取代;当T 1选自O时,R 2不存在;当T 1选自N时,R 2选自H、C 1-3烷基、-C(=O)-C 1-3烷基和-S(=O) 2-C 1-3烷基,所述C 1-3烷基、-C(=O)-C 1-3烷基和-S(=O) 2-C 1-3烷基任选被1、2或3个R b取代;R 3选自C 1-3烷基,所述C 1-3烷基任选被1、2或3个R c取代;R 4选自H和C 1-3烷基,所述C 1-3烷基任选被1、2或3个R d取代;R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I、C 1-3烷基,所述C 1-3烷基任选被1、2或3个F取代;R 8选自H和CH 3;R a分别独立地选自F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基、C 2-3炔基和C 2-3烯基,所述C 1-3烷基、C 1-3烷氧基、C 2-3炔基和C 2-3烯基任选被1、2或3个F取代;R b分别独立地选自F、Cl、Br、I、OH和NH 2;R c分别独立地选自4-8元杂环烷基,所述4-8元杂环烷基任选被1、2或3个R取代;R d分别独立地选自F、Cl、Br、I、OH、NH 2和CN;R分别独立地选自H、F、Cl、Br、OH、CN、C 1-3烷基、C 1-3烷氧基和-C 1-3烷基-O-C(=O)-C 1-3烷氨基;条件是,当R 1选自萘基时,所述萘基任选被F、Cl、Br、OH、NH 2、CF 3、CH 2CH 3和-C≡CH取代,且R 5、R 6和R 7分别独立地选自H。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中各R a分别独立地选自F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3、OCH 3、OCH 2CH 3、-CH=CH 2、-CH 2-CH=CH 2和-C≡CH,所述CH 3、CH 2CH 3、OCH 3、OCH 2CH 3、-CH=CH 2、-CH 2-CH=CH 2和-C≡CH任选被1、2或3个F取代。
- 根据权利要求2所述化合物或其药学上可接受的盐,其中各R a分别独立地选自F、OH、NH 2、CH 3、CF 3、CH 2CH 3和-C≡CH。
- 根据权利要求1~3任意一项所述化合物或其药学上可接受的盐,其中,R 1选自苯基、萘基、吲哚基和吲唑基,所述苯基、萘基、吲哚基和吲唑基任选被1、2或3个R a取代。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 2选自H、CH 3、CH 2CH 3和CH(CH 3) 2,所述CH 3、CH 2CH 3和CH(CH 3) 2选任被1、2或3个R b取代。
- 根据权利要求6所述化合物或其药学上可接受的盐,其中,R 2选自H和CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R c选自四氢吡咯基和六氢-1H-吡咯里嗪基,所述四氢吡咯基和六氢-1H-吡咯里嗪基任选被1、2或3个R取代。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 3选自CH 3,所述CH 3任选被1、2或3个R c取代。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 4选自H和CH 3,所述CH 3任选被1、2或3个R d取代。
- 根据权利要求15所述化合物或其药学上可接受的盐,其中,R 4选自H、CH 3和CH 2CN。
- 根据权利要求1~21任意一项所述的化合物或其药学上可接受的盐在制备治疗与KRAS相关疾病的药物中的应用。
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