WO2024104425A1 - Composé inhibiteur de kras, composition pharmaceutique de celui-ci et utilisation associée - Google Patents

Composé inhibiteur de kras, composition pharmaceutique de celui-ci et utilisation associée Download PDF

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WO2024104425A1
WO2024104425A1 PCT/CN2023/132030 CN2023132030W WO2024104425A1 WO 2024104425 A1 WO2024104425 A1 WO 2024104425A1 CN 2023132030 W CN2023132030 W CN 2023132030W WO 2024104425 A1 WO2024104425 A1 WO 2024104425A1
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alkyl
cycloalkyl
cancer
kras
independently
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Chinese (zh)
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谢洪明
刘海望
冯锡晖
罗国林
张英俊
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广东东阳光药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-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

Definitions

  • the present invention belongs to the field of pharmaceutical technology. Specifically, the present invention relates to a compound capable of inhibiting one or more KRAS mutants, a pharmaceutical composition thereof, and use of the compound and the pharmaceutical composition thereof in preparing a drug for preventing or treating KRAS-mediated related diseases.
  • RAS gene is one of the most commonly mutated genes in cancer (20%-25%).
  • the currently known members of the RAS gene family include KRAS, NRAS and HRAS, among which KRAS mutation is the most common, accounting for about 85%.
  • KRAS has the highest mutation rate in pancreatic ductal adenocarcinoma (PDAC), reaching 97%, followed by colorectal cancer, multiple myeloma and lung cancer, which are 52%, 42% and 32% respectively.
  • PDAC pancreatic ductal adenocarcinoma
  • KRAS The most common mutation sites of KRAS gene are codons 12, 13 and 61, and the mutation forms include KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12A, KRAS G12V, KRAS G13D and KRAS Q61H mutations.
  • RAS gene mutations are often associated with poor prognosis in cancer.
  • KRAS can be transiently activated by upstream growth factors or tyrosine kinases (such as EGFR).
  • the activated KRAS can activate downstream pathways, including the PI3K-AKT-mTOR signaling pathway that controls cell generation, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. This also lays a biological foundation for the combination of many targets.
  • KRAS G12C small molecule inhibitors In recent years, people have made some progress in drug development using the allosteric sites of KRAS G12C mutants. For example, in 2013, a research team reported the discovery of KRAS G12C small molecule inhibitors (Nature, 2013, 503, 548-551). In addition, Mirati disclosed KRAS G12D inhibitor compounds in patent WO2021041671 and a class of broad-spectrum KRAS (including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and KRAS Q61H) inhibitors in patent WO2022132200 for the treatment of KRAS-mediated cancers.
  • KRAS G12A KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and KRAS Q61H
  • KRAS is frequently mutated in various tumor types.
  • the present invention provides a compound that can inhibit one or more KRAS mutants, including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and KRAS Q61H.
  • a pharmaceutical composition containing such a compound and the use of such a compound and its pharmaceutical composition in the preparation of a drug for preventing or treating a related disease mediated by KRAS.
  • the drug treats diseases and/or conditions, especially cancer, by inhibiting KRAS activity.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
  • Y1 and Y3 are each independently -H, -D, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, C3-6 cycloalkylC1-6 alkyl, (3-6 membered) heterocyclyl- C1-6 alkyl, (5-10 membered heteroaryl) -C1-6 alkyl or C1-6 alkoxyC1-6 alkyl, wherein said Y1 and Y3 are each independently optionally substituted by 1, 2 , 3 or 4 R8a ;
  • Y2 is -H, -D or C1-6 alkyl
  • X is a bond, -O-, -S-, -NH-, -CH 2 -, -CH 2 -NH-, -CH 2 -NH-CH 2 -, -(CH 2 ) 3 -, -(CH 2 ) 2 -, -NH-CH 2 -, -O-CH 2 -, -CH 2 -O-, -CH 2 -S-, or -S-CH 2 -;
  • R 9s attached to the same carbon atom together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocyclic group, wherein The C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 R 8b ;
  • two R 9s attached to two non-adjacent atoms together with the two non-adjacent atoms attached thereto form a C 3-6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl and the 3-6 membered heterocyclic group are each independently optionally substituted by 1, 2, 3 or 4 R 8b ;
  • Ring B is C 6-12 aryl or 5-12 membered heteroaryl
  • R3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C1-4 haloalkyl;
  • Y is a bond, O or S
  • L is a C 1-6 alkylene group
  • R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C( ⁇ O)H, -C( ⁇ O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • q1 is 0, 1, 2, 3, 4, 5, or 6;
  • q2 is 1, 2, 3, 4, 5, 6, 7 or 8.
  • Y 1 and Y 3 are each independently -H, -D, C 1-4 alkyl, C 3-6 cycloalkyl, (3-6 membered)-heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl or C 1-4 alkoxyC 1-4 alkyl, wherein said Y 1 and Y 3 are each independently optionally substituted by 1, 2, 3 or 4 R 8a ;
  • Y2 is -H, -D or C1-4 alkyl
  • q1 and q2 are each as defined in the present invention.
  • R 9s attached to the same carbon atom together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl and the 3-6 membered heterocyclic group are each independently and optionally substituted by 1, 2, 3 or 4 R 8b ;
  • two R 9s attached to two non-adjacent atoms together with the two non-adjacent atoms attached thereto form a C 3-6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl and the 3-6 membered heterocyclic group are each independently optionally substituted by 1, 2, 3 or 4 R 8b ;
  • Y1 and Y3 are each independently -H, -D, -CH3 , -CH2CH3 , -( CH2 ) 2CH3 , -( CH2 ) 3CH3 , -CH (CH3)2, -CH2CH(CH3)2 , -C ( CH3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, azetidinyl, thietanyl, piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, phenyl, pyridinyl, imidazo[1,2-a]pyrazinyl, benzo[d]imidazolyl, benzopyrazolyl, benzo[c][1,2,5]oxadiazolyl, pyrrolo[2,3-d]pyrimidinyl, pyrrol
  • Y2 is -H, -D , -CH3 , -CH2CH3 , -(CH2)2CH3, -(CH2)3CH3 , -CH ( CH3 ) 2 , -CH2CH ( CH3 ) 2 , or -C( CH3 ) 3 ;
  • R 9 attached to the same carbon atom together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothi
  • Ring B is one of the following substructures
  • R 4 is -H, -D, C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC( ⁇ NH)NH 2 or -LC( ⁇ O)NR 6 R 7 , wherein the C 1-4
  • L is a C 1-4 alkylene group.
  • R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxirane, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H- indenyl, -CH2 -decalinyl, -CH2 -pyridinyl, -( CH
  • R 6 , R 7 , R 6d , R 7d , R 6e and R 7e are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -C( ⁇ O)CH 3 , -C( ⁇ O)CH 2 CH 3 , methyl, ethyl, n-propyl and isopropyl; wherein R 6 , R 7 , R 6d , R 7d , R 6e and R 7e are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
  • R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e together with the N atom to which they are attached, form pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine and imidazolidine are each independently and optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidiny
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the compound of the present invention is a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1).
  • R 3 , R 4 , R 5 , Y and T each have the meanings as described in the present invention
  • R 2a , R 2b and R 2c each have the same definition as described for R 2 in the present invention.
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.
  • the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.
  • the pharmaceutical composition can be in liquid, solid, semisolid, gel or spray form.
  • the present invention provides the use of the pharmaceutical composition described in the present invention in the preparation of a medicament for preventing, treating or alleviating diseases associated with KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation.
  • the KRAS wild-type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation-related disease described in the present invention is cancer.
  • the cancer described in the present invention is a cancer of the heart: sarcoma, myxoma, rhabdomyomas, fibromas, lipomas, or teratomas; lung cancer: bronchial cancer, non-small cell lung cancer, small cell lung cancer, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal cancer: esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, large intestine cancer; genitourinary tract cancer: kidney cancer, bladder and urethra cancer, prostate cancer, testicular cancer; liver cancer: hepatocellular carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct cancer: gallbladder cancer, ampullary cancer, bile duct cancer;
  • the present invention also provides a method for preventing or treating diseases associated with KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutations, the method comprising administering to a patient a therapeutically effective amount of a compound described herein or a pharmaceutical composition thereof.
  • the present invention also provides the use of the compounds described in the present invention or their pharmaceutical compositions for or treatment of KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation-related diseases.
  • the present invention relates to methods for preparing, separating and purifying the compound represented by formula (I) or (I-1).
  • the salts are pharmaceutically acceptable salts.
  • pharmaceutically acceptable includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.
  • the salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or (I-1) or salts of separated enantiomers of the compounds of formula (I) or (I-1), but they are not necessarily pharmaceutically acceptable salts.
  • subject refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to humans.
  • Stepoisomers are compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Including enantiomers, diastereomers, conformers (rotational isomers), geometric isomers (cis/trans isomers), atropisomers, etc. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in the present invention belong to the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compound described in the present invention includes one or more enriched isotopes of different atoms.
  • Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-keto tautomerism.
  • a specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • C 1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood as a linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is connected.
  • alkyl refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein.
  • the alkyl group contains 1-6 carbon atoms, represented by C 1-6 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, represented by C 1-4 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, represented by C 1-4 alkyl;
  • the alkyl group contains 1-3 carbon atoms and is represented by C 1-3 alkyl.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 ),
  • alkylene refers to a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon by removing two hydrogen atoms.
  • the alkylene group contains 1-6 carbon atoms, represented by C 1-6 alkylene; in other embodiments, the alkylene group contains 1-4 carbon atoms, represented by C 1-4 alkylene; in other embodiments, the alkylene group contains 1-3 carbon atoms, represented by C 1-3 alkylene; in other embodiments, the alkylene group contains 1-2 carbon atoms, represented by C 1-2 alkylene.
  • alkylene groups include, but are not limited to: -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, and the like.
  • alkenyl refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including “cis” and “trans” orientations, or "E” and “Z” orientations.
  • the alkenyl group contains 2 to 6 carbon atoms, represented by C2-6 alkenyl; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms, represented by C2-4 alkenyl.
  • alkynyl refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein.
  • the alkynyl group contains 2 to 6 carbon atoms, represented by C2-6 alkynyl; in another embodiment, the alkynyl group contains 2 to 4 carbon atoms, represented by C2-4 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl ( -CH2C ⁇ CH ), 1-propynyl (-C ⁇ C- CH3 ), and the like.
  • cyanoalkyl refers to an alkyl group substituted by one or more cyano groups, wherein cyano and alkyl groups have the definitions as described herein.
  • cyanoalkyl refers to an alkyl group substituted by one cyano group.
  • cyanoalkyl is a C 1-6 cyanoalkyl, i.e., a C 1-6 alkyl group substituted by one or more cyano groups.
  • C 1-6 cyanoalkyl is a C 1-6 alkyl group substituted by one cyano group.
  • cyanoalkyl is a C 1-4 cyanoalkyl, i.e., a C 1-4 alkyl group substituted by one or more cyano groups.
  • cyanoalkyl include, but are not limited to, -CH 2 CN, -CH 2 CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH(CN)CH 2 CH 2 CN, -CH 2 CH(CN)CH 2 CH(CH 3 )CN, and the like.
  • hydroxyalkyl refers to an alkyl group substituted by one or more hydroxyl groups, wherein alkyl and hydroxyl groups have the definitions as described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by 1, 2, 3 or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C 1-6 hydroxyalkyl group, i.e., a C 1-6 alkyl group substituted by one or more hydroxyl groups, preferably, a C 1-6 hydroxyalkyl group refers to an alkyl group substituted by one hydroxyl group.
  • hydroxyalkyl refers to a C 1-4 hydroxyalkyl group. In some embodiments, hydroxyalkyl refers to a C 1-3 hydroxyalkyl group. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH , -CH2CH2CH2CH2OH , -CH2CH2OH , -CH2CH ( OH ) CH2CH2OH , -CH2CH ( OH) CH2CH ( CH3 )OH, and the like.
  • haloalkyl means that an alkyl group is substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions as described herein.
  • the haloalkyl is C 1-6 haloalkyl, meaning that the C 1-6 alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-4 haloalkyl, meaning that the C 1-4 alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-3 haloalkyl, meaning that the C 1-3 alkyl group is substituted with one or more halogen atoms.
  • Such examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.
  • haloalkenyl means an alkenyl group substituted with one or more halogen atoms, wherein alkenyl has the definition as described herein.
  • the haloalkenyl is a C2-6 haloalkenyl, which means a C2-6 alkenyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkenyl is a C2-4 haloalkenyl, which means a C2-4 alkenyl group is substituted with one or more halogen atoms.
  • haloalkynyl means that an alkynyl group is substituted with one or more halogen atoms, wherein alkynyl has the definition as described herein.
  • the haloalkynyl is a C 2-6 haloalkynyl, which means that a C 2-6 alkynyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkynyl is a C 2-4 haloalkynyl, which means that a C 2-4 alkynyl group is substituted with one or more halogen atoms.
  • Such examples include, but are not limited to, 2-chloroethynyl (-C ⁇ CCl), 1-chloropropargyl (-CHClC ⁇ CH), 3-chloropropynyl (-C ⁇ C-CH 2 Cl), and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, wherein alkoxy and alkyl have the definitions described herein.
  • alkoxyalkyl refers to C 1-6 alkoxy C 1-6 alkyl; in other embodiments, alkoxyalkyl refers to C 1-4 alkoxy C 1-4 alkyl; in other embodiments, alkoxyalkyl refers to C 1-4 alkoxy C 1-3 alkyl; in some embodiments, alkoxyalkyl refers to C 1-3 alkoxy C 1-3 alkyl.
  • alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-isopropyl, ethoxyethyl, ethoxy-n-propyl, ethoxy-isopropyl, n-propoxyethyl, isopropoxyethyl, n-propoxy-n-propyl, n-propoxy-isopropyl, isopropoxy-n-propyl, isopropoxy-isopropyl, and the like.
  • carboxyalkyl refers to an alkyl group substituted by one or more carboxyl groups, wherein the carboxyl group and the alkyl group are specifically defined as described herein.
  • the carboxyalkyl group is a C 1-6 carboxyalkyl group, which refers to a C 1-6 alkyl group substituted by one or more carboxyl groups; in other embodiments, the carboxyalkyl group is a C 1-4 carboxyalkyl group, which refers to a C 1-4 alkyl group substituted by one or more carboxyl groups; in other embodiments, the carboxyalkyl group is a C 1-3 carboxyalkyl group, which refers to a C 1-3 alkyl group substituted by one or more carboxyl groups.
  • carboxyalkyl groups include, but are not limited to, carboxymethyl (-CH 2 COOH), 2-carboxyethyl (-(CH 2 ) 2 COOH), 3-carboxypropyl (-(CH 2 ) 3 COOH), and the like.
  • aminoalkyl refers to an alkyl group substituted by one or more amino groups, wherein alkyl and amino groups have the meanings as described herein.
  • the aminoalkyl group is a C 1-6 aminoalkyl group, which refers to a C 1-6 alkyl group substituted by one or more amino groups; in other embodiments, the aminoalkyl group is a C 1-4 aminoalkyl group, which refers to a C 1-4 alkyl group substituted by one or more amino groups; in other embodiments, the aminoalkyl group is a C 1-3 aminoalkyl group, which refers to a C 1-3 alkyl group substituted by one or more amino groups.
  • aminoalkyl groups include, but are not limited to, aminomethyl (-CH 2 NH 2 ), 2-aminoethyl (-(CH 2 ) 2 NH 2 ), 1-aminoethyl (-CH(NH 2 )CH 3 ), 1,2-diaminoethyl (-CH(NH 2 )CH 2 NH 2 ), and 3-aminopropyl (-(CH 2 ) 3 NH 2 ).
  • alkylamino refers to an amino group substituted with one or two alkyl groups, including “N-alkylamino” and "N,N- “Dialkylamino", wherein alkyl and amino groups have the meanings as described in the present invention.
  • alkylamino represents C 1-6 alkylamino, which is an alkylamino group containing 1-6 carbon atoms; in other embodiments, alkylamino represents C 1-4 alkylamino, which is an alkylamino group containing 1-4 carbon atoms; alkylamino represents C 1-3 alkylamino, which is an alkylamino group containing 1-3 carbon atoms.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino, such examples include, but are not limited to, N-methylamino (methylamino, -NHCH 3 ), N-ethylamino (ethylamino, -NHCH 2 CH 3 ), N,N-dimethylamino (dimethylamino, -N(CH 3 ) 2 ), N,N-diethylamino (diethylamino, -N(CH 2 CH 3 ) 2 ), and the like.
  • mercaptoalkyl refers to an alkyl group substituted by one or more mercapto groups, wherein the alkyl group has the meaning as described herein.
  • mercaptoalkyl refers to C 1-6 mercaptoalkyl, which is a C 1-6 alkyl group substituted by one or more mercapto groups; preferably, C 1-6 mercaptoalkyl is a C 1-6 alkyl group substituted by one mercapto group.
  • mercaptoalkyl refers to C 1-4 mercaptoalkyl.
  • mercaptoalkyl refers to C 1-3 mercaptoalkyl.
  • mercaptoalkyl examples include, but are not limited to, mercaptomethyl (-CH 2 SH), 2-mercaptoethyl (-(CH 2 ) 2 SH), 3-mercaptopropyl (-(CH 2 ) 3 SH), 2,3-dimercaptopropyl (-CH 2 CH(SH)CH 2 (SH)), and the like.
  • alkoxy means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing a C 1-6 alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing a C 1-4 alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing a C 1-3 alkoxy group.
  • the alkoxy group may be optionally substituted with one or more substituents as described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3 ), ethoxy (EtO, -OCH2CH3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3 ), 2-propoxy (i-PrO, i - propoxy , -OCH( CH3 ) 2 ), 1 -butoxy ( n-BuO, n-butoxy , -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy , -OCH2CH ( CH3 ) 2 ), 2 -butoxy (s-BuO, s-butoxy, -OCH( CH3 ) CH2CH3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC( CH3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 2 CH 3 ), 1-
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy and halogen have the same meanings as those defined herein.
  • haloalkoxy refers to a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1-6 haloalkoxy; in other embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C 1-4 haloalkoxy; in other embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 3 carbon atoms, i.e., C 1-3 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy (-OCF 3 ), monofluoromethoxy (-OCH 2 F), 2-fluoroethoxy (-OCH 2 CH 2 F), and the
  • the carbocyclyl contains 3-6 ring carbon atoms, represented by C3-6 carbocyclyl; in other embodiments, the carbocyclyl is a saturated ring containing 3-6 ring carbon atoms, represented by C3-6 cycloalkyl; in other embodiments, the C3-6 cycloalkyl is a saturated monocyclic ring.
  • the carbocyclyl contains 7-12 ring carbon atoms, represented by C7-12 carbocyclyl; in other embodiments, the carbocyclyl is a saturated ring containing 7-12 ring carbon atoms, represented by C7-12 cycloalkyl.
  • carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-1H-indenyl, octahydropentalenyl, etc.
  • the cycloalkyl contains 3-10 ring carbon atoms, i.e., C3-10 cycloalkyl; in another embodiment, the cycloalkyl contains 3-6 ring carbon atoms, i.e., C3-6 cycloalkyl; in another embodiment, the cycloalkyl contains 3-5 ring carbon atoms, i.e., C 3-5 cycloalkyl.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydropentalenyl, etc.
  • heterocycle or “heterocyclyl” means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings.
  • the heterocycle represents a monovalent heterocyclyl.
  • the sulfur atom of the ring may be optionally oxidized to S-oxide.
  • the heterocycle or heterocyclyl consists of 3-10 atoms, represented by a 3-10-membered heterocycle or a 3-10-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-9 atoms, represented by a 3-9-membered heterocycle or a 3-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-9 atoms, represented by a 5-9-membered heterocycle or a 5-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-6 atoms, represented by a 3-6-membered heterocycle or a 3-6-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-6 atoms, represented by a 5-6-membered heterocycle or a 5-6-membere
  • heterocycle examples include, but are not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.2]octane.
  • the heterocyclic group includes, but is not limited to, oxirane, aziridine, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, etc.
  • aryl refers to a monovalent, monocyclic, bicyclic and tricyclic carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring consisting of 3-7 atoms.
  • the aryl contains 6-12 ring atoms, represented by C 6-12 aryl or 6-12 membered aryl.
  • the aryl contains 6-10 ring atoms, represented by C 6-10 aryl or 6-10 membered aryl. Examples of aryl groups can include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and anthracene.
  • heteroaryl or “heteroaromatic ring” refers to a monovalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group.
  • heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable position (which may be C or N).
  • heteroaryl can be used interchangeably with the term “heteroaromatic ring” or “heteroaromatic compound”.
  • heteroaryl is a heteroaryl containing 5-12 ring atoms, represented by a 5-12 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-10 ring atoms, represented by a 5-10 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-6 ring atoms, represented by a 5-6 membered heteroaryl.
  • heteroaryl examples include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolyl, and the like.
  • alkylthio means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein alkyl has the definition as described herein.
  • alkylthio is C 1-6 alkylthio, meaning an alkylthio containing 1 to 6 carbon atoms; in other embodiments, alkylthio is C 1-4 alkylthio, meaning an alkylthio containing 1 to 4 carbon atoms; in other embodiments, alkylthio is C 1-3 alkylthio, meaning an alkylthio containing 1 to 3 carbon atoms.
  • alkylthio include, but are not limited to, methylthio (-SCH 3 ), ethylthio (-SCH 2 CH 3 ), and the like.
  • haloalkylthio refers to an alkylthio group substituted by one or more halogen atoms, wherein the alkylthio group has
  • the haloalkylthio group is a C 1-6 haloalkylthio group, which means a C 1-6 alkylthio group substituted by one or more halogens
  • the haloalkylthio group is a C 1-4 haloalkylthio group, which means a C 1-4 alkylthio group substituted by one or more halogens
  • the haloalkylthio group is a C 1-3 haloalkylthio group, which means a C 1-3 alkylthio group substituted by one or more halogens.
  • haloalkylthio group includes, but is not limited to, trifluoromethylthio (-SCF 3 ), 2,2,2-trifluoroethylthio (-SCH 2 CF 3 ), monofluoromethylthio (-SCH 2 F), and the like.
  • arylalkyl refers to an alkyl group substituted with an aryl group, wherein aryl and alkyl have the definitions described herein.
  • arylalkyl is (C 6-10 aryl)-C 1-6 alkyl or (6-10 membered aryl)-C 1-6 alkyl; in other embodiments, arylalkyl is (C 6-10 aryl)-C 1-4 alkyl or (6-10 membered aryl)-C 1-4 alkyl; in other embodiments, arylalkyl is (C 6-10 aryl)-C 1-3 alkyl or (6-10 membered aryl)-C 1-3 alkyl; in other embodiments, arylalkyl is phenyl C 1-6 alkyl; in other embodiments, arylalkyl is phenyl C 1-4 alkyl; in other embodiments, arylalkyl is phenyl C 1-3 alkyl. Examples of arylalkyl
  • heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group, wherein heteroaryl and alkyl are as defined herein.
  • heteroarylalkyl is (5-12 membered heteroaryl)-C 1-6 alkyl; in other embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-4 alkyl; in other embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-3 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-6 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-4 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-3 alkyl.
  • heteroarylalkyl include, but are not limited to, pyrimidinylmethyl, pyridinylmethyl, pyridin
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl are as defined herein.
  • heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-6 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-4 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-3 alkyl.
  • heterocyclylalkyl include, but are not limited to, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, and the like.
  • cycloalkylalkyl refers to an alkyl group substituted by a cycloalkyl group.
  • the cycloalkylalkyl group is (C 3-6 cycloalkyl)-C 1-6 alkyl; in other embodiments, the cycloalkylalkyl group is (C 3-6 cycloalkyl)-C 1-4 alkyl; in other embodiments, the cycloalkylalkyl group is (C 3-6 cycloalkyl)-C 1-3 alkyl.
  • Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.
  • halogen means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).
  • cyano means -CN or -C ⁇ N.
  • mercapto refers to -SH.
  • hydroxy refers to -OH.
  • amino refers to -NH2 .
  • jk atoms or "jk-membered” means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k>j;"jk” includes j, k and any natural number in between.
  • “3-8 atoms” or “3-8-membered”, “3-6 atoms” or “3-6-membered”, “5-10 atoms” or “5-10-membered”, or “5-6 atoms” or “5-6-membered” means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10) or 5-6 (i.e., 5 or 6) ring atoms, wherein the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, and P.
  • the ring system formed by substituent (R) q connected to the central ring by a bond represents that q substituents R can be substituted at any substitutable position or any reasonable position on the ring.
  • formula a represents that the naphthalene ring can be substituted by n R 2 , and when n is greater than 1, each R 2 can be independently selected from the same or different substituent groups.
  • prodrug used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (I-1) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues.
  • the prodrug compound of the present invention can be an ester.
  • the esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • Metal refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo.
  • the metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • the present invention also contemplates quaternary ammonium salts formed by any compound containing N groups. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium and amine cations which counter-form counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 - C8 sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof.
  • hydrate refers to an association formed by a solvent molecule being water.
  • the term "hydrate” may be used.
  • one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.
  • any disease or condition refers to ameliorating the disease or condition (i.e., alleviating
  • “treating” refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both.
  • “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • prevent refers to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to be effective in treating the disease.”
  • Therapeutically effective amount may vary with the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.
  • Nitrogen oxides of the compounds of the invention are also included within the scope of the invention.
  • Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
  • a conventional oxidizing agent e.g., hydrogen peroxide
  • the compound represented by formula (I) or (I-1) may exist in the form of a salt.
  • any structural formula provided by the present invention is also intended to represent the isotopically unenriched form and isotopically enriched form of these compounds.
  • Isotopically enriched compounds have the structure described by the general formula provided by the present invention, except that one or more atoms are replaced by atoms with selected atomic weight or mass number.
  • Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which can be used as a KRAS inhibitor, in particular as a KRAS 12D inhibitor.
  • the present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament for treating a disease and/or condition by inhibiting KRAS activity by the compound.
  • the excellent properties of the compounds of the present invention can contribute to the reduction of side effects, the expansion of therapeutic index or the improvement of tolerability.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
  • ring B, W, T, Y, R 2 , n, R 3 and R 4 are each as defined in the present invention.
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • T is wherein, Y1 and Y3 are each as defined in the present invention.
  • Y 1 and Y 3 are each independently -H, -D, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkylC 1-6 alkyl, (3-6 membered) heterocyclyl-C 1-6 alkyl , (5-10 membered heteroaryl)-C 1-6 alkyl or C 1-6 alkoxyC 1-6 alkyl, wherein said Y 1 and Y 3 are each independently optionally substituted by 1, 2, 3 or 4 R 8a , wherein R 8a has the definition as described herein.
  • Y 2 is -H, -D or C 1-6 alkyl.
  • Y 1 , Y 2 and the N atom to which they are attached together form
  • X is a bond, -O-, -S-, -NH-, -CH 2 -, -CH 2 -NH-, -CH 2 -NH-CH 2 -, -(CH 2 ) 3 -, -(CH 2 ) 2 -, -NH-CH 2 -, -O-CH 2 -, -CH 2 -O-, -CH 2 -S-, or -S-CH 2 -;
  • R 9s attached to the same carbon atom together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl and the 3-6 membered heterocyclic group are each independently and optionally substituted by 1, 2, 3 or 4 R 8b ;
  • two R 9s attached to two non-adjacent atoms and the two non-adjacent atoms attached thereto together form a C 3-6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C 3-6 cycloalkyl and the 3-6 membered heterocyclic group are each independently optionally substituted by 1, 2, 3 or 4 R 8b ;
  • R 6b , R 7b , R 6c and R 8b are each as defined in the present invention.
  • Ring B is C 6-12 aryl or 5-12 membered heteroaryl.
  • R 3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, or C 1-4 haloalkyl.
  • Y is a bond, O, or S.
  • R 4 is -H, -D, C 1-6 alkyl, 3-10 membered heterocyclyl, -L-(3-10 membered heterocyclyl), -LC 3-10 cycloalkyl, -L-(5-12 membered heteroaryl), -L-(C 6-10 aryl), -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC( ⁇ NH)NH 2 or -LC( ⁇ O)NR 6 R 7 , wherein the C 1-6 alkyl, 3-10 membered heterocyclyl, -L-(3-10 membered heterocyclyl), -LC 3-10 cycloalkyl, -L-(5-12 membered heteroaryl) and -L-(C 6-10 aryl) are each independently optionally substituted by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d
  • L is a C 1-6 alkylene group
  • R 6 , R 7 , R 6d , R 7d , R 6e and R 7e each have the same meaning as described herein.
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl.
  • n 0, 1, 2, 3, 4, 5, 6, or 7;
  • q1 is 0, 1, 2, 3, 4, 5, or 6.
  • q2 is 1, 2, 3, 4, 5, 6, 7, or 8.
  • Y 1 is -H, -D, C 1-4 alkyl, C 3-6 cycloalkyl, (3-6 membered)-heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl or C 1-4 alkoxyC 1-4 alkyl, wherein said Y 1 is optionally substituted with 1, 2, 3 or 4 R 8a ; wherein each R 8a has the definition as described herein.
  • Y 3 is -H, -D, C 1-4 alkyl, C 3-6 cycloalkyl, (3-6 membered)-heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl or C 1-4 alkoxyC 1-4 alkyl, wherein said Y 3 is optionally substituted with 1, 2, 3 or 4 R 8a ; wherein each R 8a has the definition as described herein.
  • Y 2 is -H, -D or C 1-4 alkyl.
  • Y 1 , Y 2 and the N atom to which they are attached together form
  • q1, q2 and R 9 each have the definition as described in the present invention
  • two R 9 attached to the same carbon atom together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, wherein the C 3-6 cycloalkyl and the 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 R 8b ; wherein each R 8b has the definition as described in the present invention, provided that the two R 9 attached to the same carbon atom together with the carbon atom to which they are attached do not form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl.
  • two R 9s attached to two adjacent atoms together with the two adjacent atoms to which they are attached form a double bond, a C 3-6 cycloalkyl, a 3-6 membered heterocyclyl, a 5-6 membered heteroaryl or a phenyl group, wherein the C 3-6 cycloalkyl, the 3-6 membered heterocyclyl, the 5-6 membered heteroaryl and the phenyl group are each independently optionally substituted by 1, 2, 3 or 4 R 8b ; wherein R 8b has the definition as described in the present invention.
  • two R 9 attached to two non-adjacent atoms and the two non-adjacent atoms attached thereto together form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, wherein the C 3-6 cycloalkyl and the 3-6 membered heterocyclyl are each independently optionally substituted by 1, 2, 3 or 4 R 8b ; wherein each R 8b has the definition as described in the present invention, provided that the two R 9 attached to two non-adjacent atoms and the two non-adjacent atoms attached thereto together do not form
  • Y 1 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, azetidinyl, thietidinyl, piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, phenyl, pyridinyl, imidazo[1,2-a]pyrazinyl, benzo[d]imidazolyl, benzopyrazolyl, benzo[c][1,2,5]oxadiazolyl, pyrrolo[2,3-d]pyrimidinyl,
  • Y3 is -H, -D, -CH3 , -CH2CH3 , -( CH2 ) 2CH3 , -( CH2 ) 3CH3 , -CH( CH3 ) 2 , -CH2CH ( CH3 ) 2 , -C( CH3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, azetidinyl, thietanyl, piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, phenyl, pyridinyl, imidazo[1,2-a]pyrazinyl, benzo[d]imidazolyl, benzopyrazolyl, benzo[c][1,2,5]oxadiazolyl, pyrrolo[2,3-d]pyrimidinyl, pyrrol
  • Y2 is -H, -D, -CH3 , -CH2CH3 , -( CH2 ) 2CH3 , -( CH2 ) 3CH3 , -CH( CH3 ) 2 , -CH2CH ( CH3 ) 2 , or -C( CH3 ) 3 .
  • Y 1 , Y 2 and the N atom to which they are attached together form
  • R 9 attached to the same carbon atom together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothi
  • Ring B is one of the following substructures
  • R 4 is -H, -D, C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC( ⁇ NH)NH 2 or -LC( ⁇ O)NR 6 R 7 , wherein the C 1-4
  • L is a C 1-4 alkylene group.
  • R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxiranyl, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H-indenyl, -CH 2 -decalinyl, -CH 2 -pyridinyl , -
  • R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e together with the N atom to which they are attached, form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl , C 1-4 hydroxyalkyl, C 1-4 haloalkoxy or C 1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
  • R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e together with the N atom to which they are attached, form pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine and imidazolidine are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrol
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the compound of the present invention is a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1).
  • R 3 , R 4 , R 5 , Y and T each have the meanings as described in the present invention
  • R 2a , R 2b and R 2c each have the same definition as described for R 2 in the present invention.
  • the compound described in the present invention is a compound of the following structure, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.
  • the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.
  • the pharmaceutical composition can be in liquid, solid, semisolid, gel or spray form.
  • the present invention provides the use of the pharmaceutical composition described in the present invention in the preparation of a medicament for preventing, treating or alleviating diseases associated with KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutations.
  • the KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS The disease associated with the G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation is cancer.
  • the cancer described in the present invention is a cancer of the heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma, etc.; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, etc.; gastrointestinal cancer: esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) cancer, stomach (lymphoma, leiomyo
  • Bone cancer osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor, etc.; Nervous system cancer: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans) tumors, brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, neurothecoma, retinoblastoma, congenital tumor), spinal
  • the present invention also provides a method for preventing or treating a KRAS-related disease, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof to a patient.
  • the present invention also provides the use of the compounds described in the present invention or their pharmaceutical compositions for or treatment of KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation-related diseases.
  • the present invention relates to methods for preparing, isolating and purifying the compounds of formula (I) or (I-1).
  • the salts are pharmaceutically acceptable salts.
  • pharmaceutically acceptable includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.
  • the salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or (I-1) or salts of separated enantiomers of the compounds of formula (I) or (I-1), but they are not necessarily pharmaceutically acceptable salts.
  • the pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I) or (I-1), a compound listed in the present invention, or a compound of the embodiment, and a pharmaceutically acceptable carrier.
  • the amount of the compound in the pharmaceutical composition of the present invention is effective in treating or alleviating a KRAS-mediated disease in a patient.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be directly or indirectly administered according to the needs of the patient, the compounds described in other aspects of the present invention, their metabolites or their residues.
  • the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable adjuvant, which, as used in the present invention, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form.
  • a pharmaceutically acceptable adjuvant includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc.
  • Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa
  • active ingredient is usually mixed with excipient, diluted by excipient or encapsulated in such carrier in the form of capsule, pouch, paper or other container, for example.
  • excipient can be solid, semisolid or liquid material, which is used as carrier, carrier or medium of active ingredient.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc.
  • the composition can be tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid form or in liquid medium), for example, ointments containing up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions and aseptically packaged powders.
  • the composition is formulated for oral administration.
  • the composition is formulated into tablets or capsules.
  • the compounds or pharmaceutical compositions of the present invention can be administered in the form of oral dosage forms, such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously. Intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular administration, all of which are well known to those of ordinary skill in the pharmaceutical field. They can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected mode of administration and standard pharmaceutical practice.
  • oral dosage forms such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously. Intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular administration
  • the compounds or pharmaceutical compositions of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or transdermally by use of transdermal patches.
  • the dosage administered is continuous rather than intermittent throughout the medication period.
  • the compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.
  • the compounds of the invention or pharmaceutical compositions are also coupled with soluble polymers, which serve as targeted drug carriers.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues.
  • the compounds of the invention can be coupled with a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.
  • biodegradable polymers for controlled drug release for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.
  • the dosage regimen of the compounds or pharmaceutical compositions of the present invention will vary with known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health status, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect.
  • a physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, counteract or arrest the development of cancer.
  • the compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents.
  • the compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration.
  • the compounds of the present invention can be included in a single formulation or in a separate formulation with other therapeutic agents.
  • the amount of each component in a typical daily dose and typical dosage form may be reduced relative to the usual dose when administered alone, taking into account the additive or synergistic effects of the therapeutic agents when administered in combination.
  • the compounds or pharmaceutically acceptable salts or hydrates thereof or pharmaceutical compositions thereof involved in the present invention can be effectively used to prevent, treat or alleviate diseases mediated by KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutations, especially cancer.
  • the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma, etc.; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, etc.; gastrointestinal cancer: esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosar
  • Gynecological cancer uterine cancer (endometrial cancer, granulosa cell tumor, stromal cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryo rhabdomyosarcoma), fallopian tube cancer, ovarian cancer, breast cancer, etc.; blood cancer: acute or chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), etc.; skin cancer: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipo
  • the present invention will further illustrate the technical scheme of the present invention with the following examples.
  • the following examples are only used to illustrate the specific implementation method of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of protection of the present invention.
  • the technical means or methods not specifically described are conventional technical means or methods in the art.
  • temperatures are set forth in degrees Celsius (°C) unless otherwise indicated, and room temperature in the examples means 15°C–30°C; in some examples, room temperature is 20°C–30°C.
  • Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
  • reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringe. All glassware was dried.
  • the chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.
  • the low-resolution mass spectrometry (MS) data were measured using an Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5%-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), electrospray ionization (ESI), at 210 nm/254 nm, with UV detection.
  • LiHMDS Lithium bis(trimethylsilyl)amide M,mol/L mole/liter
  • X, q2, R2 , R3 and R9 are as defined in the present invention; n1 is a natural number of 1-6; Hal is a halogen, preferably Cl or Br; Ra is a C1-4 alkyl, preferably methyl or ethyl; t is a natural number of 1-6, preferably 1 or 2; and the 3-10 membered heterocyclic group is as defined in the present invention, and may be optionally substituted by a substituent described in the present invention.
  • Compound (IA-1) reacts with di-tert-butyl dicarbonate under appropriate conditions (such as in the presence of DMAP and imidazole in a dichloromethane solvent) to obtain compound (IA-2); compound (IA-2) first reacts with TMPMgCl-LiCl, and then the reaction product reacts with 1,2-dibromotetrachloroethane to obtain compound (IA-3); compound (IA-3) is deaminated under acidic conditions to obtain compound (IA-4); compound (IA-4) reacts with 2,2,2-triisopropylsilyl acetylene under appropriate conditions (such as Pd(PPh 3 ) 2 Cl 2 and CuI) coupling reaction to obtain compound (IA-5); compound (IA-5) and 2,2,2-trichloroacetyl isocyanate to obtain compound (IA-6); compound (IA-6) and ammonia methanol solution to obtain compound (IA-7); compound (IA-7) and phosphorus oxych
  • X, q2, n, R2 , R3 , R5 and R9 have the definitions as described in the present invention;
  • Hal is a halogen, preferably Cl or Br;
  • t is a natural number of 1-6, preferably 1 or 2;
  • the 3-10 membered heterocyclic group has the definitions as described in the present invention, and can be optionally substituted by the substituents described in the present invention.
  • Compound (IB-1) reacts with phosphorus oxychloride in the presence of DIPEA to obtain compound (IB-2); compound (IB-2) reacts with compound (IA-9) under appropriate conditions (such as the presence of DIPEA) to obtain compound (IB-3); compound (IB-3) reacts with compound (IA-11) under appropriate conditions (such as heating, under the presence of DIPEA) to obtain compound (IB-4); compound (IB-4) reacts with compound (IB-5) under the presence of a suitable catalyst (such as XPhos Pd G3) to obtain compound (IB).
  • a suitable catalyst such as XPhos Pd G3
  • X, q2, R 2 , R 3 , R 5 and R 9 have the definitions as described in the present invention;
  • Hal is a halogen, preferably Cl or Br;
  • t is a natural number of 1-6, preferably 1 or 2;
  • n1 is a natural number of 1-6;
  • the 3-10 membered heterocyclic group has the definition as described in the present invention, and can be optionally substituted by the substituents described in the present invention.
  • Compound (IB-4) is reacted with compound (IA-13) in the presence of a suitable catalyst (such as XPhos Pd G3) to obtain compound (IC-1); compound (IC-1) is reacted under acidic conditions (such as TMSOTf, CF 3 SO 3 H, etc.) to give compound (IC).
  • a suitable catalyst such as XPhos Pd G3
  • IC-1 compound (IC-1) is reacted under acidic conditions (such as TMSOTf, CF 3 SO 3 H, etc.) to give compound (IC).
  • X, q2, R2 , R3 , R5 and R9 have the definitions as described in the present invention;
  • Hal is a halogen, preferably Cl or Br;
  • t is a natural number of 1-6, preferably 1 or 2;
  • n2 is a natural number of 1-5;
  • the 3-10 membered heterocyclic group has the definition as described in the present invention, and can be optionally substituted by the substituents described in the present invention.
  • Compound (IB-4) reacts with compound (ID-1) under the action of a suitable catalyst (such as XPhos Pd G3) to obtain compound (ID-2); compound (ID-2) reacts under the action of CsF to obtain compound (ID-3); compound (ID-3) is reacted under acidic conditions (such as TMSOTf) to obtain compound (ID).
  • a suitable catalyst such as XPhos Pd G3
  • compound (ID-2) reacts under the action of CsF to obtain compound (ID-3
  • compound (ID-3) is reacted under acidic conditions (such as TMSOTf) to obtain compound (ID).
  • step 1 and step 2 The yield of step 1 and step 2 is 45%.
  • Relative signal value pERK (signal value of 800 channel) / GAPDH (signal value of 700 channel)
  • Inhibition rate % 100-(Signal value of each sample-Relative signal value of quality control product)/(Signal value of DMSO well-Relative signal value of quality control product) ⁇ 100
  • the compounds of the present invention can effectively inhibit the phosphorylation of ERK protein in KRAS wild-type and KRAS mutant cell lines.

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  • Organic Chemistry (AREA)
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Abstract

La présente invention se rapporte au domaine technique des produits pharmaceutiques et concerne en particulier un composé inhibiteur de KRAS, une composition pharmaceutique de celui-ci, et une utilisation associée. Plus particulièrement, la présente invention concerne un composé représenté par la formule (I), ou un stéréoisomère de celui-ci, un tautomère de celui-ci, un oxyde d'azote de celui-ci, un solvate de celui-ci, un métabolite de celui-ci, un sel pharmaceutiquement acceptable de celui-ci, ou un promédicament de celui-ci. Le composé et la composition pharmaceutique de celui-ci selon la présente invention peuvent être utilisés pour préparer un médicament pour prévenir ou traiter des maladies liées à KRAS de type sauvage, ou KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D ou KRAS Q61H, en particulier pour préparer un médicament pour prévenir ou traiter le cancer.
PCT/CN2023/132030 2022-11-17 2023-11-16 Composé inhibiteur de kras, composition pharmaceutique de celui-ci et utilisation associée WO2024104425A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022105855A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022132200A1 (fr) * 2020-12-15 2022-06-23 Mirati Therapeutics, Inc. Inhibiteurs pan-kras d'azaquinazoline
WO2022184178A1 (fr) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2023274324A1 (fr) * 2021-06-30 2023-01-05 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci, et utilisation associée
WO2023020518A1 (fr) * 2021-08-18 2023-02-23 Jacobio Pharmaceuticals Co., Ltd. Dérivés de n-cyclopropylpyrido [4, 3-d] pyrimidin-4-amine et leurs utilisations
WO2023020519A1 (fr) * 2021-08-18 2023-02-23 Jacobio Pharmaceuticals Co., Ltd. Dérivés de 1, 4-oxazépane et leurs utilisations
WO2023061463A1 (fr) * 2021-10-15 2023-04-20 广东东阳光药业有限公司 Nouveau composé de pyrimidopyridine, composition pharmaceutique de celui-ci et utilisation associée
WO2023098426A1 (fr) * 2021-12-02 2023-06-08 上海和誉生物医药科技有限公司 Dérivés de 7-(naphtalén-1-yl)pyrido[4,3-d]pyrimidine, leur procédé de préparation et leur utilisation
WO2023134465A1 (fr) * 2022-01-11 2023-07-20 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et utilisation associée

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022105855A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022132200A1 (fr) * 2020-12-15 2022-06-23 Mirati Therapeutics, Inc. Inhibiteurs pan-kras d'azaquinazoline
WO2022184178A1 (fr) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2023274324A1 (fr) * 2021-06-30 2023-01-05 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci, et utilisation associée
WO2023020518A1 (fr) * 2021-08-18 2023-02-23 Jacobio Pharmaceuticals Co., Ltd. Dérivés de n-cyclopropylpyrido [4, 3-d] pyrimidin-4-amine et leurs utilisations
WO2023020519A1 (fr) * 2021-08-18 2023-02-23 Jacobio Pharmaceuticals Co., Ltd. Dérivés de 1, 4-oxazépane et leurs utilisations
WO2023061463A1 (fr) * 2021-10-15 2023-04-20 广东东阳光药业有限公司 Nouveau composé de pyrimidopyridine, composition pharmaceutique de celui-ci et utilisation associée
WO2023098426A1 (fr) * 2021-12-02 2023-06-08 上海和誉生物医药科技有限公司 Dérivés de 7-(naphtalén-1-yl)pyrido[4,3-d]pyrimidine, leur procédé de préparation et leur utilisation
WO2023134465A1 (fr) * 2022-01-11 2023-07-20 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et utilisation associée

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