WO2024008178A1 - Inhibiteur de kras g12d et son application en médecine - Google Patents
Inhibiteur de kras g12d et son application en médecine Download PDFInfo
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- WO2024008178A1 WO2024008178A1 PCT/CN2023/106296 CN2023106296W WO2024008178A1 WO 2024008178 A1 WO2024008178 A1 WO 2024008178A1 CN 2023106296 W CN2023106296 W CN 2023106296W WO 2024008178 A1 WO2024008178 A1 WO 2024008178A1
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- WIPO (PCT)
- Prior art keywords
- compound
- cycloalkyl
- alkyl
- alkylene
- halogen
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- 229940126204 KRAS G12D inhibitor Drugs 0.000 title 1
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- 239000004005 microsphere Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- FMASTMURQSHELY-UHFFFAOYSA-N n-(4-fluoro-2-methylphenyl)-3-methyl-n-[(2-methyl-1h-indol-4-yl)methyl]pyridine-4-carboxamide Chemical compound C1=CC=C2NC(C)=CC2=C1CN(C=1C(=CC(F)=CC=1)C)C(=O)C1=CC=NC=C1C FMASTMURQSHELY-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 102200006531 rs121913529 Human genes 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical compound FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HNINFCBLGHCFOJ-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NCC2CCC1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-UHFFFAOYSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
- 229910052725 zinc Chemical class 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/535—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D471/12—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 three hetero rings
-
- 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
- C07D487/08—Bridged systems
-
- 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 relates to the field of medical technology, specifically to the compound of formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutical salt, its preparation method, pharmaceutical composition containing the compound, and its use as Uses of drugs to treat cancer.
- RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, and 43% of multiple myeloma. And RAS gene mutations are present in 32% of lung adenocarcinomas.
- the most common mutation mode of RAS is point mutation, which often occurs in codons 12, 13, and 61. Among them, mutations in codon 12 are the most common, such as G12C, G12D or G12V.
- KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; while MIRATI is leading the research and development of G12D inhibitor (WO2021041671A1).
- KRAS has always been a target of concern for drug developers. Although progress has been made in this field, there is still a need for improved KRAS G12D mutant protein inhibitors to meet additional clinical needs.
- the technical problem to be solved by the present invention is to overcome the problem of lack of KRAS G12D mutant protein inhibitors in the prior art, and provide a compound represented by the general formula (I) and its application.
- the general formula (I) provided by the present invention The compound shown in I) has a good inhibitory effect on KRAS G12D mutant protein.
- the present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
- X is selected from bond, NH, O or S;
- L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- , the -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
- the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14
- the membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group
- Selected from in is a double bond, Selected from Z configuration or E configuration;
- R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 3-14 cycloalkyl, 3-14 membered heterocyclyl Ring group, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ;
- R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
- R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
- R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocycle group, C 6-18 aryl or 5-18 membered heteroaryl, optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy replaced;
- n is selected from 0, 1, 2, 3 or 4.
- X in formula (I) is O.
- L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
- Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
- the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
- the fused ring in formula (I) is selected from
- R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
- R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 Alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
- R in formula (I) is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkene base, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
- R in formula (I) is selected from
- R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 3-14 cycloalkyl-O-.
- R3 in formula (I) is selected from H, hydroxyl, methyl,
- R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy, preferably F.
- R5 in formula (I) is H.
- formula (I) is selected from (IA) or (IB):
- formula (I) is selected from (IA-1) and (IB-1):
- the compound of formula (I) is selected from (IA-1) and (IB-1), wherein:
- R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ;
- the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene -C 6-18 Aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
- R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
- X is selected from bond, NH, O or S;
- L is selected from bond or -C 1-3 alkylene-
- R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl are optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or Substituted with C 1-6 alkyl.
- the present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
- X is selected from bond, NH, O or S;
- L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- , the -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
- the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14
- the membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group
- Selected from in is a double bond, Selected from Z configuration or E configuration;
- R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 3-14 cycloalkyl, 3-14 membered heterocyclyl Ring group, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ;
- R 3 or R 4 are independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy , C 3 -14 Cycloalkyl-O-, haloalkyl or hydroxyalkyl is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or substituted by hydroxyl;
- R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
- R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18
- the heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
- n is selected from 0, 1, 2, 3 or 4.
- X in formula (I) is O.
- L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
- Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
- the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
- the fused ring in formula (I) is selected from
- R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
- R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
- R in formula (I) is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
- R in formula (I) is selected from
- R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-14 Cycloalkyl-O-.
- R in formula (I) is selected from H, halogen, hydroxyl, methyl, methoxy,
- R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy, preferably F.
- R5 in formula (I) is H.
- formula (I) is selected from (IA) or (IB):
- formula (I) is selected from (IA-1) or (IB-1):
- the compound of formula (I) is selected from (IA-1) and (IB-1), wherein:
- R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ;
- the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene -C 6-18 Aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
- R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
- X is selected from bond, NH, O or S;
- L is selected from bond or -C 1-3 alkylene-
- R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl are optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or Substituted with C 1-6 alkyl.
- formula (I) is selected from (IA-1-1) or (IB-1-1):
- the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
- the R 4 is selected from hydrogen or halogen
- the R 6 is selected from hydrogen or halogen
- the R 7 is selected from alkyl, haloalkyl or cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
- the present invention provides a compound represented by general formula (I), or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
- X is selected from bond, NR a , O or S;
- L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- ;
- the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 5-14 cycloalkyl, 5-14
- the one-membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, Amino, nitro, hydroxyl, replaced;
- the two R 6 in can together form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group with the atoms to which they are connected.
- the C 3-8 cycloalkyl group and 3-8 membered heterocyclyl group are optional ground is further replaced by one or more R a ;
- R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl
- the ring group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more R a ;
- R 3 or R 4 are independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl
- the base -O-, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , cyano, amino, nitro or hydroxyl substituted;
- R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
- R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18
- the heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
- Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
- n is selected from 0, 1, 2, 3 or 4.
- X in formula (I) is O.
- L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
- Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
- the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
- the fused ring in formula (I) is selected from
- R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
- formula (I) Selected from in Indicates Z configuration or E configuration.
- R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl; the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
- R in formula (I) is selected from Among them, the
- Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
- R in formula (I) is selected from
- R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-14 Cycloalkyl-O-.
- R in formula (I) is selected from H, halogen, hydroxyl, methyl, methoxy,
- R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably F.
- R5 in formula (I) is H.
- formula (I) is selected from (IA) or (IB):
- formula (I) is selected from (IA-1) or (IB-1):
- formula (I) is selected from (IA-1') or (IB-1'):
- the compound of formula (I) is selected from (IA-1), (IB-1), (IA-1') or (IB-1'), wherein:
- the R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl; wherein, the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a Substituted, the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene - C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
- the R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; wherein, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1- 6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl ;
- the X is selected from bond, NH, O or S;
- the L is selected from bond or -C 1-3 alkylene-;
- the R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, so The C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro substituted by C 1-6 alkyl group.
- formula (I) is selected from (IA-1-1) or (IB-1-1):
- the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
- the R 4 is selected from hydrogen or halogen
- the R 6 is selected from hydrogen or halogen
- the R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl; preferably it is methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
- formula (I) is selected from (IA-1'-1) or (IB-1'-1):
- the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
- the R 4 is selected from hydrogen or halogen
- the R 6 is selected from hydrogen or halogen
- the R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
- the present invention provides a compound represented by general formula (I), or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
- X is selected from bond, NR a , O or S;
- L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- ;
- the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 5-14 cycloalkyl, 5-14
- the one-membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, Amino, nitro, hydroxyl, replaced;
- the two R 6 in can together form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group with the atoms to which they are connected.
- the C 3-8 cycloalkyl group and 3-8 membered heterocyclyl group are optional ground is further replaced by one or more R a ;
- R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl
- the ring group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more R a ;
- R 3 is independently selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy; the C 1-6 alkoxy, C 3-14 cycloalkyl -O- or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro or substituted by hydroxyl;
- R 4 is independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 ring Alkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3- 14 cycloalkyl-O-, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogens, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 substituted by haloalkyl, cyano, amino, nitro or hydroxyl;
- R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
- R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18
- the heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
- n is selected from 0, 1, 2, 3 or 4.
- each R b in formula (I) is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl.
- X in formula (I) is selected from bonds, NH, O or S;
- the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14
- the membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group
- Selected from in is a double bond, Selected from Z configuration or E configuration;
- R 3 is independently selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy, said C 1-6 alkoxy or C 3-14 cycloalkyl- O- is further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
- R 4 is selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or hydroxyalkyl optionally further Substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
- Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 haloalkyl.
- X in formula (I) is O.
- L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
- Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
- the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
- the fused ring described in formula (I) is selected from
- R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl Or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more Substituted by halogen, hydroxyl, cyano, amino, nitro or C 1-6 alkyl.
- Formula (I) Selected from described may optionally be further substituted by one or more halogens, C 1-6 alkyl or replaced.
- Formula (I) Selected from in Indicates Z configuration or E configuration.
- R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl; the C 6-18 aryl or 5-18 membered heteroaryl is optionally further One or more R a is substituted, R a is independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2- 6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
- R 2 in formula (I) is selected from Among them, the
- Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
- R 2 in formula (I) is selected from
- R 3 in formula (I) is selected from C 1-6 alkoxy or C 3-14 cycloalkyl-O-.
- R 3 in formula (I) is selected from methoxy
- R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably F.
- R 5 in Formula (I) is H.
- the compound of formula (I) described in formula (I) is selected from formula (IA) or (IB):
- the compound of formula (I) is selected from formula (IA-1) or (IB-1):
- the compound of formula (I) is selected from formula (IA-1') or (IB-1'):
- the R 2 is selected from C 6-18 aryl or 5-18 yuan Heteroaryl; wherein, the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a , and the R a is independently selected from H, hydroxyl, cyano, Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene-C 3- 14- cycloalkyl, -C 0-3 alkylene-(3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-( 5-18 membered heteroaryl);
- the R 3 is selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy; wherein, the C 1-6 alkoxy, C 3-14 cycloalkyl Alkyl-O- or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, Substituted by nitro or hydroxyl;
- R 4 is selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; wherein, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl or C 1-6 The haloalkoxy group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro or hydroxyl;
- the X is selected from bond, NH, O or S;
- the L is selected from bond or -C 1-3 alkylene-;
- the R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, so The C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens, hydroxyl groups , cyano, amino, nitro or C 1-6 alkyl substituted.
- formula (I) is selected from formula (IA-1-1) or (IB-1-1):
- the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
- the R 4 is selected from hydrogen or halogen
- the R 6 is selected from hydrogen or halogen
- the R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl; preferably it is methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
- formula (I) is selected from (IA-1'-1) or (IB-1'-1):
- the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
- the R 4 is selected from hydrogen or halogen
- the R 6 is selected from hydrogen or halogen
- the R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
- the compound of formula (I) is selected from:
- the compound of formula (I) relates to an intermediate compound, and the intermediate compound is selected from:
- the present invention also provides a method for preparing intermediate compound M13, which includes the following steps: reacting racemate M9 with a chiral acid to generate the corresponding salt, and dissociating it under alkaline conditions to obtain S-configured free base M13.
- the chiral acid is selected from L-(-)-di-p-toluoyltartaric acid, L-(-)-dibenzoyltartaric acid or L-(-)-dibenzoyltartaric acid.
- p-Methoxybenzoyltartaric acid is selected from L-(-)-di-p-toluoyltartaric acid, L-(-)-dibenzoyltartaric acid or L-(-)-dibenzoyltartaric acid.
- the preparation method of intermediate compound M13 includes the following steps:
- the preparation method of intermediate M13 further includes the following steps:
- Dissolve M9 in organic solvent 1 raise the temperature and stir to dissolve, to obtain a solution of M9; dissolve L-(-)-di-p-methylbenzoyltartaric acid in organic solvent 2 to form an acid solution; slowly add the acid solution dropwise to In the solution of M9, the acid solution is added dropwise. After heating and dissolving, the organic solvent 3 is added dropwise to the reaction solution. After the dropwise addition is completed, the temperature is slowly cooled and crystallized. The sample is filtered and the filter cake is vacuum dried to obtain (S)- The crude product of DPLT salt, the crude product of (S)-DPLT salt is recrystallized in organic solvent 4 to obtain (S)-DPLT salt M13-1;
- the organic solvent 1 in step 1) is selected from the group consisting of 2-methyltetrahydrofuran, ethanol, acetonitrile, ethyl ketone, and ethanol.
- the organic solvent 2 in step 1) is selected from ethyl acetate, ethanol, isopropyl alcohol, ethanone, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof.
- the organic solvent 3 in step 1) is selected from ethyl acetate, isopropyl alcohol, isopropyl acetate, methyl tert-butyl ether, n-heptane or a mixture thereof.
- the organic solvent 4 in step 1) is selected from isopropyl alcohol/acetonitrile ethanol/acetonitrile/ethyl acetate, methanol/acetonitrile/ethyl acetate, ethanol/ethyl ketone/ethyl acetate, ethanol/methyl tert.
- the organic solvent 5 in step 2) is selected from dichloromethane/methanol, 2-methyltetrahydrofuran F, ethyl acetate or a mixture thereof.
- the organic solvent 6 in step 2) is selected from dichloromethane/methanol, 2-methyltetrahydrofuran or ethyl acetate.
- the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of at least one compound represented by formula (I), its stereoisomer, tautomer, deuterated product or Medicinal salt.
- the present invention provides the use of the compound represented by structural formula (I) or its pharmaceutical composition in the preparation of medicines.
- the application is in the preparation of drugs for the treatment and/or prevention of cancer.
- the application is the application of preparing drugs for treating diseases mediated by KRAS G12D.
- the disease is cancer.
- the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, cholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
- the present invention also provides a method for treating and/or preventing diseases, which includes administering to the treatment subject a therapeutically effective amount of at least any one compound represented by structural formula (I), its stereoisomer, tautomer, deuterium substitutes or pharmaceutically acceptable salts or pharmaceutical compositions containing them.
- the present invention also provides a method for treating and/or preventing diseases mediated by KRAS G12D, which includes administering to the treatment subject a therapeutically effective amount of at least any one of the compounds represented by structural formula (I), its stereoisomers, Tautomers, deuterated compounds or pharmaceutically acceptable salts or pharmaceutical compositions containing them.
- the present invention also provides a method for treating cancer, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable Salts or pharmaceutical compositions containing them.
- the KRAS G12D-mediated disease is cancer.
- the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xuwang cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
- halogen refers to fluorine, chlorine, bromine or iodine.
- alkyl includes linear or branched monovalent saturated hydrocarbon groups.
- alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
- " 1-6 " in "C 1-6 alkyl” refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
- Alkoxy refers to the oxygen ether form of the aforementioned linear or branched alkyl group, that is, -O-alkyl.
- alkylene refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the alkylene's point of attachment to the rest of the compound. Similarly, “C 1-3 " in C 1-3 alkylene refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
- haloalkyl refers to the aforementioned alkyl group in which one or more H has been replaced by a halogen atom, such as C 1-6 haloalkyl.
- oxo or "oxo” refers to an oxygen atom in the form of a divalent substituent which, when attached to C, forms a carbonyl group and which, when attached to a heteroatom, forms a sulfoxide or sulfone or N-oxide group group.
- aromatic ring means having aromatic characteristics (having (4n+2) delocalized ⁇ electrons, where n is Integer) polyunsaturated ring carbocyclic or heterocyclic ring.
- aryl refers to an unsubstituted or substituted monocyclic or fused ring aromatic group including atoms of a carbocyclic ring.
- a C 6-18 aryl group is preferred, and a C 6-10 monocyclic or bicyclic aromatic ring group is more preferred.
- Preferred are phenyl and naphthyl; most preferred are naphthyl.
- the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, where the ring attached to the parent structure is an aryl ring, non-limiting examples include but are not limited to benzocyclopentyl.
- heterocyclyl refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic atom selected from N, O and/or S.
- the heterocyclyl group may include monocyclic or polycyclic rings (e.g., having 2, 3 or 4 fused rings, Spiral ring, bridge ring, etc.).
- Heterocyclyl groups can be connected to other parts of the compound via ring carbon atoms or ring heteroatoms.
- 3-14-membered heterocyclic groups Preferred are 3-14-membered heterocyclic groups, and the "3-14-membered" in the 3-14-membered heterocyclic groups refers to heterocyclic groups containing 3-14 C, N, O or S ring-forming atoms; more preferably 5-14 membered heterocyclyl and 3-8 membered heterocyclyl, more preferably 3-6 membered heterocyclyl.
- the nitrogen or sulfur heteroatoms can be selectively oxidized, and the nitrogen heteroatoms can be selectively quaternized.
- heterocyclyl groups include, but are not limited to Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxypiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, Tetrahydroxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone and tetrahydroxadiazolyl.
- the heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is the heterocyclyl group.
- heteroaryl in the present invention, unless otherwise stated, refers to a monocyclic or polycyclic ring with at least one heteroatom (for example, with 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.) Aromatic heterocycle, the heteroatom is selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized.
- heteroaryl groups include but are not limited to thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiodi Azolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl or isoquinolyl.
- the heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
- cycloalkyl refers to a ring system having at least one cyclized alkyl group.
- C 3-14 cycloalkyl is preferred, where "C 3-14 " means that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms .
- Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.).
- the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclyl or heteroaryl ring, where it is connected to the parent structure The rings joined together are cycloalkyl.
- substituted means that one or more hydrogen atoms in the group are replaced by the same or different substituents, respectively.
- the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy group, tert-butoxy group, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C(OCH 3 ), cyano group, nitro group, -CF 3 , -OCF 3 , amino group, dimethyl group amino, methylthio, sulfonyl and acetyl groups.
- linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
- salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low prices), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low prices), potassium, sodium, and zinc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred.
- Nontoxic organic bases capable of being derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines.
- non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine Acid, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
- ion exchange resins and arginine betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylamin
- the compound provided by the present invention is a base
- its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
- acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, parapexic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydriodic acid, perchloric acid, cyclohexane sulfonic acid, salicylic acid, 2-naphthalene sulfonic acid, saccharinic
- prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
- the prodrug refers to a functional derivative that is easily converted into the desired compound in the body.
- any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite after administration to the recipient; Residues.
- the compounds described in the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and Optical isomers.
- the present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
- the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as their mixtures.
- substitution of compounds of formula (I) with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
- composition refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
- the purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
- pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
- the pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with appropriate pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
- Typical routes of administration of the compounds of the invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, Subcutaneous and intravenous administration.
- treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
- the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
- treatment encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
- the term "effective amount” means (i) treating or preventing a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described in .
- the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
- the compounds of the present invention have excellent activities in terms of enzymatic activity, cell activity, PK, bioavailability, etc., and can be used to treat and/or prevent diseases mediated by KRAS G12D.
- the compound of the present invention compared to MART1133 (Compared to Compound D1), the compound of the present invention, has higher whole blood exposure and lower clearance in intravenous administration; it has better PO exposure (AUC) and Oral bioavailability (F%), the oral absorption of the compounds of the present invention is significantly better than that of MART1133.
- Figure 1 is a stereoscopic polarizing microscope diagram of a single crystal sample of compound M13-1.
- Figure 2 is an analytical diagram of the single crystal structure of compound M13-1.
- Figure 3 shows the distribution of compounds in tumor tissues of NCI-H1975 tumor-bearing mice.
- NIS N-iodosuccinimide
- PE petroleum ether
- mCPBA m-chloroperoxybenzoic acid
- CsF cesium fluoride
- TBDPSCl tert-butyldiphenylsilyl chloride
- DPPA diphenylphosphate azide
- CDI N,N'-carbonyldiimidazole
- DIEA N,N-diisopropylethylamine
- CataCXium A Pd G3 methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II);
- SphosPdG2 Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II);
- DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
- mCPBA m-chloroperoxybenzoic acid
- LAH lithium aluminum tetrahydride
- TFA trifluoroacetic acid
- BINAP 1,1'-binaphthyl-2,2'-bisdiphenylphosphine
- compound M1-4 (187g) and difluoromethyl (2-pyridyl) sulfone (184g) were dissolved in anhydrous DMF (1.4L), and potassium tert-butoxide (107g) was added dropwise at -50°C.
- DMF (460mL) solution after the dropwise addition is completed, control the temperature to react at -40°C for 2 hours.
- saturated ammonium chloride solution dropwise at -50°C until the solution becomes weakly acidic, and naturally warm to room temperature for 18 hours. , filter to obtain the filtrate, add EA (1.4L) to dilute, filter again to obtain the filtrate, and concentrate.
- Dissolve compound M2-1 (65.00g) in CH 3 CN (82.00 mL) at room temperature, cool in a water bath, slowly add hydrochloric acid (4M/dioxane) (38.43g), stir and react at room temperature for about 16 hours , a white solid precipitated in a suspended state.
- the reaction mixture was filtered, and the filter cake was rinsed with a small amount of acetonitrile, drained, and the filtrate was discarded.
- compound M2-2 (36.00g) was dissolved in acetonitrile (180.00mL), NIS (66.32g) and p-toluenesulfonic acid (2.12g) were added, and the reaction was heated and kept at 70°C under nitrogen protection. Cool the reaction solution to 50°C, add 900 mL of water, and a pinkish-white solid powder will precipitate. Beat for half an hour; filter, rinse the filter cake with water, and drain it.
- compound M2-3 (57.50g) was dissolved in DMF (22.00mL), zinc cyanide (32.22g), tetrakis triphenylphosphine palladium (12.19g) and powdered Molecular sieve (20.00 mL) was added, and the reaction was heated and kept at 100°C for about 7 hours in a nitrogen atmosphere. Remove the oil bath, cool to room temperature naturally, and wait for post-processing. Use diatomaceous earth to assist filtration, filter the reaction mixture, and drain it; collect the filtrate and concentrate at 60-70°C to obtain a pale yellow solid crude product.
- Rinse the filter residue with 500 mL of ethyl acetate and drain it; collect the rinse liquid, combine it with the crude product, and concentrate again until no liquid is distilled; add 700 mL of ethyl acetate to dissolve and concentrate the solid crude product obtained, and then use 250 mL of saturated sodium chloride each time , washed 3 times and separated. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain a light yellow solid. Add 160 mL of PE/EA 3/1 mixture, beat for half an hour, filter, and drain.
- M10-1 (54g) was added to a 1L three-necked flask, 500mL ACN was added, NIS (80g) and TsOH (5.1g) were added. After raising the temperature to 70°C and reacting for 1 hour, add 2.5L of water dropwise, filter, and dissolve the filter cake with EA. After liquid separation, the organic phase was concentrated to obtain the target compound M10-2 (94g).
- M10-2 (88g) was added to a 1L three-necked flask, 500mL DMF was added, and CuCN (31g) was added. After raising the temperature to 125°C and reacting for 16 hours, add 2L of water dropwise, then add it to 2L of water, filter, wash the filter cake with water, and dissolve EA. The aqueous phase was extracted twice with EA, the organic phases were collected and combined, and concentrated to obtain the target product M10-3 (55.4g). ESI-MS m/z:207.0[M] - .
- Single crystal culture and identification Weigh compound M13-1, dissolve it with 1 ml of butanone/water (19/1, v/v) mixed solvent, transfer the clarified sample to a butanone atmosphere for gas-liquid diffusion overnight, and obtain a single crystal sample.
- the stereoscopic polarizing microscope picture of the single crystal sample is shown in Figure 1
- the single crystal structure analysis is shown in Figure 2
- the single crystal structure information table is as follows.
- ratio solvent 200ml, stir for 20 minutes, separate and extract, repeat twice; combine the organic phases, wash the organic phase with 200ml of pure water, and then wash with 200ml of saturated brine, and finally dry the organic phase with anhydrous sodium sulfate.
- the organic phase was filtered, and the filtrate was concentrated. After concentration, it was evaporated twice with an ACN jacket to obtain 5.17g (S)-(2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol M13, R/S The isomer ratio is 0.8%:99.2%.
- Example 1 Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-(difluoromethylene) Tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- Synthesis of alcohol
- compound 1-1 (0.3g), cataCXium A Pd G3 (40mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4, 5,5-Tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.53g) and potassium phosphate (0.33g) were dissolved in THF (6 mL) and water (1 mL) were heated to 70°C and reacted for 3 hours.
- Dissolve compound 1-2 (0.31g) in DMF (3mL), add cesium fluoride (0.5g) in batches at room temperature, after the reaction is completed, drop 15mL of water into the reaction liquid, a large amount of solid precipitates, and filter to obtain The solid is dried to obtain the product 1-3 (0.31 g, 76% yield).
- ESI-MS m/z 775.1[M+H] + .
- Dissolve compound 1-3 (0.31g) in DCM (3mL) at room temperature, add trifluoroacetic acid (1mL) thereto, after the reaction is completed, add the reaction solution dropwise to the protective sodium bicarbonate solution at 0°C. , add DCM to separate the layers to obtain the organic layer, wash with saturated brine once, dry over anhydrous sodium sulfate, and concentrate.
- the concentrate was preparatively purified by Pre-HPLC to give product 1 (31 mg, 13% yield).
- Example 2 Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-(difluoromethylene) Tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)-8-fluoro-5-isopropoxypyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl- Synthesis of 6-fluoronaphthalene-2-ol
- Example 3 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-isopropoxy-2- ((2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -Synthesis of 2-alcohol
- Example 5 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethoxy-8-fluoro-2-(( 2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -Synthesis of alcohol
- Example 6 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-ethoxy-8-fluoropyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthalene-2-ol
- Example 7 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-5-methoxy-2- ((2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyne-6-fluoronaphthalene- Synthesis of 2-alcohols
- Example 8 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthalene-2-ol
- Example 9 Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-cyclopropoxy-8-fluoro-2- (2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -Synthesis of 2-alcohol
- Example 39 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- Synthesis of 2-alcohols
- Dissolve compound 39-1 (300 mg) in the previous step in 5 mL of methanol, then add Pd/C (50 mg), replace with hydrogen 5 times, react at room temperature for 20 min, filter through diatomaceous earth, and concentrate the filtrate under reduced pressure. The concentrate is passed through a column Purification by chromatography gave the target compound 39-2 (208 mg).
- Dissolve compound 39-3 (330mg) in DCM (5mL), then add TBSCl (800mg) and imidazole (550mg) in sequence, react at room temperature for 0.5h, extract the reaction solution with DCM and water, retain the organic phase, and add anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure. The concentrate is purified by column chromatography to obtain target compound 39-4 (270 mg).
- Dissolve compound 39-4 (270mg) in DCM (5mL), then add m-CPBA (270mg), react at room temperature for 0.5h, add an appropriate amount of saturated sodium sulfite solution and stir for 20min to quench, extract the reaction solution with DCM and water, and retain The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain target compound 39-5 (150 mg).
- Example 55 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- Synthesis of alcohol
- Example 109 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2-(difluoro methylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthyl-2-amine
- Step 1 Synthesis of Compound 109-1
- Example 110 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Synthesis of hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine
- Dissolve 110-1 (760mg) and intermediate M8 (980mg) in a mixed solvent of 1,4-dioxane (15mL) and water (3mL), add potassium phosphate (888mg), and add cataCXium A under nitrogen protection Pd G3 (101 mg), heat to 100°C and react for 3 hours. Stop heating, cool to room temperature, add water to dilute (40 mL), extract twice with dichloromethane, 40 ml each time, combine the organic phases, wash the organic phases twice with water, dry over anhydrous sodium sulfate, and concentrate. The concentrate was separated and purified by column chromatography (DCM:MeOH 20:1) to obtain 760 mg of compound 110-2.
- Dissolve 110-3 (635mg), benzophenone imine (234mg) and cesium carbonate (631mg) in 1,4-dioxane (15mL), add BINAP (40mg) and palladium acetate (15mg) under nitrogen protection ), rise to 100°C and react for 1 hour.
- Dissolve 110-4 (450 mg) in a mixed solution of hydrochloric acid solution (5 mL, 2 mol/L) and THF (10 mL), and stir at room temperature for 15 min. Quench the reaction solution in saturated sodium carbonate solution, extract with DCM twice, 30 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain crude product 110-5, which can be directly used without purification. Cast the next reaction.
- Example 112 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Synthesis of Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-1,6-difluoronaphthalene-2-amine
- Example 120 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-2-((2-(di Fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl6-fluoro Synthesis of naphthalene-2-ol
- Example 121 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoroalkyl) Methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyridin[4,3d]pyrimidin-7-yl)-5-ethynyl-1,6-difluoro Synthesis of naphthalene-2-ol
- Step 1 Synthesis of Compound 121-1
- Example 122 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-(2,2,2-trifluoroethoxy)pyrido[4,3d]pyrimidine-7- Synthesis of 5-ethynyl-6-fluoronaphthalene-2-ol
- Step 8 Synthesis of Compound 122
- Example 123 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(2,2,2-trifluoroethoxy)pyridine[4,3d]pyrimidin-7-yl)-5-ethyne Synthesis of 6-fluoronaphthalene-2-ol
- Step 1 Synthesis of Compound 123-1
- Example 125 Compound 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol Synthesis
- reaction solution was poured into saturated NH 4 Cl solution, and extracted twice with EA.
- the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA, 5% EA) to obtain compound 125. -1 (1.8g yield 79.6%).
- Example 141 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- Synthesis of 2-amines
- Step 1 Synthesis of Compound 141-1
- Example 143 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthyl-2-amine
- Step 1 Synthesis of Compound 143-1
- Example 180 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2,6-dimethylenetetrakis) Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Synthesis of fluoronaphthalen-2-ol
- Example 181 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-vinylnaphthalene- Synthesis of 2-alcohols
- Dissolve compound 181-2 (95 mg) in DCM (2 mL), then add TBSCl (220 mg) and imidazole (150 mg) in sequence, react at room temperature for 0.5 h, extract the reaction solution with DCM and water, retain the organic phase, and add anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure, and the concentrate is purified by column chromatography to obtain target compound 181-3 (90 mg).
- Dissolve compound 181-3 (90 mg) in DCM (2 mL), then add m-CPBA (90 mg), react at room temperature for 0.5 h, add an appropriate amount of saturated sodium sulfite solution and stir for 20 min to quench, extract the reaction solution with DCM and water, and retain The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain target compound 181-4 (60 mg).
- Example 214 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( ((S)-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Synthesis of fluoronaphthalen-2-ol
- Step 1 Synthesis of Compound 214-1
- Dissolve compound 214-1 (19.75g 22.41mmol) in DMF, add CsF (34.05g 224.14mmol), and react in a 35°C oil bath for 4 hours. After the reaction is complete, use an ice bath to cool down the temperature to 10°C. Water (800 ml) is slowly added dropwise to produce a large amount of solid, which is filtered to obtain a filter cake. Dissolve it in EA (200 ml), wash it once with saturated brine (100 ml), separate the liquids to obtain the organic phase, and purify it by column chromatography (DCM:MeOH 20:1) to obtain compound 214-2 (14.82g) .
- KRAS G12D mutant tumor cells AGS ( CRL-1739 TM ) was plated in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well, and placed in a cell culture incubator for overnight culture. After the cells adhere to the wall, add the compound to be tested according to the final concentration Add 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, 0nM (the final concentration of DMSO is 0.5%) into the 96-well plate, incubate at 37°C for 96 hours, and then add 50 ⁇ L Cell-titer GLO to each well. solution, shake and mix well, incubate at room temperature for 10 minutes, read the Luminescence value on a multifunctional microplate reader, and calculate and convert the luminescence value data into an inhibition percentage. And calculate the percentage of cell proliferation inhibition according to the following formula:
- Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
- KRAS G12D mutant tumor cells AGS ( CRL-1739 TM ) at a cell density of 4 ⁇ 10 4 /well Spread in a 96-well plate and culture in a cell culture incubator overnight. After the cells are adhered, the compound to be tested is added to the 96-well plate at the final concentration of 3000nM, 600nM, 120nM, 24nM, 4.8nM, 0.96nM, 0.19nM, and 0.5% DMSO. After culturing for 3 hours, use pERK HTRF Kit (Cisbio) Lyse each treated cell sample (40ul/well) in the 96-well plate with the lysis buffer in the 96-well plate.
- Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
- KRAS G12D mutant tumor cells HPAC, A427, Aspc-1, LS180, and Panc04.03 were spread in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well and placed in a cell culture incubator for overnight culture. After the cells are adhered, the compound to be tested is added to the 96-well plate according to the final concentration of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, 0nM (the final DMSO concentration is 0.5%), and cultured at 37°C. After 96 hours, add 50 ⁇ L of Cell-titer GLO working solution to each well, shake and mix, and incubate at room temperature for 10 minutes. Read the Luminescence value on a multifunctional microplate reader, and calculate and convert the luminescence value data into an inhibition percentage. And calculate the percentage of cell proliferation inhibition according to the following formula:
- Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
- KRAS G12D mutant tumor cells HPAC, A427, Aspc-1, LS180, and Panc04.03 were spread in a 96-well plate at a cell density of 4 ⁇ 10 4 /well and placed in a cell culture incubator for overnight culture. After the cells are adhered, the compound to be tested is added to the 96-well plate at the final concentration of 3000nM, 600nM, 120nM, 24nM, 4.8nM, 0.96nM, 0.19nM, and 0.5% DMSO. After culturing for 3 hours, use pERK HTRF Kit (Cisbio) Lyse each treated cell sample (40ul/well) in the 96-well plate with the lysis buffer in the 96-well plate.
- Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
- Intravenous administration investigation Mix the compound with the solvent 10% DMSO/5% Solutol/85% physiological saline, vortex and sonicate to prepare a 0.2 mg/ml clear intravenous injection solution.
- Balbc female mice aged 6 to 7 weeks were selected and intravenously administered compounds 7, 110, 141 and D1, and whole blood samples were collected at 5min, 15min, 30min, 1h, 2h, 4h, 7h and 24h.
- the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA).
- the dosage and experimental protocol are shown in Table 5 below, and the results are shown in Table 6.
- the tested mouse PK data are as follows in Table 6:
- mice the oral exposure (AUC) and oral bioavailability (F%) of compound 110 are higher than those of compound D1; the oral exposure (AUC) and oral bioavailability (F%) of compound 109 are higher than Compound D1.
- Pharmacological experiment 7 PK investigation of compounds in beagle dogs
- Pharmacological experiment 8 PK investigation of compounds in tumor tissues of NCI-H1975 tumor-bearing mice
- a Balbc nude nude mouse model of subcutaneous xenograft tumor of human lung adenocarcinoma cell NCI-H1975 was constructed. After the tumor volume reached 200 mm, 21 tumor-bearing mice were selected and administered Compound 7 and D1 1mpk IV Cassette. The solvent was 10% DMSO/5% Solutol/85% saline. Mouse whole blood samples and tumor tissue samples were collected at 0.5h, 4h, 7h, 24h, 48h, 72h, and 96h after administration. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA). The results are shown in Table 12.
- Tumor tissue was collected at 0.5h, 4h, 7h, 24h, 48h, 72h, and 96h after administration, and the concentrations of compound 7 and D1 in the tumor tissue were detected.
- the detection results are as shown in Figure 3.
Abstract
L'invention concerne un composé de formule (I), et un stéréoisomère, un tautomère, un produit deutéré ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation associé, une composition pharmaceutique contenant le composé, et une application de celui-ci en tant que médicament pour le traitement et/ou la prévention de maladies médiées par KRAS.
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CN202211580338.X | 2022-12-09 | ||
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WO2015080988A1 (fr) * | 2013-11-29 | 2015-06-04 | Merck Sharp & Dohme Corp. | Composés de n-benzenesulfonamide à substitution bicycloamine ayant une activité sélective dans des canaux sodiques voltage-dépendants |
WO2022042630A1 (fr) * | 2020-08-26 | 2022-03-03 | InventisBio Co., Ltd. | Composés hétéroaryle, leurs procédés de préparation et leurs utilisations |
CN114615981A (zh) * | 2019-08-29 | 2022-06-10 | 米拉蒂治疗股份有限公司 | Kras g12d抑制剂 |
WO2022173678A1 (fr) * | 2021-02-09 | 2022-08-18 | Genentech, Inc. | Composés d'oxazépine tétracycliques et leurs utilisations |
WO2022187528A1 (fr) * | 2021-03-05 | 2022-09-09 | Nikang Therapeutics, Inc | Dérivés de quinazoline amine en tant qu'inhibiteurs de kras |
WO2022228568A1 (fr) * | 2021-04-30 | 2022-11-03 | 劲方医药科技(上海)有限公司 | Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale |
WO2023072188A1 (fr) * | 2021-10-29 | 2023-05-04 | 贝达药业股份有限公司 | Inhibiteurs de kras g12d et leur utilisation en médecine |
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WO2015080988A1 (fr) * | 2013-11-29 | 2015-06-04 | Merck Sharp & Dohme Corp. | Composés de n-benzenesulfonamide à substitution bicycloamine ayant une activité sélective dans des canaux sodiques voltage-dépendants |
CN114615981A (zh) * | 2019-08-29 | 2022-06-10 | 米拉蒂治疗股份有限公司 | Kras g12d抑制剂 |
WO2022042630A1 (fr) * | 2020-08-26 | 2022-03-03 | InventisBio Co., Ltd. | Composés hétéroaryle, leurs procédés de préparation et leurs utilisations |
WO2022173678A1 (fr) * | 2021-02-09 | 2022-08-18 | Genentech, Inc. | Composés d'oxazépine tétracycliques et leurs utilisations |
WO2022187528A1 (fr) * | 2021-03-05 | 2022-09-09 | Nikang Therapeutics, Inc | Dérivés de quinazoline amine en tant qu'inhibiteurs de kras |
WO2022228568A1 (fr) * | 2021-04-30 | 2022-11-03 | 劲方医药科技(上海)有限公司 | Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale |
WO2023072188A1 (fr) * | 2021-10-29 | 2023-05-04 | 贝达药业股份有限公司 | Inhibiteurs de kras g12d et leur utilisation en médecine |
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