WO2023186137A1 - 吲哚酮衍生物及其在医药上的应用 - Google Patents
吲哚酮衍生物及其在医药上的应用 Download PDFInfo
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- WO2023186137A1 WO2023186137A1 PCT/CN2023/085662 CN2023085662W WO2023186137A1 WO 2023186137 A1 WO2023186137 A1 WO 2023186137A1 CN 2023085662 W CN2023085662 W CN 2023085662W WO 2023186137 A1 WO2023186137 A1 WO 2023186137A1
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- Prior art keywords
- methyl
- pyrrole
- compound
- ylidene
- alkyl
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ICJYWDHNTMJKFP-UHFFFAOYSA-N ethyl 1h-pyrrole-3-carboxylate Chemical compound CCOC(=O)C=1C=CNC=1 ICJYWDHNTMJKFP-UHFFFAOYSA-N 0.000 description 1
- NGIJGIMEKGYNFJ-UHFFFAOYSA-N ethyl 2-methyl-6-oxo-4,5-dihydro-1h-cyclopenta[b]pyrrole-3-carboxylate Chemical compound O=C1CCC2=C1NC(C)=C2C(=O)OCC NGIJGIMEKGYNFJ-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 101150078861 fos gene Proteins 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- UIUXUFNYAYAMOE-UHFFFAOYSA-N methylsilane Chemical compound [SiH3]C UIUXUFNYAYAMOE-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- SCZVXVGZMZRGRU-UHFFFAOYSA-N n'-ethylethane-1,2-diamine Chemical compound CCNCCN SCZVXVGZMZRGRU-UHFFFAOYSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- MQDVUDAZJMZQMF-UHFFFAOYSA-N pyridin-2-ylurea Chemical compound NC(=O)NC1=CC=CC=N1 MQDVUDAZJMZQMF-UHFFFAOYSA-N 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000005503 thioxanyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Definitions
- This application is a Chinese application with a CN application number of 202210316295.8 and an application date of April 1, 2022. As a basis, and claiming its priority, the disclosure content of the CN application is again incorporated into this application as a whole.
- the present invention relates to an indolinone derivative or its stereoisomer and its application in medicine.
- HPK1 hematopoietic progenitor kinase 1
- MAP4K1 hematopoietic progenitor kinase 1
- HPK1 belongs to the MAP4K family and is a serine/threonine kinase that is mainly expressed in hematopoietic cells.
- HPK1 negatively regulates the immune response of T cells and B cells through the AP-1, NF- ⁇ B, Erk2 and Fos pathways.
- T cells HPK1 can phosphorylate the T cell receptor adapter protein SLP-76. Activation of SLP-76 downregulates the AP-1 and Erk2 signaling pathways, resulting in weakened T cell proliferation.
- BCR B cell receptor
- HPK1 is a potential therapeutic target.
- loss of HPK1 can increase the production of Th1 cytokines in T cells; T cells lacking HPK1 proliferate faster and have a stronger inhibitory effect on tumor growth.
- HPK1 inhibitor drugs their selectivity is not high enough.
- Small molecule inhibitors of HPK1 will simultaneously inhibit other T cell kinases or other members of the MAP4K family, including MAP3K2, MAP4K3, MAP4K4, MAP4K5 and MAP4K6.
- MAP4K3 is also called GLK kinase, and its biological role is exactly opposite to HPK1.
- GLK can promote the activation of the TCR pathway by binding to downstream adapter proteins. Therefore, researchers urgently need to screen for HPK1 inhibitors with higher selectivity to better meet clinical needs.
- the object of the present invention is to provide new indolinone derivatives or all stereoisomers thereof, pharmaceutical compositions thereof and their use in the preparation of anti-tumor drugs.
- One or more embodiments of the present invention provide a compound represented by general formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof:
- R 1 is selected from halogen, cyano, C 1-3 haloalkyl
- R 2B is selected from C 1-3 alkyl
- R 2A is selected from -(CO)N(R 3 ) 2 ;
- R 3 is each independently selected from H, C 1-6 alkyl; the C 1-6 alkyl is optionally further selected from -N(C 1-6 alkyl) 2 or 3 to 12-membered heterocycle The alkyl substituent is substituted; the 3 to 12-membered heterocycloalkyl optionally contains 1 to 3 heteroatoms selected from N; the 3 to 12-membered heterocycloalkyl is optionally further Substituted with a substituent selected from C 1-6 alkyl;
- a is selected from 1, 2, 3 or 4.
- One or more embodiments of the present invention provide compounds or stereoisomers or pharmaceutically acceptable salts thereof, and the compounds are selected from:
- the present invention also provides a pharmaceutical composition, which includes:
- the present invention also provides the use of pharmaceutical compositions or the compounds or their stereoisomers or pharmaceutically acceptable salts in the preparation of anti-tumor drugs.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, (also called heavy hydrogen), tritium (T, also called superheavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
- the isotopes of carbon include 12 C,
- Alkyl refers to a linear or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably An alkyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.
- Alkoxy refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom.
- Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
- alkyl is the same as the definition of "alkyl" mentioned above.
- Aryl refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered monocyclic ring, a 5- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, which can be a bridged ring or a spiro ring.
- non-limiting examples include phenyl, naphthyl.
- the aryl group may be optionally further substituted by one or more substituents.
- Heteroaryl refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered monocyclic ring, a 5- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains 1 to 6 members selected from N , O or S heteroatoms, preferably 3 to 8-membered heterocyclyl groups.
- the selectively substituted N and S in the ring of the heterocyclyl group can be oxidized to various oxidation states.
- the heterocyclyl group can be connected to a heteroatom or a carbon atom, and the heterocyclyl group can be a bridged ring or a spiro ring.
- Non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidylbenzimidazolyl, benzopyridinyl, pyrrolopyridinyl.
- a heteroaryl group When a heteroaryl group is substituted, it may be optionally further substituted with one or more substituents.
- Heterocyclyl or “heterocycle” refers to a saturated or unsaturated heteroaromatic ring or a non-heteroaromatic ring. When selected from a heteroaromatic ring, its definition is the same as the definition of "heteroaryl"above; when selected from a non-heteroaromatic ring, When it is an aromatic ring, it can be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system, and contains 1 to 4 heteroatoms selected from N, O or S, preferably 3 to 8 Heterocyclic group.
- the selectively substituted N and S in the ring of "heterocyclyl” or “heterocycle” can be oxidized into various oxidation states; the “heterocyclyl” or “heterocycle” can be connected to a heteroatom or a carbon atom; ""Heterocyclyl” or “heterocycle” may be a bridged ring or a spiro ring.
- heterocyclyl or “heterocycle” include oxyethyl, glycidyl, aziridyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azazoyl, diazazoyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxany
- “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, where "other chemical components” refers to pharmaceutically acceptable Acceptable carriers, excipients and/or one or more other therapeutic agents.
- Carrier refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
- Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound.
- Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.
- Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
- heterocyclyl optionally substituted by alkyl means that the alkyl group may but not necessarily be present, and this description includes the case in which the heterocyclyl is substituted by an alkyl group, and the case in which the heterocyclyl is not substituted by an alkyl group.
- heterocyclyl optionally substituted by alkyl
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR was measured using Bruker Avance III 400 and Bruker Avance 300 nuclear magnetic instruments. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetrahydrofuran. Methylsilane (TMS);
- MS measurement uses Agilent 6120B (ESI) and Agilent 6120B (APCI);
- Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
- the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
- the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
- N,N-diisopropylethylamine (0.62g, 4.80mmol) and 2-(7-azobenzotriazole)-N,N,N′,N '-Tetramethylurea hexafluorophosphate (1.3g, 3.5mmol) was added to a solution of compound 1c (1.0g, 3.2mmol) in N,N-dimethylformamide (10mL), and the reaction was stirred for 0.5h after the drops were completed.
- N, N-diisopropylethylamine (54 mg, 0.41 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'- Tetramethylurea hexafluorophosphate (107 mg, 0.3 mmol) was added to a solution of compound 3c (100 mg, 0.27 mmol) in N, N-dimethylformamide (2 mL), stirred for 0.5 h, and N, N- Diethylethylenediamine (33 mg, 0.28 mmol) was stirred for 2 h; LC-MS detected the reaction until the end of the reaction; water (4 mL) was added dropwise, stirred for 10 min, filtered, and the solid was sent to preparation for separation to obtain compound 3 (yellow solid, 69 mg, Yield: 52.0%).
- N, N-diisopropylethylamine 58 mg, 0.45 mmol
- 2-(7-azobenzotriazole)-N, N, N', N'- Tetramethylurea hexafluorophosphate 126 mg, 0.33 mmol
- 4a 100 mg, 0.30 mmol
- N, N-dimethylformamide 2 mL
- N, N-diisopropylethylamine 174 mg, 1.35 mmol
- 2-(7-azobenzotriazole)-N, N, N', N'- Tetramethylurea hexafluorophosphate 126 mg, 0.33 mmol
- N, N-dimethylformamide 2 mL
- N, N- Diethylethylenediamine 38 mg, 0.33 mmol
- LC-MS detected the reaction until the end of the reaction; water (10 mL) was added dropwise, stirred for 10 min, filtered, and the solid was sent for preparation and separation (preparation by acid method) to obtain compound 5 ( Yellow solid, 20 mg, yield: 15.7%).
- N,N-diisopropylethylamine (0.16g, 1.28mmol) and 2-(7-azobenzotriazole)-N,N,N', N′-Tetramethylurea hexafluorophosphate (0.26 g, 0.67 mmol) was added to compound (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-
- 1,4,5,6-tetrahydrocyclopentanoic acid [b]pyrrole-3-carboxylic acid 1c (0.20g, 0.64mmol) to a solution of N,N-dimethylformamide (5mL), drop the mixture and stir to react 0.5h; add (1-methylazetidin-3-yl)methylamine (67.0mg, 0.67mmol), stir and react for 2h; LC-MS detects until the reaction is completed; add water (10mL) dropwise, stir for 10min, and pump
- MAP4K1 (HPK1) Recombinant Human Protein (purchased from Thermo Fisher, item number:
- PV6355 kinase tracer 222 (purchased from Thermo Fisher, Catalog No.: PV6121); LanthaScreen TM Eu-anti-GST Antibody (purchased from Thermo Fisher, Catalog No.: PV5594); 5 ⁇ Kinase Buffer A (purchased from Thermo Fisher, Catalog No.: PV3189 ).
- test compound (starting from 1250 nM, 4-fold dilution, 8 concentrations in total) to a 384-well white plate;
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Abstract
提供通式(I)所示的吲哚酮衍生物及其在制备抗肿瘤药物中的应用。
Description
本申请是以CN申请号为202210316295.8,申请日为2022年4月1日的中国申请
为基础,并主张其优先权,该CN申请的公开内容再次作为整体引入本申请中。
本发明涉及一种吲哚酮衍生物或者其立体异构体及其在医药上的应用。
HPK1(hematopoietic progenitor kinase 1,造血祖细胞激酶1),又名MAP4K1,属于MAP4K家族,是一种丝氨酸/苏氨酸激酶,主要在造血细胞中表达。HPK1通过AP-1、NF-κB、Erk2和Fos途径对T细胞和B细胞的免疫应答进行负向调控。例如,在T细胞中,HPK1可磷酸化T细胞受体适配器蛋白SLP-76,SLP-76的激活使得AP-1和Erk2信号通路的下调,从而导致T细胞增殖减弱。另外,在B细胞中,HPK1则通过磷酸化SLP-76的旁系同源物BLINK下调B细胞受体(BCR)信号的转导。
因此,HPK1是一个潜在的治疗靶点,研究发现抑制HPK1的活性可增强T细胞和B细胞的活性,从而提高抗肿瘤免疫。例如HPK1的缺失能增加T细胞中Th1细胞因子的产生;HPK1缺失的T细胞增殖更快,对肿瘤生长的抑制效果更强。另外,研究人员发现同时抑制HPK1和PD-L1的活性能显著增强T细胞的抗肿瘤效应。因此HPK1抑制剂有望成为治疗癌症的创新疗法,或与已有癌症免疫疗法联用,提高治疗癌症的效果。
迄今为止,HPK1抑制剂药物研发所面临的主要挑战是选择性不够高,HPK1的小分子抑制剂会同时抑制其他T细胞激酶或MAP4K家族的其他成员,包括MAP3K2、MAP4K3、MAP4K4、MAP4K5和MAP4K6。其中MAP4K3又称为GLK激酶,其生物学作用与HPK1正好相反。GLK可以通过与下游接头蛋白结合,促进TCR通路的激活。因此研发人员迫切需要筛选到选择性更高的HPK1的抑制剂,以更好地满足临床需求。
发明内容
本发明的目的是提供新的吲哚酮衍生物或者其所有的立体异构体、其药物组合物以及其在制备抗肿瘤药物中的用途。
本发明的一个或多个实施方式提供通式(I)所示的化合物,或者其立体异构体、药学上可接受的盐:
其中:
R1选自卤素、氰基、C1-3卤代烷基;
R2B选自C1-3烷基;
R2A选自-(CO)N(R3)2;
R3各自独立地选自H、C1-6烷基;所述的C1-6烷基任选地进一步被选自-N(C1-6烷基)2或者3至12元杂环烷基的取代基所取代;所述的3至12元杂环烷基任选地含有1至3个选自N的杂原子;所述的3至12元杂环烷基任选地进一步被选自C1-6烷基的取代基所取代;
a选自1、2、3或4。
本发明的一个或多个实施方式提供化合物或者其立体异构体、药学上可接受的盐,所述的化合物选自:
本发明还提供一种药物组合物,所述药物组合物包括:
(1)上述化合物或其立体异构体、药学上可接受的盐;
(2)药学上可接受的载体和/或赋形剂。
本发明还提供药物组合物或者所述化合物或其立体异构体、药学上可接受的盐在制备抗肿瘤药物中的用途。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“芳基”是指是指取代的或未取代的芳香环,其可以是5至8元的单环、5至12元双环或者10至15元三环体系,其可以是桥环或者螺环,非限制性实施例包括苯基、
萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“杂芳基”是指取代的或未取代的芳香环,其可以是5至8元的单环、5至12元双环或者10至15元三环体系,且包含1至6个选自N、O或S的杂原子,优选3至8元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂环基可以是桥环或者螺环,非限制性实施例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。当杂芳基被取代时,可以任选进一步被1个或多个取代基所取代。
“杂环基”或“杂环”是指饱和或不饱和的杂芳环或者非杂芳环,当选自杂芳环时,其定义与上文“杂芳基”定义相同;当选自非杂芳环时,其可以是3至10元的单环、4至12元双环或者10至15元三环体系,且包含1至4个选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以任选进一步被0个或者多个取代基所取代。
当上文所述的“烷基”、“烷氧基”、“芳基”、“杂芳基”、“杂环基”或者“杂环”被取代时,可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C1-6烷基氨基、=O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRq4Rq5、=NRq6、-C(=O)OC1-6烷基、-OC(=O)C1-6烷基、-C(=O)NRq4Rq5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)OC6-10芳基、-OC(=O)C6-10芳基、-OC(=O)C5-10杂芳基、-C(=O)OC5-10杂芳基、-OC(=O)C3-8杂环烷基、-C(=O)OC3-8杂环烷基、-OC(=O)C3-8环烷基、-C(=O)OC3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C2-6烯基或者-NHC(=O)C2-6炔基的取代基所取代,且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8杂环烷基或者-NHC(=O)C3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRq4Rq5或者=O的取代基所取代;Rq1选自C1-6烷基、C1-6烷氧基或者C6-10芳基;Rq2、Rq3选自H或者C1-6烷基;Rq4、Rq5选自H、C1-6烷基、-NH(C=NRq1)NRq2Rq3、-S(=O)2NRq2Rq3、-C(=O)Rq1或者-C(=O)NRq2Rq3,其中所述的C1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代;或者Rq4与Rq5及N原子形成一个3至8元杂环,所述的环可以含有1个或者多个选自N、O或者S的杂原子。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未
必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker Avance III 400和Bruker Avance 300核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用Agilent 6120B(ESI)和Agilent 6120B(APCI);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例1
(Z)-N-(2-(二乙氨基)乙基)-6-(5-氟-2-氧代吲哚-3-亚乙基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物1
(Z)-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
第一步:
(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸乙酯1b
Ethyl(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylate
在25℃,且氮气保护下,将哌啶(20.00g,0.24mol)滴加到化合物1a(9.80g,0.05mol)和5-氟-2-氧化吲哚(7.9g,52.0mmol)的N,N-二甲基甲酰胺(100mL)溶液中,滴毕升温至110℃搅拌反应21h;LC-MS检测至反应结束;降至室温静置10h,过滤,滤饼用无水乙醇(150mL)打浆30min,抽滤,滤饼烘干得到化合物1b(黄色固体,10.0g,产率:62.0%)。
1H NMR(400MHz,DMSO)δ11.76(s,1H),10.62(s,1H),7.21(d,1H),6.93(t,1H),6.83(dd,1H),4.20(q,2H),3.53(s,2H),3.04(d,2H),2.62(s,3H),1.29(t,3H).
LC-MS m/z(ESI)=341.2[M+1].
第二步:
(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸1c
(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid
在25℃,且氮气保护下,将一水合氢氧化锂(6.20g,0.12mol)加到化合物1b(10.0g,24.0mmol)的二氧六环(180mL)和水(90mL)溶液中,滴加甲醇(2mL)和二甲基亚砜(2mL),升至110℃搅拌反应8h;LC-MS检测至反应结束;降至20℃,滴加盐酸水溶液(1N)调节PH=2,过滤,乙醇(100mL)打浆30min,过滤,滤饼烘干得到化合物1c(黄色固体,8.5g,产率:94.0%)。
1H NMR(400MHz,DMSO)δ11.51(s,1H),10.61(s,1H),7.18(dd,1H),6.92-6.76(m,2H),3.54-3.48(m,2H),3.02(d,2H),2.61(s,3H).
LC-MS m/z(ESI)=313.4[M+1].
第三步:
(Z)-N-(2-(二乙氨基)乙基)-6-(5-氟-2-氧代吲哚-3-亚乙基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物1
(Z)-N-(2-(diethylamino)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在25℃,且氮气保护下,将N,N-二异丙基乙胺(0.62g,4.80mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(1.3g,3.5mmol)加到化合物1c(1.0g,3.2mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕搅拌反应0.5h;加入N,N-二乙基乙二胺(0.37g,3.20mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(10mL)搅拌30min,抽滤,滤饼用无水乙醇(2mL)打浆30min,过滤,固体烘干得到化合物1(黄色固体,0.43g,产率:33.1%)。
1H NMR(400MHz,DMSO)δ11.65(s,1H),10.59(s,1H),7.22(dd,1H),6.99(t,1H),6.94-6.88(m,1H),6.82(dd,1H),3.59(d,2H),3.27(dd,2H),3.10(d,2H),2.59(s,3H),2.56-2.51(m,6H),0.98(t,,6H).
LC-MS m/z(ESI)=411.5[M+1].
实施例2
(Z)-N-(2-(二乙氨基)乙基)-6-(6-氟-2-氧代吲哚-3-亚乙基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺(S)-2-羟基琥珀酸盐化合物2
(Z)-N-(2-(diethylamino)ethyl)-6-(6-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide(S)-2-hydroxysuccinate
第一步:
3-(4-(乙氧羰基)-5-甲基-1H-吡咯-3-基)丙酸2b
3-(4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-3-yl)propanoic acid
在25℃下,将乙酸钠(196.0g,2.4mol)加到5-氨基乙酰丙酸盐酸盐(200.0g,1.2mol)和乙酰乙酸乙酯(155.0g,1.2mol)的水(1.2L)溶液中,氮气保护下升至100℃搅拌反应6h;TLC检测至反应结束;降至25℃,过滤,30%的乙醇(300mL)洗涤,滤饼烘干得到化合物2b(白色固体,238.0g,产率:89.0%)。
1H NMR(400MHz,DMSO)δ11.95(s,1H),10.95(s,1H),6.40(d,1H),4.13(q,2H),2.86-2.71(m,2H),2.44-2.38(m,2H),2.35(s,3H),1.25(t,3H).
LC-MS m/z(ESI)=226.3[M+1].
第二步:
2-甲基-6-氧代-1,4,5,6-四氢环戊烷[b]吡咯-3-羧酸乙酯2c
ethyl 2-methyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate
在25℃,氮气保护下,将甲磺酸(491.0g,5.1mol)缓慢滴加到五氧化二磷(49.0g,0.4mol)中,滴毕升至100℃反应1h,降至40℃,分批加入化合物2b(65.0g,0.3mol),40℃反应1h,后降至25℃反应10h;TLC检测至反应结束;降至0℃,滴加饱和碳酸氢钠溶液(10L)淬灭,调节PH=8,过滤,水洗(1.0L),滤饼烘干得到化
合物2c(黄色固体,60g,产率:99.0%)。
1H NMR(400MHz,CDCl3)δ11.48(s,1H),4.29(q,2H),3.03(dd,2H),2.92-2.87(m,2H),2.69(s,3H),1.36(t,3H).
LC-MS m/z(ESI)=208.4[M+1].
第三步:
(Z)-6-(6-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-羧酸乙酯2d
E thyl(Z)-6-(6-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylate
在25℃,氮气保护下,将哌啶(28.50g,0.34mol)滴加到化合物2c(14.00g,0.07mol)和6-氟-2-氧化吲哚(11.20g,0.07mol)的N,N-二甲基甲酰胺(100mL)溶液中,滴毕升温至110℃搅拌反应21h;LC-MS检测至反应结束;降至室温静置10h,过滤,滤饼用无水乙醇(150mL)打浆30min,抽滤,滤饼烘干得到化合物2d(黄色固体,18.0g,产率:79.0%)。
1H NMR(400MHz,DMSO)δ11.76(s,1H),10.61(s,1H),7.20(dd,1H),6.96-6.89(m,1H),6.83(dd,1H),4.20(q,2H),3.60-3.50(m,2H),3.10-2.99(m,2H),2.62(s,3H),1.29(t,3H).
LC-MS m/z(ESI)=341.2[M+1].
第四步:
(Z)-6-(6-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-羧酸2e
(Z)-6-(6-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid
在25℃下,将一水合氢氧化锂(11.00g,0.27mol)加到化合物2d(18.00g,0.05mol)的二氧六环(360mL)和水(180mL)溶液中,滴加甲醇(2mL)和二甲基亚砜(2mL),升至110℃搅拌反应12h;LC-MS检测至反应结束;降至20℃,滴加盐酸水溶液(1N)调节PH=2,过滤,乙醇(100mL)打浆30min,过滤,滤饼烘干得到化合物2e(黄色固体,15.3g,产率:93.0%)。
LC-MS m/z(ESI)=313.4[M+1].
第五步:
(Z)-N-(2-(二乙氨基)乙基)-6-(6-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺2f
(Z)-N-(2-(diethylamino)ethyl)-6-(6-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在25℃,氮气保护下,将N,N-二异丙基乙胺(6.2g,50.0mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(13.4g,35.0mmol)加到化合物2e(10.0g,32.0mmol)的N,N-二甲基甲酰胺(100mL)溶液中,滴毕搅拌反应0.5h;加入N,N-二乙基乙二胺(3.70g,32.00mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(100mL)搅拌30min,抽滤,滤饼用无水乙醇(50mL)打浆30min,过滤,固体烘干得到化合物2f(黄色固体,11.4g,产率:87.0%)。
1H NMR(400MHz,DMSO)δ11.53(s,1H),10.72(s,1H),7.38(dd,1H),6.94(t,1H),6.80-6.74(m,1H),6.67(dd,1H),3.57-3.50(m,2H),3.28(dd,2H),3.11-3.04(m,2H),2.58(s,3H),2.56-2.50(m,6H),0.99(t,6H).
LC-MS m/z(ESI)=411.3[M+1].
第六步:
(Z)-N-(2-(二乙氨基)乙基)-6-(6-氟-2-氧代吲哚-3-亚乙基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺(S)-2-羟基琥珀酸盐化合物2
(Z)-N-(2-(diethylamino)ethyl)-6-(6-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide(S)-2-hydroxysuccinate
在氮气保护下,将化合物2f(1.0g,2.4mmol)和L-苹果酸(0.33g,2.40mmol)的甲醇(10mL)溶液升至65℃搅拌反应5.0h;降至室温,抽滤,滤饼烘干得到化合物2(黄色固体,1.1g,产率:83.0%)。
1H NMR(400MHz,DMSO)δ11.58(s,1H),10.74(s,1H),7.41(dd,1H),7.20(s,1H),6.82-6.75(m,1H),6.69(dd,1H),3.99(dd,1H),3.56(d,2H),3.44(d,2H),3.15-3.07(m,2H),2.92(d,6H),2.59(s,3H),2.56-2.51(m,1H),2.35(dd,1H),1.12(t,6H).
LC-MS m/z(ESI)=411.3[M+1].
实施例3
(Z)-6-(6-溴-5-氟-2-氧代吲哚-3-亚基)-N-(2-(二乙氨基)乙基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物3
(Z)-6-(6-bromo-5-fluoro-2-oxoindolin-3-ylidene)-N-(2-(diethylamino)ethyl)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
第一步:
2-甲基-6-氧代-1,4,5,6-四氢环戊二[b]吡咯-3-羧酸3b
2-methyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid
在25℃下,将氢氧化钠(4.6g,0.11mol)加到3a(12.0g,0.06mol)的四氢呋喃(120mL)和水(28mL)溶液中,加毕升温至60℃搅拌反应8h;LC-MS检测至反应结束;降至室温,盐酸水溶液(1N)调PH=3,过滤,滤饼烘干得到化合物3b(白色固体,7.5g,产率:74.0%)。
1H NMR(400MHz,DMSO)δ12.12(s,1H),12.04(s,1H),2.87-2.82(m,2H),2.69-2.65(m,2H),2.45(s,3H).
LC-MS m/z(ESI)=180.5[M+1].
第二步:
(Z)-6-(6-溴-5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-羧酸3c
(Z)-6-(6-bromo-5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid
在25℃,氮气保护下,将哌啶(1.2g,13.9mmol)滴加到化合物3b(0.5g,2.8mmol)和6-溴-5-氟吲哚啉-2-酮(0.71g,3.1mmol)的N,N-二甲基甲酰胺(5mL)溶液中,滴毕升温至110℃搅拌反应21h;LC-MS检测至反应结束;降至室温静置,过滤,滤饼用无水乙醇(2mL)打浆30min,抽滤,滤饼烘干得到化合物3c(黄色固体,
0.23g,产率:21.0%)。
LC-MS m/z(ESI)=392.1[M+1].
第三步:
(Z)-6-(6-溴-5-氟-2-氧代吲哚-3-亚基)-N-(2-(二乙氨基)乙基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物3
(Z)-6-(6-bromo-5-fluoro-2-oxoindolin-3-ylidene)-N-(2-(diethylamino)ethyl)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在25℃,氮气保护下,将N,N-二异丙基乙胺(54mg,0.41mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(107mg,0.3mmol)加到化合物3c(100mg,0.27mmol)的N,N-二甲基甲酰胺(2mL)溶液中,搅拌反应0.5h,加入N,N-二乙基乙二胺(33mg,0.28mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(4mL)搅拌10min,抽滤,固体送制备分离,得到化合物3(黄色固体,69mg,产率:52.0%)。
1H NMR(400MHz,DMSO)δ11.59(s,1H),10.67(s,1H),7.35(d,1H),7.04-6.96(m,2H),3.57(s,2H),3.27(d,2H),3.08(s,2H),2.58(s,3H),2.52(d,6H),0.98(t,6H).
LC-MS m/z(ESI)=489.5[M+1].
实施例4
(Z)-N-(2-(二乙氨基)乙基)-6-(5,6-二氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物4
(Z)-N-(2-(diethylamino)ethyl)-6-(5,6-difluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
第一步:
(Z)-6-(5,6-二氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-羧酸4a
(Z)-6-(5,6-difluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid
在25℃,氮气保护下,将哌啶(1.2g,13.9mmol)滴加到3b(0.5g,2.8mmol)和5,6-二氟二氢吲哚-2-酮(0.52g,3.10mmol)的N,N-二甲基甲酰胺(5mL)溶液中,滴毕升温至110℃搅拌反应21h;LC-MS检测至反应结束;降至室温静置,过滤,滤饼用无水乙醇(10mL)打浆30min,抽滤,滤饼烘干得到化合物4a(黄色固体,0.32g,产率:35.0%)。
LC-MS m/z(ESI)=331.4[M+1].
第二步:
(Z)-N-(2-(二乙氨基)乙基)-6-(5,6-二氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物4
(Z)-N-(2-(diethylamino)ethyl)-6-(5,6-difluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在25℃,氮气保护下,将N,N-二异丙基乙胺(58mg,0.45mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(126mg,0.33mmol)加到4a(100mg,0.30mmol)的N,N-二甲基甲酰胺(2mL)溶液中,搅拌反应0.5h,加入N,N-二乙基乙二胺(38mg,0.33mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(4mL)搅拌10min,抽滤,固体送制备分离(酸法制备),得到化合物4(黄色固体,56mg,产率:43.7%)。
1H NMR(400MHz,DMSO)δ11.64(s,1H),10.74(s,1H),9.22(s,1H),7.51-7.29(m,2H),6.88(dd,1H),3.56(dd,4H),3.27-3.16(m,6H),3.15(s,2H),2.61(s,3H),1.22(t,6H).
LC-MS m/z(ESI)=429.5[M+1].
实施例5
(Z)-N-(2-(二乙基氨基)乙基)-2-甲基-6-(2-氧代-5-(三氟甲基)吲哚-3-亚基)-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物5
(Z)-N-(2-(diethylamino)ethyl)-2-methyl-6-(2-oxo-5-(trifluoromethyl)indolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
第一步:
(Z)-2-甲基-6-(2-氧代-5-(三氟甲基)吲哚-3-亚基)-1,4,5,6-四氢环戊烷[b]吡咯-3-羧酸乙酯化合物5b
ethyl(Z)-2-methyl-6-(2-oxo-5-(trifluoromethyl)indolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate
在25℃,氮气保护下,将2c(0.5g,2.41mmol)和5-三氟甲基-2-氧化吲哚(0.51g,2.53mmol)溶解在哌啶(5mL)溶液中,升温至110℃搅拌反应12h;LC-MS检测至反应结束;降至室温静置,加入水(20mL),室温搅拌30分钟后过滤,滤饼用无水乙醇(5mL)打浆30min,过滤,滤饼烘干得到化合物5b(棕色固体,0.4g,产率:42.0%)。
1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),11.00(s,1H),7.60(s,1H),7.46(d,1H),7.04(d,1H),4.21(q,2H),3.67-3.57(m,2H),3.10-3.02(m,2H),2.63(s,3H),1.29(t,3H).
LC-MS m/z(ESI)=391.10[M+1].
第二步:
(Z)-2-甲基-6-(2-氧代-5-(三氟甲基)吲哚-3-亚基)-1,4,5,6-四氢环戊烷[b]吡咯-3-羧酸化合物5c
(Z)-2-methyl-6-(2-oxo-5-(trifluoromethyl)indolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid
在25℃下,将一水合氢氧化锂(0.43g,10.25mmol)加到化合物5b(0.4g,1.02mmol)的二氧六环(4mL)和水(2mL)溶液中,滴加甲醇(0.4mL)和二甲基亚砜(0.4mL),升至110℃搅拌反应8h;LC-MS检测至反应结束;降至20℃,滴加盐酸水溶液(1N)调节PH=2,过滤,乙醇(100mL)打浆30min,过滤,滤饼烘干得到化合物5c(黄色固体,0.1g,产率:27.0%)。
LC-MS m/z(ESI)=363.10[M+1].
第三步:
(Z)-N-(2-(二乙基氨基)乙基)-2-甲基-6-(2-氧代-5-(三氟甲基)吲哚-3-亚基)-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物5
(Z)-N-(2-(diethylamino)ethyl)-2-methyl-6-(2-oxo-5-(trifluoromethyl)indolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在25℃,氮气保护下,将N,N-二异丙基乙胺(174mg,1.35mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(126mg,0.33mmol)加到化合物5c(100mg,0.27mmol)的N,N-二甲基甲酰胺(2mL)溶液中,搅拌反应0.5h,加入N,N-二乙基乙二胺(38mg,0.33mmol),室温搅拌过夜;LC-MS检测至反应结束;滴加水(10mL)搅拌10min,抽滤,固体送制备分离(酸法制备),得到化合物5(黄色固体,20mg,产率:15.7%)。
1H NMR(400MHz,DMSO)δ11.65(s,1H),11.01(s,1H),7.62(s,1H),7.45(d,1H),7.04(d,1H),6.95(t,1H),3.67-3.65(m,2H),3.16-3.14(m,2H),2.61(s,3H),2.52-2.48(m,8H),1.12(t,6H).
LC-MS m/z(ESI)=461.20[M+1].
实施例6
第一步:
(Z)-N-(2-(氮杂环丁烯-1-基)乙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物6
(Z)-N-(2-(azetidin-1-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.16g,1.28mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(0.26g,0.67mmol)加到化合物(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸1c(0.20g,0.64mmol)的N,N-二甲基甲酰胺(5mL)溶液中,滴毕搅拌反应0.5h;加入2-(氮杂环丁烷-1-基)乙基-1-胺(67.0mg,0.67mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(10mL)搅拌10min,抽滤,固体烘干得到标题化合物6(黄色固体,0.12g,产率:49.0%)
1H NMR(400MHz,DMSO)δ11.65(s,1H),10.59(s,1H),7.22(dd,J=9.7,2.3Hz,1H),7.04(t,J=5.6Hz,1H),6.94-6.88(m,1H),6.83(dd,J=8.4,4.7Hz,1H),3.57(d,J=3.6Hz,2H),3.14(dd,J=14.7,7.8Hz,8H),2.58(s,3H),2.46(d,J=6.7Hz,2H),1.96(p,J=6.9Hz,2H).
LC-MS m/z(ESI)=395.2[M+1]
实施例7
第一步:
(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-N-(1-甲基氮杂环丁烷-3-基)甲基)-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物7
(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-N-((1-methylazetidin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.16g,1.28mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(0.26g,0.67mmol)加到化合物(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸1c(0.20g,0.64mmol)的N,N-二甲基甲酰胺(5mL)溶液中,滴毕搅拌反应0.5h;加入(1-甲基氮杂环丁烷-3-基)甲胺(67.0mg,0.67mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(10mL)搅拌10min,抽滤,固体烘干得到标题化合物7(黄色固体,0.14g,产率:58.0%)
1H NMR(400MHz,DMSO)δ11.65(s,1H),10.59(s,1H),7.37(t,J=5.5Hz,1H),7.22(d,J=9.6Hz,1H),6.90(dd,J=12.6,5.2Hz,1H),6.83(dd,J=8.4,4.8Hz,1H),3.56(s,2H),3.38(s,3H),3.18(t,J=7.1Hz,2H),3.13(d,J=6.2Hz,2H),2.89(t,J=6.2Hz,2H),2.57(s,3H),2.18(s,3H).
LC-MS m/z(ESI)=395.2[M+1]
实施例8
第一步:
(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物8
(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.16g,1.28mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(0.26g,0.67mmol)加到化合物(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸1c(0.20g,0.64mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入2-(4-甲基哌嗪-1-基)乙烷-1-胺(92.0mg,0.67mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,固体烘干得到标题化合物8(黄色固体,99.0mg,产率:35.0%)
1H NMR(400MHz,DMSO)δ11.66(s,1H),10.59(s,1H),7.24(dd,J=9.7,2.4Hz,1H),7.00(t,J=5.4Hz,1H),6.95-6.88(m,1H),6.83(dd,J=8.4,4.8Hz,1H),3.59(d,J=2.6Hz,2H),3.30(d,J=6.4Hz,2H),3.16-3.06(m,2H),2.59(s,3H),2.42(dd,J=30.5,23.9Hz,10H),2.16(s,3H).
LC-MS m/z(ESI)=438.3[M+1]
实施例9
第一步:
(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-N-(3-(4-甲基哌嗪-1-基)丙基)-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物9
(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.16g,1.28mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(0.26g,0.67mmol)加到化合物(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸1a(0.20g,0.64mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入3-(4-甲基哌嗪-1-基)丙-1-胺(101.0mg,0.67mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,固体烘干得到标题化合物9(黄色固体,129.0mg,产率:46.0%)。
1H NMR(400MHz,DMSO)δ11.64(s,1H),10.58(s,1H),7.25-7.19(m,2H),6.94-6.88(m,1H),6.83(dd,J=8.4,4.8Hz,1H),3.57(d,J=5.4Hz,2H),3.25-3.19(m,2H),3.13(d,J=6.5Hz,2H),2.57(s,3H),2.46-2.26(m,10H),2.18(s,3H),1.66(dd,J=14.1,7.0Hz,2H).
LC-MS m/z(ESI)=452.3[M+1]
生物实验:
HPK1激酶抑制试验
1.试验材料
MAP4K1(HPK1)Recombinant Human Protein(购自Thermo Fisher,货号:
PV6355);kinase tracer 222(购自Thermo Fisher,货号:PV6121);LanthaScreen TM Eu-anti-GST Antibody(购自Thermo Fisher,货号:PV5594);5×Kinase Buffer A(购自Thermo Fisher,货号:PV3189)。
2.实验步骤
(1)加入4μL受试化合物(1250nM起,4倍稀释,共8个浓度)至384孔白板;
(2)每孔加入8μL HPK1/Antibody Mix,1000rpm离心20s,室温孵育10min;
(3)每孔加入4μL Tracer 222,1000rpm离心20s,25℃孵育60min;
(4)利用酶标仪(Thermo fisher,Varioskan LUX)测定荧光值。利用GraphPad Prism 8进行IC50的计算。
结果表明,本发明化合物对HPK1具有显著的抑制活性。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (4)
- 通式(I)所示的化合物,或者其立体异构体、药学上可接受的盐:
其中:R1选自卤素、氰基、C1-3卤代烷基;R2B选自C1-3烷基;R2A选自-(CO)N(R3)2;R3各自独立地选自H、C1-6烷基;所述的C1-6烷基任选地进一步被选自-N(C1-6烷基)2或者3至12元杂环烷基的取代基所取代;所述的3至12元杂环烷基任选地含有1至3个选自N的杂原子;所述的3至12元杂环烷基任选地进一步被选自C1-6烷基的取代基所取代;a选自1、2、3或4。 - 根据权利要求1所述的化合物或者其立体异构体,所述的化合物选自:或者
- 一种药物组合物,所述药物组合物包括:(1)权利要求1~2任一项所述的化合物或其立体异构体、药学上可接受的盐;(2)药学上可接受的载体和/或赋形剂。
- 权利要求3所述的药物组合物或者权利要求1~2任一项所述的化合物或其立体异构体、药学上可接受的盐在制备抗肿瘤药物中的用途。
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WO2008067756A1 (fr) * | 2006-12-04 | 2008-06-12 | Jiangsu Simcere Pharmaceutical R & D Co., Ltd. | Dérivés de 3-pyrrolo-cyclohexylène-2-dihydro-indolinone et utilisations de ceux-ci |
WO2012122921A1 (zh) * | 2011-03-15 | 2012-09-20 | 江苏先声药物研究有限公司 | 一种酪氨酸激酶抑制剂的盐形式 |
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WO2005016875A2 (en) * | 2003-08-06 | 2005-02-24 | Sugen, Inc. | Geometrically restricted 3-cyclopentylidene-1,3-dihydroindol-2-ones as potent protein kinase inhibitors |
WO2008067756A1 (fr) * | 2006-12-04 | 2008-06-12 | Jiangsu Simcere Pharmaceutical R & D Co., Ltd. | Dérivés de 3-pyrrolo-cyclohexylène-2-dihydro-indolinone et utilisations de ceux-ci |
WO2012122921A1 (zh) * | 2011-03-15 | 2012-09-20 | 江苏先声药物研究有限公司 | 一种酪氨酸激酶抑制剂的盐形式 |
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