CN115724844A - Heterocyclic compound with antitumor activity and application thereof - Google Patents
Heterocyclic compound with antitumor activity and application thereof Download PDFInfo
- Publication number
- CN115724844A CN115724844A CN202211473008.0A CN202211473008A CN115724844A CN 115724844 A CN115724844 A CN 115724844A CN 202211473008 A CN202211473008 A CN 202211473008A CN 115724844 A CN115724844 A CN 115724844A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- radical
- halogen
- cycloalkyl
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000000259 anti-tumor effect Effects 0.000 title description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- -1 isotopic derivative Substances 0.000 claims abstract description 182
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 239000012453 solvate Substances 0.000 claims abstract description 32
- 229940002612 prodrug Drugs 0.000 claims abstract description 30
- 239000000651 prodrug Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 230000003287 optical effect Effects 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 11
- 230000001404 mediated effect Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 180
- 229910052736 halogen Inorganic materials 0.000 claims description 62
- 150000002367 halogens Chemical class 0.000 claims description 62
- 125000000623 heterocyclic group Chemical group 0.000 claims description 35
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 30
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 29
- 125000000304 alkynyl group Chemical group 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 238000006467 substitution reaction Methods 0.000 claims description 22
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
- 102000016914 ras Proteins Human genes 0.000 claims description 19
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000004043 oxo group Chemical group O=* 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 10
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 8
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 230000035772 mutation Effects 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 230000001613 neoplastic effect Effects 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 102200006538 rs121913530 Human genes 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 2
- 101100421901 Caenorhabditis elegans sos-1 gene Proteins 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000004969 haloethyl group Chemical group 0.000 claims description 2
- 125000004970 halomethyl group Chemical group 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 238000011282 treatment Methods 0.000 claims 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 230000005764 inhibitory process Effects 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 7
- 229940126271 SOS1 inhibitor Drugs 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000011161 development Methods 0.000 abstract description 4
- 230000000155 isotopic effect Effects 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 101710146001 Son of sevenless homolog 1 Proteins 0.000 abstract description 3
- 102100032929 Son of sevenless homolog 1 Human genes 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 239000000543 intermediate Substances 0.000 description 54
- 125000004432 carbon atom Chemical group C* 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 25
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 24
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000006413 ring segment Chemical group 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 description 15
- 108700022176 SOS1 Proteins 0.000 description 15
- 102000057028 SOS1 Human genes 0.000 description 15
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 101150100839 Sos1 gene Proteins 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000007858 starting material Substances 0.000 description 13
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 102000016285 Guanine Nucleotide Exchange Factors Human genes 0.000 description 4
- 108010067218 Guanine Nucleotide Exchange Factors Proteins 0.000 description 4
- 108700020796 Oncogene Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 102200006539 rs121913529 Human genes 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 description 3
- RFEFCOOLRAJDMY-UHFFFAOYSA-N 1-(difluoromethyl)cyclopropan-1-amine;hydrochloride Chemical compound Cl.FC(F)C1(N)CC1 RFEFCOOLRAJDMY-UHFFFAOYSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 108700022174 Drosophila Son of Sevenless Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 230000004850 protein–protein interaction Effects 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 102100029974 GTPase HRas Human genes 0.000 description 2
- 101710113436 GTPase KRas Proteins 0.000 description 2
- 102100039788 GTPase NRas Human genes 0.000 description 2
- 102000018898 GTPase-Activating Proteins Human genes 0.000 description 2
- 108091006094 GTPase-accelerating proteins Proteins 0.000 description 2
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 2
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 2
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- LJCYPWAXWYGFOO-UHFFFAOYSA-N 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC([N+]([O-])=O)=CC(C(F)(F)F)=C1 LJCYPWAXWYGFOO-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MRHGOAKYYORQGQ-UHFFFAOYSA-N 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbaldehyde Chemical compound CSC1=NC(Cl)=C(C=O)C(Cl)=N1 MRHGOAKYYORQGQ-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101100096578 Arabidopsis thaliana SQD2 gene Proteins 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000713858 Harvey murine sarcoma virus Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 1
- 101000868154 Homo sapiens Son of sevenless homolog 2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 206010069755 K-ras gene mutation Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100288142 Mus musculus Klkb1 gene Proteins 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 102000010995 Pleckstrin homology domains Human genes 0.000 description 1
- 108050001185 Pleckstrin homology domains Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000713810 Rat sarcoma virus Species 0.000 description 1
- 102100032930 Son of sevenless homolog 2 Human genes 0.000 description 1
- NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- JRYOZJIRAVZGMV-UHFFFAOYSA-N cyclopropanecarboximidamide;hydron;chloride Chemical compound Cl.NC(=N)C1CC1 JRYOZJIRAVZGMV-UHFFFAOYSA-N 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- ZVXHZSXYHFBIEW-UHFFFAOYSA-N dimethyl 2-fluoropropanedioate Chemical compound COC(=O)C(F)C(=O)OC ZVXHZSXYHFBIEW-UHFFFAOYSA-N 0.000 description 1
- LRBPFPZTIZSOGG-UHFFFAOYSA-N dimethyl 2-methylpropanedioate Chemical compound COC(=O)C(C)C(=O)OC LRBPFPZTIZSOGG-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 108040001860 guanyl-nucleotide exchange factor activity proteins Proteins 0.000 description 1
- 102000009543 guanyl-nucleotide exchange factor activity proteins Human genes 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 102000046752 human SOS1 Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 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
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl 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])* 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229960003278 osimertinib Drugs 0.000 description 1
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 108010014186 ras Proteins Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 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
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000003419 tautomerization reaction Methods 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
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a compound, or tautomer, optical isomer, hydrate, solvate, isotopic derivative, prodrug or pharmaceutically acceptable salt thereof. The compound designed by the invention has a novel structure, and provides a new direction for the development of SOS-1 inhibitor drugs. The research on the in vitro enzyme activity inhibition activity shows that the compounds have stronger inhibition effect on SOS-1 and can be used as prospect compounds for treating SOS-1 inhibitor mediated diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a compound serving as an SOS1 inhibitor, and a preparation method and application of the compound.
Background
The currently known RAS family shares three genes: KRAS (Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog), and HRAS (Harvey murine sarcoma virus oncogene). RAS family proteins are a class of small molecule gtpases and are the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic gtpase activity and slow nucleotide exchange rates. Binding of Gtpase Activating Proteins (GAPs), such as NF1, increases gtpase activity of RAS family proteins.
Mutations in the RAS enzyme are closely associated with tumorigenesis, and RAS mutation types vary among different types of tumors. In human tumors, KRAS mutations (e.g. amino acids G12, G13, Q61, a 146) are most common, accounting for approximately 85%, NRAS (e.g. amino acids G12, G13, Q61, a 146) and HRAS (e.g. amino acids G12, G13, Q61) accounting for 12% and 3%, respectively. Alterations (e.g., mutations, overexpression, gene amplification) of RAS family proteins have also been described as resistance mechanisms against cancer drugs such as: EGFR antibodies cetuximab (cetuximab) and panitumumab (panitumumab)) and the EGFR tyrosine kinase inhibitor oxitinib (osimertinib). For oncogenic RAS mutants, GAP activity is impaired or greatly reduced, leading to permanent activation, which is the basis for oncogenic RAS signaling. Direct inhibition of RAS has proven to be extremely challenging and difficult to administer due to the picomolar affinity of GTP for its binding site, the lack of other well-defined pockets, and the fact that RAS interacts with GEF, GAP, and effectors via extended and flat protein-protein interaction surfaces. Therefore, inhibition of RAS activation by targeting the upstream guanine nucleotide exchange factor protein, SOS, may be of new interest.
There are two human isoforms of SOS, SOS1 and SOS2, but most studies have focused on SOS1. Human SOS1 comprises 1333 amino acids (15 kDa) and consists of an N-terminal domain, a Dbl Homology (DH) domain, a Pleckstrin Homology (PH) domain, including a Ras exchanger motif (Rem) domain and a Cdc25 domain, and a C-terminal region. Wherein pH, rem and Cdc25 are SOS cat Components of the core catalytic domain.
In the past decades, RAS family protein-SOS 1 protein interactions have gained increasing acceptance. In addition, more recently, research has been conducted to combine rational design and screening platforms to identify small molecule inhibitors to SOS1, i.e., compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins. SOS1 inhibitors of the bis-heterocyclic class are described, for example CN111372932A/CN 113200981A.
Although some small molecules of SOS1 inhibitors have been disclosed, no SOS1 inhibitors have yet been developed and marketed, and thus the development of new compounds with potential for marketing, with better potency and pharmacokinetic results, is still an urgent need. The invention designs a series of compounds with a new structure shown in a general formula, finds that the compounds with the structure show excellent effects and actions, and has positive significance for the development of the SOS1 inhibitor.
Disclosure of Invention
The invention aims to provide a compound with a brand-new structure as an SOS1 inhibitor, a preparation method of the compound and application of the compound in treating SOS1 mediated diseases.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof,
wherein,
R 1 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted with 0-3R which may be the same or different a Substitution;
R a each occurrence is independently selected from halogen, amino, cyano, hydroxy, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl) (C) 1-6 Alkyl), -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OC (O) -C 1-6 Alkyl, -NHCO-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CON (C) 1-6 Alkyl) (C 1-6 Alkyl), -S (O) 2 -C 1-6 Alkyl, -NHS (O) 2 -C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 4-10 Cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl) (C 1-6 Alkyl), -CO-C 1-6 Alkyl and substituted benzeneCOO-C 1-6 Alkyl, -OC (O) -C 1-6 Alkyl, -NHCO-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CON (C) 1-6 Alkyl) (C) 1-6 Alkyl), -S (O) 2 -C 1-6 Alkyl, -NHS (O) 2 -C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 4-10 Cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl are each optionally substituted with one or more of the following substituents: halogen, amino, cyano, hydroxy, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NH (C) 1-6 Alkyl), -N (C) 1-6 Alkyl radical) 2 ;
R 2 Selected from hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -C 1-6 alkyl-NH (C) 1-6 Alkyl), -C 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -C 1-6 alkyl-NH (C) 1-6 Alkyl), -C 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted by one or more C 1-6 Alkyl, hydroxy, mercapto or halogen substitution;
R 3 selected from halogen, hydroxy, mercapto, cyano, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 0-6 alkyl-NH 2 、C 0-6 Alkyl radical-NH-C 1-6 Alkyl radical, C 0-6 alkyl-N (C) 1-6 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-6 Alkyl, -OC 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl, wherein said C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 0-6 alkyl-NH 2 、C 0-6 alkyl-NH-C 1-6 Alkyl radical, C 0-6 alkyl-N (C) 1-6 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-6 Alkyl, -OC 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl is each optionally substituted with one or more hydroxy, mercapto, amino, cyano, halogen, C 1-6 Alkyl substitution;
ring A is selected from C 4-12 Cycloalkyl of, C 4-12 Cycloalkenyl group of (1), C 6-12 Aryl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl;
R 4 each independently selected from hydrogen, cyano, halogen, amino, hydroxyl, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 0-6 alkyl-NH-C 1-6 Alkyl, -C 0-6 alkyl-N (C) 1-6 Alkyl) (C 1-6 Alkyl group), C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl; wherein, the C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy, -C 0-6 alkyl-NH-C 1-6 Alkyl, -C 0-6 alkyl-N (C) 1-6 Alkyl) (C) 1-6 Alkyl group), C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl are each optionally substituted with one or more of the following substituents: halogen, hydroxy, mercapto, amino, -SO 2 -C 1-4 Alkyl, oxo, C 1-6 Alkoxy radical, C 3-6 A cycloalkyloxy group; w =0,1,2,3,4.
Unless otherwise specified, the heteroatoms in the heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, with the number of heteroatoms being 1,2,3 or 4.
Preferably, the present invention provides a compound having a structure represented by formula (II), or a prodrug, tautomer, optical isomer, geometric isomer, solvate or pharmaceutically acceptable salt thereof:
the definition of each substituent in the formula (II) is described as the formula (I).
In a preferred embodiment of the invention, R 1 Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 member heterocyclyl, said R 1 Are each optionally substituted by one or more of the same or different R a And (4) substitution.
Further preferably, R 1 Is selected from C 3-6 Monocyclic alkyl radical, said R 1 Are each optionally substituted by one or more of the same or different R a And (4) substitution.
Further preferably, R 1 Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, R 1 Are each optionally substituted by one or more identical or different R a And (4) substitution.
Even more preferably, R 1 Selected from cyclopropyl, said R 1 Are each optionally substituted by one or more identical or different R a And (4) substitution.
In a preferred embodiment of the invention, R a Independently at each occurrence is selected from halogen, amino, cyano, hydroxy, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 The alkoxy groups are each optionally substituted with one or more of the following substituents: halogen, amino, cyano, hydroxyl, oxo, nitro.
Further preferably, R a Each occurrence is independently selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl radical, said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Each alkynyl group is optionally substituted with one or more of the following substituents: halogen, hydroxyl.
Further preferably, R a Each occurrence is independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl.
Even more preferably, R a Each occurrence is independently selected from trifluoromethyl, difluoromethyl, monofluoromethyl.
In a preferred embodiment of the invention, R 1 Selected from difluoromethyl-substituted cyclopropyl.
In a preferred embodiment of the invention, R 2 Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 An alkynyl group; said C is 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 The alkynyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy, C 1-6 An alkyl group.
Further preferably, R 2 Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, wherein said C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl is optionally substituted by one or more C 1-6 Alkyl, hydroxy or halogen;
further preferably, R 2 Selected from hydrogen, halogen, amino, C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, said C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Each alkyl is optionally substituted with one or two hydroxy or halo;
further preferably, R 2 Selected from hydrogen, methyl, ethyl, isopropyl, amino, F, cl, br, methoxy, ethoxy, formyl, acetyl.
Even more preferably, R 2 Selected from hydrogen, methyl, amino, F, cl, br, methoxy, acetyl.
In a preferred embodiment of the invention, R 3 Selected from halogen, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-4 Alkyl, -OC 1-6 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 3-6 Cycloalkyl, -O-3-10 membered heterocyclyl, wherein said C is 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-4 Alkyl, -OC 1-6 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 3-6 Cycloalkyl, -O-3-10 membered heterocyclylAre each optionally substituted by one or more halogens, C 1-6 Alkyl substitution.
Further preferably, R 3 Selected from halogen, amino, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-NH 2 、-OC 1-4 alkyl-NH-C 1-4 Alkyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 Alkyl radical-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-6 membered heterocyclyl, wherein said C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-NH 2 、-OC 1-4 alkyl-NH-C 1-4 Alkyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-6 membered heterocyclyl are each optionally substituted by one or more halogen, C 1-4 Alkyl substitution.
Further preferably, R 3 Selected from halogen, amino, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 Alkyl-3-6 membered heterocyclic group, said C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 The alkyl-3-6 membered heterocyclyl is each optionally substituted with one or two methyl groups.
Further excellenceOptionally, R 3 Selected from F, cl, br, amino, -OCH 3 、-SCH 3 Cyclopropyl, -CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 N(CH 3 ) 2 、
In a preferred embodiment of the invention, ring A is selected from C 6-12 Aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl.
Further preferably, ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl.
Further preferably, ring a is selected from phenyl, pyridyl.
Further preferably, ring a is selected from phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
In a preferred embodiment of the invention, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl; wherein, the C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl are each optionally substituted with one or more of the following substituents: halogen, hydroxy, amino, -SO 2 -C 1-4 Alkyl, oxo; w =0,1,2,3.
Further preferably, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 A hydroxyalkyl group; wherein, the C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 The hydroxyalkyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy, amino; w =1,2,3.
Further preferably, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl, isopropyl; wherein, the nailThe radicals ethyl, n-propyl and isopropyl are each optionally substituted by one or more of the following substituents: halogen, hydroxy; w =1,2,3.
Further preferably, R 4 Each independently selected from hydrogen, halogen, amino, methyl, ethyl, isopropyl; wherein the methyl, ethyl, isopropyl groups are all optionally substituted with one or more of the following substituents: halogen, hydroxy; w =1,2,3.
Further preferably, R 4 Each independently selected from hydrogen, F, cl, br, I, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF 2 CH 2 OH、-C(CH 3 ) 2 OH、-CF 2 CH 3 ;w=1,2,3。
Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
the invention also provides a pharmaceutical composition, which comprises the compound shown in the invention, or a tautomer, a stereoisomer, an optical isomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof.
The invention also provides a medicinal composition which comprises the compound shown in the invention, or tautomer, stereoisomer, optical isomer, solvate, prodrug or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials.
The invention also aims to provide the application of the compound shown in the invention, or the tautomer, the stereoisomer, the optical isomer, the solvate, the prodrug or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating diseases caused by SOS1 mediation and/or RAS mutation.
Preferably, the disease is cancer or tumor, and related diseases thereof. More preferably, the disease is lung cancer; still more preferably, the disease is non-small cell lung cancer. Still further, the disease is KRAS G12C mutant non-small cell lung cancer.
The invention also aims to provide application of the compound shown in the invention, or a tautomer, a stereoisomer, an optical isomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating cancer or tumor diseases.
Preferably, the cancer or neoplastic disease is lung cancer; more preferably, the cancer or neoplastic disease is non-small cell lung cancer.
It is also an object of the present invention to provide a method for preventing and/or treating a disease mediated by SOS1 and/or mutated RAS comprising administering to a patient a therapeutically effective amount of a compound of the present invention, or a tautomer, stereoisomer, optical isomer, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.
In some embodiments, the disease is cancer or tumor, and diseases associated therewith. Further, the disease is lung cancer. Further, the disease is non-small cell lung cancer. Still further, the disease is KRAS G12C mutant non-small cell lung cancer.
The invention also aims to provide application of the compound shown in the invention, or a tautomer, a stereoisomer, an optical isomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof in vitro non-diagnostic and non-therapeutic inhibition of the activity of guanine nucleotide exchange factors (GEFs), wherein the guanine nucleotide exchange factors are selected from SOS1.
Definition of
The terms "optional," "any," "optionally," or "optionally" refer to a subsequently described event or circumstance which may, but need not, occur, and include instances where said event or circumstance occurs and instances where it does not.
The term "oxo" means that two hydrogen atoms at the same substitution position are replaced with the same oxygen atom to form a double bond.
Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably 1-10 carbon atoms (i.e., C) 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C) 1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C) 1-6 Alkyl) such as "C 1-6 By alkyl is meant that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2,3,4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C) 2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C) 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl), 2-5 carbon atoms (i.e., C) 2-5 Alkenyl), 2-4 carbon atoms (i.e., C) 2-4 Alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C) 2 Alkenyl) such as "C 2-6 By alkenyl "is meant that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl, and the like.
Unless otherwise specified, the term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. Alkynyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C) 2-10 Alkynyl) and further preferably contains 2 to 8 carbon atoms (C) 2-8 Alkynyl) and more preferably contains 2 to 6 carbon atoms (i.e., C) 2-6 Alkynyl), 2-5 carbon atoms (i.e., C) 2-5 Alkynyl), 2-4 carbon atoms (i.e., C) 2-4 Alkynyl), 2-3 carbon atoms (i.e., C) 2-3 Alkynyl), 2 carbon atoms (i.e., C) 2 Alkynyl) such as "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having the specified number of carbon atoms, preferably comprising 3 to 12 carbon atoms (i.e., C) 3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C) 3-10 Cycloalkyl group), further preferably 3 to 6 carbon atoms (C) 3-6 Cycloalkyl), 4 to 6 carbon atoms (C) 4-6 Cycloalkyl), 5 to 6 carbon atoms (C) 5-6 Cycloalkyl groups). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
Unless otherwise specified, "cycloalkenyl" means consisting of the sub-groups monocyclic, bicyclic and spiro-hydrocarbon rings, however, the system is unsaturated, i.e. there is at least oneA C-C double bond but no aromatic system. Preferably containing 3 to 12 carbon atoms (i.e. C) 3-12 Cycloalkenyl) and more preferably 3 to 10 carbon atoms (C) 3-10 Cycloalkenyl group), further preferably 3 to 6 carbon atoms (C) 3-6 Cycloalkenyl) of 4 to 6 carbon atoms (C) 4-6 Cycloalkenyl group), 5 to 6 carbon atoms (C) 5-6 Cycloalkenyl groups).
Unless otherwise specified, the term "alkoxy" refers to an-O-alkyl group, as defined above, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2,3,4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like. The term "alkylthio" is identical to the term "alkoxy", except that-O-alkyl is replaced by-S-alkyl.
The term "halogen" or "halo" means, unless otherwise specified, F, cl, br, I. The term "haloalkyl" means an alkyl group as defined above wherein one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 、CF 3 、CHCl 2 、CH 2 Cl、CH 2 Br、CH 2 I、CH 2 CF 3 、CF 2 CF 3 And so on.
Unless otherwise specified, the term "heterocyclyl" means a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, of non-aromatic structure, containing from 3 to 20 ring atoms, wherein 1,2,3, or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably 3 to 14 ring atoms, further preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e. 1,2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
Unless otherwise specified, "heterocycloalkyl" means a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, the ring atoms being as defined above, i.e. containing from 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), the number of heteroatoms being from 1 to 4 (1, 2,3 or 4), preferably from 1 to 3 (1, 2 or 3), wherein the heteroatoms are each independently selected from N, O or S. Preferably 3 to 14 ring atoms ("3-14 membered heterocycloalkyl"), more preferably 3 to 10 ring atoms ("3-10 membered heterocycloalkyl"), even more preferably 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), even more preferably 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), even more preferably 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), even more preferably 5 to 6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted (a "substituted heterocycloalkyl") with one or more substituents. Some exemplary "heterocycloalkyl" groups have been given above for the "heterocyclyl" or "heterocyclic" moiety, and also include, but are not limited to, aziridinyl, oxetanyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxiranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiacyclohexyl, oxazolidinyl, dioxanyl, dithiacyclohexyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinidinyl, and the like.
Unless otherwise specified, the term "aryl" denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing from 6 to 16 carbon atoms, or from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, or from 6 to 10 carbon atoms, preferably from 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, or the like.
Unless otherwise specified, the term "heteroaryl" denotes an aromatic monocyclic or polycyclic ring system containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2,3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms is preferably 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, phthalizinyl, pyrrolo [ 4232 zft 4232-b ] pyridyl, imidazo [ 4234 zft 4234-a ] pyridyl, pyrazolo [ 5364 zft 5364-865a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [ 3525-b ] pyridazinyl, [ 3735 zxft 32385256-b ] pyridazinyl, triazolo [ 35523727-56 a ] triazolo [ 523883 ] pyrimidinyl, and the like.
Unless otherwise specified, the terms "pharmaceutically acceptable salt," "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refer to a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit/risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base or free acid with a suitable reagent. For example, the free base function may be reacted with a suitable acid.
Unless otherwise specified, the term "solvate" or "solvate" means a physical association of a compound of the invention with a solvent molecule (whether organic or inorganic). The physical association includes hydrogen bonding. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. In certain instances, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular and/or disordered arrangement. Solvates encompass solution phases and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
The compounds of the invention include, unless otherwise specified, "isotopic derivatives" thereof, meaning that the compounds of the invention can exist in an isotopically labelled or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number which is the largest number found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes commonly used as isotopic labels are: an isotope of hydrogen, 2 h and 3 h; carbon isotope: 13 c and 14 c; chlorine isotope: 35 cl and 37 cl; fluorine isotope: 18 f; iodine isotope: 123 i and 125 i; nitrogen isotope: 13 n and 15 n; oxygen isotope: 15 O, 17 o and 18 isotopes of O and sulfur 35 And S. These isotopically labeled compounds can be used to study the distribution of pharmaceutically acceptable molecules in tissues. In particular 3 H and 13 c, because they are easy to label and convenient to detect, the application is more extensive. Certain heavy isotopes, such as heavy hydrogen (c: (b)) 2 H, i.e., deuterium), can enhance metabolic stability and extend half-life to provide therapeutic benefits with reduced dosage. Isotopically labeled compounds are generally synthesized by known synthetic techniques as are non-isotopically labeled compounds, starting with already labeled starting materials. In the present invention, "isotopic derivatives" (e.g., deuterons) are included within the scope of the compounds of the present invention.
Unless otherwise specified, the term "optical isomers" refers to substances that have identical molecular structures and similar physicochemical properties, but differ in optical activity.
Unless otherwise specified, the term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
Unless otherwise specified, the term "tautomer" refers to structural isomers that have different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
The term "prodrug", unless otherwise specified, refers to a drug that is converted in vivo to the parent drug. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they can be bioavailable by oral administration, whereas the parent cannot. The prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. An example, but not limiting of, of a prodrug would be any compound of formula I that is administered as an ester ("prodrug") to facilitate delivery across a cell membrane, where water solubility is detrimental to mobility, but once intracellular water solubility is beneficial, it is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to show an active moiety.
Unless otherwise specified, the terms "optionally substituted", "optionally substituted with … …", "optionally substituted with … …" mean that the hydrogen at the substitutable site of the group is unsubstituted or substituted with one or more substituents preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaromatic ring group, wherein C is 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaromatic ring radicals optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, said oxo refers to a group in which two H at the same substitution position are replaced with the same O to form a double bond, and said "= NH" refers to a group in which two H at the same substitution position are replaced with the same-NH-to form a double bond.
The invention has the beneficial effects that:
the invention designs a compound with novel structure, and provides a new direction for the development of SOS1 inhibitor drugs. In-vitro enzymology inhibition test researches show that the compounds have stronger inhibition effect on SOS1 and can be used as prospect compounds for treating SOS 1-mediated diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials are shown herein for illustrative purposes only.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass spectrometry (LC-MS) or/and liquid chromatography (HPLC). NMR was measured using Bruker AVANCE III 600MHz, LC-MS using LCMS WATERS ACQUITY UPLC H-Class PLUS or/and SQD2; the instruments used for HPLC were WATERS e 2695-2998 or/and Agilent 1100.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
Preparation example 1: synthesis of intermediate A
(1) Synthesis of intermediate A-2:
1- (3-Nitro-5-trifluoromethyl-phenyl) -ethanone (10.00g, 43.0 mmol) was dissolved in ethanol (200 mL), followed by addition of iron powder (7.22g, 129.0 mmol), concentrated hydrochloric acid (50 mL) and reaction of the system at 80 ℃ for 2h. LCMS monitored no residue of starting material, temperature reduced filtration, solvent evaporated from filtrate under reduced pressure, and column chromatography of residue purified (dichloromethane: methanol =50, 1-20) to give a-2 (8.12g, 40.0mmol, 92%). ESI-MS (m/z): 204.12[ M ] +H] + 。
(2) Synthesis of intermediate A-3:
a-2 (27.02g, 133.0mmol) was dissolved in tetrahydrofuran (50 mL), followed by addition of (R) - (+) -2-methyl-2-propanesulfinamide (24.24g, 200.0mmol) and Ti (OEt) 4 (91.02g, 399mmol), the system is reacted at 80 ℃ for 2h, and LCMS monitors that no raw material remains. The reaction solution was quenched with ice water, and the precipitate was separatedDissolved in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and the residue was column-chromatographically separated and purified (dichloromethane: methanol = 50. ESI-MS (m/z): 307.12[ deg. ] M + H] + 。
(3) Synthesis of intermediate A-4:
a-3 (34.65g, 113.1mmol) was dissolved in tetrahydrofuran (50 mL) and sodium borohydride (6.42g, 169.7 mmol) was added at-78 ℃. The reaction was allowed to slowly warm to room temperature and LCMS monitored that no starting material remained. The reaction solution was quenched with ice water, extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was column-chromatographically separated and purified (dichloromethane: methanol = 50. ESI-MS (m/z): 309.10[ M ] +H] + 。
(4) Synthesis of intermediate a:
a-4 (28.43g, 92.2mmol) was dissolved in dioxane hydrochloride solution (50 mL) and reacted at room temperature for 2h, LCMS monitored no residue, solvent was distilled off under reduced pressure to give intermediate A as hydrochloride salt which was directly used in the next reaction. ESI-MS (m/z): 205.22[ 2 ] M + H] + 。
The following intermediates can be obtained by reference to the synthetic method of intermediate a or by reference to the related synthetic method in CN110167928 a. If desired, the crude product is purified by chromatography.
Example 1: synthesis of Compound 1
Synthesis of intermediate 1-1
Cyclopropaneamidine hydrochloride (10.04g, 83.3 mmol) was dissolved in methanol (100 mL), dimethyl malonate (13.21g, 100.0 mmol) and sodium methoxide (11.24g, 208.0 mmol) were added, the system was heated to 60 ℃ and stirred for reaction for 1.5 hours, the system was cooled to room temperature, water (100 mL) was added, the system pH was adjusted to 4-5 with concentrated hydrochloric acid, and a white solid was precipitated. Suction filtration and drying of the solid gave 1-1 (11.01g, 87%). ESI-MS (m/z): 153.02[ 2 ] M + H] + 。
Synthesis of intermediate 1-2
Phosphorus oxychloride (55.43g, 361.5 mmol) was added dropwise to N, N-dimethylformamide (10.57g, 144.6 mmol) at 0 ℃ and stirring was continued at this temperature for 1 hour. Intermediate 1-1 (11.01g, 72.3mmol) was then added portionwise at 0 ℃. The reaction solution was allowed to spontaneously warm to room temperature and stirred for 1 hour. The reaction solution was heated to 120 ℃ and reacted for 3 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate (40 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a brown oil, and the residue was column chromatographically separated and purified (petroleum ether: ethyl acetate =100: 1-40) to give 1-2 (4.02g, 26%). ESI-MS (m/z): 217.18[ M ] +H] + 。
Synthesis of intermediates 1 to 3
A mixture of intermediate 1-2 (4.02g, 18.5 mmol), p-toluenesulfonic acid (327.2mg, 1.90mmol), ethylene glycol (1.72g, 27.8 mmol) and toluene (50 mL) was heated to reflux for 3 hours and LCMS monitored for no residue. After the reaction mixture was concentrated, water (100 mL) was added to the residue, and extraction was performed with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50. ESI-MS (m/z): 261.28[ M ] +H] + 。
Synthesis of intermediates 1 to 4
A mixture of intermediates 1-3 (3.81g, 14.6 mmol), dimethyl 2-fluoromalonate (2.63g, 17.5 mmol), cesium carbonate (9.51g, 29.2mol) and dimethyl sulfoxide (50 mL) was reacted at room temperature for 5 hours and LCMS monitored for no residue of starting material. Water (100 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfateAnd (5) drying. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether: ethyl acetate =20: 1-5:1) to give 1-4 (4.49g, 82%). ESI-MS (m/z): 375.28[ M ] +H] + 。
Synthesis of intermediates 1 to 5
A mixture of intermediates 1 to 4 (4.49g, 12.0 mmol), lithium chloride (2.54g, 60.0 mmol) and dimethyl sulfoxide (50 mL) was heated to 110 ℃ and reacted for 2 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate =20: 1-3:1) to afford intermediates 1-5 (1.10g, 29%). ESI-MS (m/z): 317.12[ M ] +H] + 。
Synthesis of intermediates 1 to 6
A mixture of intermediate 1-5 (1.10g, 3.47mmol), intermediate D (776mg, 4.10mmol), N-diisopropylethylamine (879mg, 6.80mmol) and dimethyl sulfoxide (30 mL) was warmed to 110 ℃ for reaction for 3 hours, and LCMS monitored that no residue was left. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate =20: 1-2:1) to give 1-6 (798mg, 49%). ESI-MS (m/z): 470.28[ M ] +H] + 。
Synthesis of intermediates 1 to 8
Intermediates 1-6 (798mg, 1.70mmol) were dissolved in DMSO (10 mL) and CAN (5 mL). 20% aqueous sodium hydroxide (272mg, 6.80mmol) was added, the mixture was stirred for 30 minutes, and no residue was detected by LCMS to give intermediate 1-7, to the system were added triethylamine (344mg, 3.40mmol), 1-difluoromethylcyclopropane-1-amine hydrochloride (318mg, 2.21mmol), and HATU (856 mg, 2.25mmol), the mixture was stirred for 20 minutes, and no residue was detected by LCMS. Water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1-1:2) to give 1-8 (204mg, 22%). ESI-MS (m/z): 545.12[ M ] +H] + 。
Synthesis of Compound 1
Intermediates 1-8 (204mg, 0.37mmol) were dissolved in 2-propanol (10 mL). 2 drops of concentrated HCl were added and the mixture was stirred at 50 ℃ for 1 hour and LCMS monitored that no starting material remained. The reaction mixture was basified with aqueous ammonia, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol =40, 1-15, 2% aqueous ammonia was added) to give compound 1 (100mg, 56%). ESI-MS (m/z): 483.12[ M ] +H] + 。
1 HNMR(600MHz,DMSO-d 6 )δ9.06-8.98(m,2H),7.57(dd,J=7.2Hz,J=7.2Hz,1H),7.53(dd,J=6.6Hz,J=6.6Hz,1H),7.32(d,J=7.2Hz,1H),7.24(t,J=54Hz,1H),6.34(t,J=56Hz,1H),5.56-5.52(m,1H),1.84-1.79(m,1H),1.58(d,J=7.2Hz,3H),1.53-1.43(m,4H),1.08-1.04(m,1H),0.89-0.86(m,1H),0.75-0.71(m,1H),0.47-0.43(m,1H).
Example 2: synthesis of Compound 2
Synthesis of intermediate 2-1
A mixture of intermediates 1-3 (3.81g, 14.6 mmol), dimethyl methylmalonate (2.56g, 17.5 mmol), cesium carbonate (9.51g, 29.2mol) and dimethyl sulfoxide (50 mL) was reacted at room temperature for 5 hours and LCMS monitored for no residue of starting material. The reaction mixture was added with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate =20: 1-5:1) to give intermediate 2-1 (4.50 g, yield 83%). ESI-MS (m/z): 371.88[ M ] +H] + 。
Synthesis of intermediate 2-2
A mixture of intermediate 2-1 (4.50g, 12.1mmol), lithium chloride (2.56g, 60.5mmol) and dimethyl sulfoxide (50 mL) was heated to 110 ℃ and reacted for 2 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate =20: 1-3:1) to afford intermediate 2-2 (1.50 g, yield 40%)。ESI-MS(m/z):313.72[M+H] + 。
Synthesis of intermediates 2-3
A mixture of compound 2-2 (1.50g, 4.80mmol), intermediate D (1.09g, 5.76mmol), N-diisopropylethylamine (1.24g, 9.60mmol) and dimethyl sulfoxide (30 mL) was warmed to 110 deg.C for 3 hours and LCMS monitored for the absence of residual material. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate =20: 1-2:1) to give intermediate 2-3 (1.70 g, yield 70%). ESI-MS (m/z): 466.28[ 2 ] M + H] + 。
Synthesis of intermediates 2 to 5
Intermediate 2-3 (1.70g, 3.65mmol) was dissolved in DMSO (10 mL) and CAN (5 mL). 20% aqueous sodium hydroxide (532mg, 13.3mmol) was added, the mixture stirred for 30 minutes and LCMS monitored for no residue of starting material to give intermediate 2-4. Triethylamine (737mg, 7.30mmol), 1-difluoromethylcyclopropane-1-amine hydrochloride (632mg, 4.40mmol) and HATU (1.67g, 4.40mmol) were added and the mixture stirred for 20 minutes and LCMS monitored that no starting material remained. Water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1-1:2) gave intermediate 2-5 (593 mg, yield 30%). ESI-MS (m/z): 541.12[ M ] +H] + 。
Synthesis of Compound 2
Intermediate 2-5 (593mg, 1.10mmol) was dissolved in 2-propanol (10 mL), 2 drops of concentrated HCl were added, the mixture was stirred at 50 ℃ for 1 hour, and the starting material was monitored by LCMS for no residue. The reaction mixture was basified with aqueous ammonia, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol =40, 1-15, 2% aqueous ammonia was added) to obtain compound 2 (295 mg, yield 56%). ESI-MS (m/z): 479.21[ M ] +H] + 。
Examples 3 to 12
Examples 3-12 Compounds 3-12 can be prepared by reference to the preparation of example 1
Example 13: synthesis of Compound 13
A mixture of 2- (methylthio) -4,6-dichloro-5-pyrimidinecarbaldehyde (11.0g, 49.5mmol), p-toluenesulfonic acid (852mg, 4.95mmol), ethylene glycol (4.59g, 74.0mmol), and toluene (100 mL) was heated under reflux for 3 hours, and LCMS monitored that no starting material remained. After the reaction mixture was concentrated, water (100 mL) was added to the residue, and extraction was performed with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate =50: 1-20). ESI-MS (m/z): 267.10[ M ] +H] + 。
Synthesis of intermediate 13-2
A mixture of intermediate 13-1 (8.00g, 30.0mmol), dimethyl malonate (4.76g, 36.0mmol), cesium carbonate (19.5g, 60.0mmol), and dimethyl sulfoxide (100 mL) was reacted at room temperature for 2 hours, and LCMS monitored that no residue was left. The reaction mixture was added with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography separation and purification (petroleum ether: ethyl acetate =20: 1-5:1) to give intermediate 13-2 (9.00 g, yield 83%). ESI-MS (m/z): 363.08[ 2 ] M + H] + 。
Synthesis of intermediate 13-3
Intermediate 13-2 (9.00g, 24.8mmol), lithium chloride (5.26g, 124) were added.0 mmol) and dimethyl sulfoxide (100 mL) were heated to 110 ℃ for 2 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (100 mL. Times.2), and dried over anhydrous sodium sulfate. The crude was purified by silica gel column chromatography (petroleum ether: ethyl acetate =20: 1-3:1) to afford intermediate 13-3 (2.01 g, yield 26%). ESI-MS (m/z): 305.28[ M ] +H] + 。
Synthesis of intermediate 13-4
A mixture of intermediate 13-3 (2.00g, 6.56mmol), intermediate D (1.49g, 7.87mmol), N-diisopropylethylamine (1.70g, 13.1 mmol) and dimethyl sulfoxide (80 mL) was warmed to 110 deg.C for 3 hours and LCMS monitored for the absence of residual material. Water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography separation and purification (petroleum ether: ethyl acetate =20: 1-2:1) to give intermediate 13-4 (1.9 g, yield 63%). ESI-MS (m/z): 458.28[ M ] +H] + 。
Synthesis of intermediate 13-6
Intermediate 13-4 (1.903g, 4.16mmol) was dissolved in DMSO (10 mL) and CAN (5 mL). 20% aqueous sodium hydroxide (664mg, 16.6 mmol) was added, the mixture stirred for 30 minutes and LCMS monitored for no residue of starting material to give intermediate 13-5. Triethylamine (840mg, 8.32mmol), 1-difluoromethylcyclopropane-1-amine hydrochloride (717mg, 4.99mmol) and HATU (2.37g, 6.24mmol) were added, the mixture was stirred for 20 minutes, and LCMS was used to monitor that no residue was left. Water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1-1:2) to give intermediate 13-6 (600 mg, yield 27%). ESI-MS (m/z): 533.12[ 2 ] M + H] + 。
Synthesis of Compound 13
13-6 (600mg, 1.13mmol) was dissolved in 2-propanol (10 mL). 2 drops of concentrated HCl were added and the mixture was stirred at 50 ℃ for 1 hour and LCMS monitored that no starting material remained. The reaction mixture was basified with aqueous ammonia, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol =40:1, 2% ammonia water added) to give compound 13 (319 mg, yield 60%) ESI-MS (m/z): 471.13[ 2 ] M + H] + 。
Examples 14 to 28
Examples 14-28 Compounds 14-28 can be prepared by the method of preparation of reference example 1
Comparative example 1
The compound I-82 (page 138 of the specification) in the prior art patent CN111372932A (published Japanese 2020.07.03) has the following structure:(hereinafter referred to as control Compound 1).
Comparative example 2
Compound 21 (pages 31-33 of the specification) in prior art patent CN113200981a (published 2021.08.03) has the following structure:(hereinafter referred to as control Compound 2).
Biological activity assay experiment:
1.K-Ras G12D binding assay with hSOS1
This assay can be used to examine the efficacy of compounds to inhibit protein-protein interactions between SOS1 and KRAS G12D. Determination of the binding of Compounds to K-Ras by homogeneous time-resolved fluorescence (HTRF) detection of Tag1-hSOS1 bound by anti-Tag1-Tb3+ (donor) to Tag2-KRASG12D (acceptor) bound by anti-Tag2-XL665 G12D Inhibition with hSOS1。
Reagent:
KRAS-G12D/SOS1 BINDING ASSAY KITS,Cisbio,Cat No.63ADK000CB21PEH;
GTP,Sigma,Cat No.V900868;
the test steps are as follows:
dissolving a compound to be tested in DMSO (dimethylsulfoxide) to prepare a 10mM stock solution; after 1000-fold dilution with DMSO solution, 3-fold gradient dilutions were performed sequentially, with 11 concentration gradients, starting at 10. Mu.M. 0.1. Mu.L of compound was transferred to 384-well plates by means of Echo acoustics system; adding 5 mu L of Tag2-KRASG12D & GTP mixed solution into each hole, and centrifuging at 1000rpm for 1min; add 5. Mu.L of Tag1-hSOS1 into each well, centrifuge at 1000rpm for 1min; incubating at 25 deg.C for 15min; adding 10 mu L of anti-Tag1-Tb3+ and anti-Tag2-XL665 mixed solution into each well, centrifuging at 1000rpm for 1min, and incubating for 2h at 4 ℃; the fluorescence signals at 615nm (Cryptote) and 665nm (XL 665) were read with an Envision 2104.
And (3) data analysis:
fitting Compound IC Using Graphpad Prism 8 nonlinear regression equation 50 A value;
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope));
X:Log of cpd concentration;
Y:665/615ratio;
compounds of the examples tested according to the above method, inhibit the activity IC of SOS-1 50 Less than 50nM.
Representative compounds of the examples were tested according to the above method and found to inhibit SOS-1 activity. Compound activity data are shown in the table below.
Note that A represents IC 50 Greater than or equal to 5nm and less than 10nm, B represents IC 50 Greater than or equal to 10nm and less than 20nm.
2.3D cell proliferation inhibition assay
Cell proliferation inhibition assay for detecting compounds inhibiting SOS1 mediation at the level of 3D cells in vitroProliferation and growth of tumor cell lines, using3D detection method.
Reagents and materials:
NCI-H358: KRAS G12C mutant non-small cell lung cancer (NSCLC);
RPMI 1640medium,Gibco,A10491-01;
FBS,Gibco,10099141C;
the testing steps are as follows:
cell culture
Day 1, passage of NCI-H358 to T75 cell culture flasks;
day 3, remove medium, wash once with DPBS, use 2mL TrypLE at room temperature or 37 ℃ TM Express Enzyme digests cells until the cells shed; adding 5mL of fresh culture medium, and centrifuging at 1000rpm for 5min; the supernatant was discarded, 5mL of fresh medium was added to resuspend the cells, and 40. Mu.L/Well after cell counting was seeded in 3D cell plates (Echo modified 384-Well Polypropylene Microplate 2.0, clear, flat Bottom)
3D cell proliferation inhibition
Day 1, dissolving the test compound in DMSO to prepare a 10mM stock solution; diluting 1000 times by using a DMSO solution, and sequentially carrying out 3-time gradient dilution on the diluted solutions, wherein the initial concentration is 10 mu M; adding 200nL of compound to the plate;
day 8, 40. Mu.L/well 3D CTG reagent was added and signal values were measured by Envision.
And (3) data analysis:
fitting Compound IC Using Graphpad Prism 8 nonlinear regression equation 50 A value;
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope));
X:Log of cpd concentration;
Y:Percent inhibition(%inh)
the compounds in the examples tested according to the above method, NCI-H358 cell proliferation inhibitory activity data are shown in the following table.
Note that A represents IC 50 Greater than or equal to 50nm and less than 100nm, B represents IC 50 Greater than or equal to 100nm and less than 200nm.
3. In vivo pharmacokinetic study in mice
This experiment investigated the pharmacokinetic behavior of a single dose, single intravenous injection or gavage administration of the compound of example 1, control compound 1 and control compound 2 in ICR mice.
Test animals:
ICR mice were 6, male, divided into 2 groups of 3 mice each, purchased from beijing weitongli limited.
Drug solvent:
intravenous vehicle: 5% DMSO +95% HP- β -CD (0.1 g/ml);
gastric perfusion solvent: 5% DMSO +10% CrEL +85% water.
The sampling method comprises the following steps:
the intravenous injection group is used for 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after the administration is finished, the intragastric administration group is used for 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after the administration is finished, 100 mu L of blood is respectively taken from orbital veins of mice and placed in a heparin sodium anticoagulation tube, 8000rmp within 2h of the collected venous blood of the mice is centrifuged for 10 minutes to separate blood plasma, the blood plasma is transferred and placed in a 1.5mL centrifuge tube and transferred to a refrigerator at minus 80 ℃ for storage, and the test tube is used for LC-MS/MS analysis.
The results of the pharmacokinetic parameters of mice in vivo under intravenous injection dosage of 2mg/Kg and oral gavage dosage of 10mg/Kg of the embodiment of the invention are shown in the following table:
and (4) conclusion: the compounds of the invention exhibit better pharmacokinetic properties in mouse PK studies.
Claims (13)
1. A compound of formula (I), or a tautomer, stereoisomer, optical isomer, solvate, prodrug, or a pharmaceutically acceptable salt thereof, having the structure:
wherein,
R 1 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkenyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted with 0-3R which may be the same or different a Substitution;
R a each occurrence is independently selected from the group consisting of halogen, amino, cyano, hydroxy, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl) (C 1-6 Alkyl), -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OC (O) -C 1-6 Alkyl, -NHCO-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CON (C) 1-6 Alkyl) (C 1-6 Alkyl), -S (O) 2 -C 1-6 Alkyl, -NHS (O) 2 -C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 4-10 Cycloalkenyl radicals4-10 membered heterocyclic group, C 6-10 Aryl, 5-to 10-membered heteroaryl, said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl) (C 1-6 Alkyl), -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OC (O) -C 1-6 Alkyl, -NHCO-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CON (C) 1-6 Alkyl) (C 1-6 Alkyl), -S (O) 2 -C 1-6 Alkyl, -NHS (O) 2 -C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 4-10 Cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl are each optionally substituted with one or more of the following substituents: halogen, amino, cyano, hydroxy, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl radical, C 3-8 Cycloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Hydroxyalkyl, 4-to 10-membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NH (C) 1-6 Alkyl), -N (C) 1-6 Alkyl radical) 2 ;
R 2 Selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano, amino, nitro and C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -C 1-6 alkyl-NH (C) 1-6 Alkyl), -C 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -C 1-6 alkyl-NH (C) 1-6 Alkyl), -C 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-10 Cycloalkyl radical, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted by one or more C 1-6 Alkyl, hydroxy, mercapto or halogen substitution;
R 3 selected from halogen, hydroxy, mercapto, cyano, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 0-6 alkyl-NH 2 、C 0-6 alkyl-NH-C 1-6 Alkyl radical, C 0-6 alkyl-N (C) 1-6 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-6 Alkyl, -OC 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl, wherein said C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 0-6 alkyl-NH 2 、C 0-6 alkyl-NH-C 1-6 Alkyl radical, C 0-6 alkyl-N (C) 1-6 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-6 Alkyl, -OC 1-6 alkyl-N (C) 1-6 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl is each optionally substituted with one or more hydroxy, mercapto, amino, cyano, halogen, C 1-6 Alkyl substitution;
ring A is selected from C 4-12 Cycloalkyl of, C 4-12 Cycloalkenyl group of (A), C 6-12 Aryl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl;
R 4 each independently selected from hydrogen, cyano, halogen, amino, hydroxyl, mercapto, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 0-6 alkyl-NH-C 1-6 Alkyl, -C 0-6 alkyl-N (C) 1-6 Alkyl) (C 1-6 Alkyl), C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl radicals, 3-a 6-membered heterocyclyl group; wherein, the C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Alkoxy, -C 0-6 alkyl-NH-C 1-6 Alkyl, -C 0-6 alkyl-N (C) 1-6 Alkyl) (C 1-6 Alkyl group), C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl are each optionally substituted with one or more of the following substituents: halogen, hydroxy, mercapto, amino, -SO 2 -C 1-4 Alkyl, oxo, C 1-6 Alkoxy radical, C 3-6 A cycloalkyloxy group; w =0,1,2,3,4;
unless otherwise indicated, the heteroatoms in the heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4.
3. The compound of claim 1 or 2, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is 1 Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 member heterocyclyl, said R 1 Are each optionally substituted by one or more of the same or different R a Substitution;
further preferably, R 1 Is selected from C 3-6 Monocyclic alkyl radical, said R 1 Are each optionally substituted by one or more of the same or different R a Substitution;
further preferably, R 1 Selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein R is 1 Are each optionally substituted by one or more identical or different R a Substitution;
even more preferably, R 1 Selected from cyclopropyl, said R 1 Are each optionally substituted by one or more identical or different R a Substitution;
most preferably, R 1 Selected from difluoromethyl-substituted cyclopropyl.
4. The compound of any one of claims 1-3, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is a Independently at each occurrence is selected from halogen, amino, cyano, hydroxy, oxo, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 The alkoxy groups are each optionally substituted with one or more of the following substituents: halogen, amino, cyano, hydroxy, oxo, nitro;
further preferably, R a Each occurrence is independently selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 The alkynyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy;
further preferably, R a Each occurrence is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl;
even more preferably, R a Each occurrence is independently selected from trifluoromethyl, difluoromethyl, monofluoromethyl.
5. The compound according to any one of claims 1 to 4, or a tautomer, stereoisomer, or photo-isomer thereofA chemical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is 2 Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 An alkynyl group; said C is 1-6 Alkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl, -CO-C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 The alkynyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy, C 1-6 An alkyl group;
further preferably, R 2 Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, wherein said C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl is optionally substituted by one or more C 1-6 Alkyl, hydroxy or halogen substitution;
further preferably, R 2 Selected from hydrogen, halogen, amino, C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Alkyl radical, said C 1-4 Alkyl, -O-C 1-4 Alkyl, -S-C 1-4 Alkyl, -CO-C 1-4 Each alkyl is optionally substituted with one or two hydroxy or halo;
further preferably, R 2 Selected from hydrogen, methyl, ethyl, isopropyl, amino, F, cl, br, methoxy, ethoxy, formyl, acetyl;
even more preferably, R 2 Selected from hydrogen, methyl, amino, F, cl, br, methoxy, acetyl.
6. The compound of any one of claims 1-5, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is 3 Selected from halogen, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-4 Alkyl, -OC 1-6 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, - -O- -C 0-6 Alkyl-3-10 membered heterocyclyl, wherein said C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-6 alkyl-NH 2 、-OC 1-6 alkyl-NH-C 1-4 Alkyl, -OC 1-6 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-10 membered heterocyclyl are each optionally substituted by one or more halogen, C 1-6 Alkyl substitution;
further preferably, R 3 Selected from halogen, amino, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-NH 2 、-OC 1-4 alkyl-NH-C 1-4 Alkyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-6 membered heterocyclyl, wherein said C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 0-4 alkyl-NH 2 、C 0-4 alkyl-NH-C 1-4 Alkyl radical, C 0-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-NH 2 、-OC 1-4 alkyl-NH-C 1-4 Alkyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 alkyl-C 3-6 Cycloalkyl, -O-C 0-6 Alkyl-3-6 membered heterocyclyl are each optionally substituted by one or more halogen, C 1-4 Alkyl substitution;
further preferably, R 3 Selected from halogen, amino, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 Alkyl-3-6 membered heterocyclic group, said C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl radical, C 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, -OC 1-4 alkyl-N (C) 1-4 Alkyl radical) 2 、-O-C 0-6 Each alkyl-3-6 membered heterocyclyl is optionally substituted with one or two methyl groups;
7. The compound of any one of claims 1-6, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein ring a is selected from C 6-12 Aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;
further preferably, ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl;
further preferably, ring a is selected from phenyl, pyridyl;
even more preferably, ring A is selected from phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
8. The compound of any one of claims 1-7, or a tautomer, stereoisomer, optical isomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, wherein R is 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl; wherein, the C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl radical, C 3-6 Halocycloalkyl, 3-6 membered heterocyclyl are each optionally substituted with one or more of the following substituents: halogen, hydroxy, amino, -SO 2 -C 1-4 Alkyl, oxo; w =0,1,2,3;
further preferably, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 A hydroxyalkyl group; wherein, the C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 The hydroxyalkyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy, amino; w =1,2,3;
further preferably, R 4 Each independently selected from hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl, isopropyl; wherein the methyl, ethyl, n-propyl, isopropyl groups are each optionally substituted with one or more of the following substituents: halogen, hydroxy; w =1,2,3;
further preferably, R 4 Each independently selected from hydrogen, halogen, amino, methyl, ethyl, isopropyl; wherein the methyl, ethyl and isopropyl groups are all optionally substituted by one or more of the following substituents: halogen, hydroxy; w =1,2,3;
further preferably, R 4 Are respectively independentIs selected from hydrogen, F, cl, br, I, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF 2 CH 2 OH、-C(CH 3 ) 2 OH、-CF 2 CH 3 ;w=1,2,3。
11. a pharmaceutical composition characterized by: comprising a compound of any one of claims 1-10, or a tautomer, optical isomer, solvate, prodrug, or a pharmaceutically acceptable salt thereof.
12. Use of a compound according to any one of claims 1 to 10, or a tautomer, an optical isomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a medicament for the prophylaxis and/or treatment of a disease caused by SOS 1-mediated and/or RAS mutations; preferably, the disease is cancer or tumor, and related diseases thereof; more preferably, the disease is lung cancer; further preferably, the disease is non-small cell lung cancer; still further, the disease is KRAS G12C mutant non-small cell lung cancer.
13. Use of a compound according to any one of claims 1 to 10, or a tautomer, optical isomer, solvate, prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a medicament for the prophylaxis and/or treatment of cancer or a tumor disease; preferably, the cancer or neoplastic disease is lung cancer; more preferably, the cancer or neoplastic disease is non-small cell lung cancer.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2021113820884 | 2021-11-22 | ||
CN202111382088 | 2021-11-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115724844A true CN115724844A (en) | 2023-03-03 |
Family
ID=85297895
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211473008.0A Pending CN115724844A (en) | 2021-11-22 | 2022-11-21 | Heterocyclic compound with antitumor activity and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115724844A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115960079A (en) * | 2023-03-16 | 2023-04-14 | 英矽智能科技(上海)有限公司 | Azetidine derivatives, their preparation and their pharmaceutical use |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111372932A (en) * | 2017-12-21 | 2020-07-03 | 勃林格殷格翰国际有限公司 | Novel benzylamino-substituted pyridopyrimidinones and derivatives as SOS1 inhibitors |
CN113200981A (en) * | 2021-02-10 | 2021-08-03 | 杭州英创医药科技有限公司 | Heterocyclic compounds as SOS1 inhibitors |
CN114907341A (en) * | 2021-02-08 | 2022-08-16 | 武汉人福创新药物研发中心有限公司 | Pyridopyrimidinone derivatives, and preparation method and application thereof |
CN115215844A (en) * | 2021-04-21 | 2022-10-21 | 苏州泽璟生物制药股份有限公司 | Substituted pyrimido-ring inhibitor and preparation method and application thereof |
CN115942936A (en) * | 2020-06-24 | 2023-04-07 | 勃林格殷格翰国际有限公司 | Anti-cancer combination therapy comprising SOS1 inhibitor and KRAS G12C inhibitor |
-
2022
- 2022-11-21 CN CN202211473008.0A patent/CN115724844A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111372932A (en) * | 2017-12-21 | 2020-07-03 | 勃林格殷格翰国际有限公司 | Novel benzylamino-substituted pyridopyrimidinones and derivatives as SOS1 inhibitors |
CN115942936A (en) * | 2020-06-24 | 2023-04-07 | 勃林格殷格翰国际有限公司 | Anti-cancer combination therapy comprising SOS1 inhibitor and KRAS G12C inhibitor |
CN114907341A (en) * | 2021-02-08 | 2022-08-16 | 武汉人福创新药物研发中心有限公司 | Pyridopyrimidinone derivatives, and preparation method and application thereof |
CN113200981A (en) * | 2021-02-10 | 2021-08-03 | 杭州英创医药科技有限公司 | Heterocyclic compounds as SOS1 inhibitors |
CN115215844A (en) * | 2021-04-21 | 2022-10-21 | 苏州泽璟生物制药股份有限公司 | Substituted pyrimido-ring inhibitor and preparation method and application thereof |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115960079A (en) * | 2023-03-16 | 2023-04-14 | 英矽智能科技(上海)有限公司 | Azetidine derivatives, their preparation and their pharmaceutical use |
CN115960079B (en) * | 2023-03-16 | 2023-05-09 | 英矽智能科技(上海)有限公司 | Azetidine derivatives, their preparation and their use in medicine |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111704611B (en) | Aryl spiro SHP2 inhibitor compound, preparation method and application | |
CN112225724B (en) | Benzimidazole compound kinase inhibitor and preparation method and application thereof | |
CN110382499B (en) | FGFR inhibitor and application thereof | |
TW202128691A (en) | Kras mutein inhibitors | |
WO2012019427A1 (en) | Phthalazinone ketone derivative, preparation method thereof, and pharmaceutical use thereof | |
JP2022542162A (en) | Heterocyclic amide compound and its production method and use | |
JP2023520595A (en) | Pyrazolopyridazinone compound, pharmaceutical composition thereof and use thereof | |
CN115368373A (en) | Spirocyclic compound and use thereof | |
KR20210066839A (en) | FGFR4 inhibitors and uses thereof | |
WO2021263246A1 (en) | Novel cell metabolism modulating compounds and uses thereof | |
TW202110848A (en) | A substituted fused bicyclic derivative, a preparation method thereof, and medical applications thereof | |
CN115724844A (en) | Heterocyclic compound with antitumor activity and application thereof | |
CN115368378A (en) | Substituted macrocyclic compounds, compositions containing the same and uses thereof | |
WO2021078227A1 (en) | Fused heteroaryl derivative, preparation method therefor, and application thereof in medicine | |
CN115066423A (en) | PD-L1 antagonist compounds | |
CN109111439B (en) | Amide compound, composition containing same and application thereof | |
WO2023143147A1 (en) | Pyridazopyridone compounds, pharmaceutical composition thereof and use thereof | |
CN113493439B (en) | Substituted acrylamide derivative, composition and application thereof | |
CN115697988B (en) | 3, 4-Dihydro isoquinoline compound and application thereof | |
CN113336760B (en) | Substituted amide derivatives, compositions and uses thereof | |
JP7398156B2 (en) | A class of trialromatic compounds targeting the STAT3 bifunctional phosphorylation site and their applications | |
CN115417868B (en) | Heterocyclic compound with antitumor activity and application thereof | |
TWI827429B (en) | Carbonyl bridged heterocyclic compounds, compositions and applications thereof | |
CN116265462A (en) | Heterocyclic compound with antitumor activity and application thereof | |
CN115677601A (en) | Compound with anti-tumor activity and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |