CN115340499B - BCL-XL inhibitors and uses thereof - Google Patents
BCL-XL inhibitors and uses thereof Download PDFInfo
- Publication number
- CN115340499B CN115340499B CN202110524420.XA CN202110524420A CN115340499B CN 115340499 B CN115340499 B CN 115340499B CN 202110524420 A CN202110524420 A CN 202110524420A CN 115340499 B CN115340499 B CN 115340499B
- Authority
- CN
- China
- Prior art keywords
- bcl
- compound
- alkylene
- alkyl
- membered
- 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.)
- Active
Links
- 229940122035 Bcl-XL inhibitor Drugs 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 208000026278 immune system disease Diseases 0.000 claims abstract description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 claims description 9
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 abstract description 22
- 108090000623 proteins and genes Proteins 0.000 abstract description 22
- 230000006909 anti-apoptosis Effects 0.000 abstract description 19
- 239000000203 mixture Substances 0.000 abstract description 13
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 5
- 229940002612 prodrug Drugs 0.000 abstract description 4
- 239000000651 prodrug Substances 0.000 abstract description 4
- 239000012453 solvate Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 description 52
- 125000000753 cycloalkyl group Chemical group 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 23
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 229910052736 halogen Inorganic materials 0.000 description 18
- 150000002367 halogens Chemical class 0.000 description 17
- 239000001257 hydrogen Substances 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000002947 alkylene group Chemical group 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- 239000012146 running buffer Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 108700000711 bcl-X Proteins 0.000 description 3
- 102000055104 bcl-X Human genes 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001514 detection method Methods 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- -1 hydroxy, carboxy, amino Chemical group 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 102000051485 Bcl-2 family Human genes 0.000 description 1
- 108700038897 Bcl-2 family Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 description 1
- 102000013535 Proto-Oncogene Proteins c-bcl-2 Human genes 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000000277 Splenic Neoplasms Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical group C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- MAWOHFOSAIXURX-UHFFFAOYSA-N cyclopentylcyclopentane Chemical group C1CCCC1C1CCCC1 MAWOHFOSAIXURX-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- JLYAXFNOILIKPP-KXQOOQHDSA-N navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 description 1
- 229950004847 navitoclax Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 201000002471 spleen cancer Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis 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
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a BCL-XL inhibitor and application thereof, and belongs to the field of chemical medicines. The BCL-XL inhibitor is a compound shown in a formula I, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof. The compound can effectively bind with the BCL-XL anti-apoptosis protein and inhibit the activity of the BCL-XL anti-apoptosis protein; therefore, the anti-apoptosis protein can be used for preventing or treating diseases related to the BCL-XL anti-apoptosis protein, such as cancers, immune diseases, autoimmune diseases and the like. The compound can be used for preparing a BCL-XL inhibitor or preparing a medicine and a medicine composition for preventing or treating diseases related to BCL-XL anti-apoptosis proteins. In addition, the compound has good pharmacological characteristics, good stability and high possibility of patent medicine, and has the advantages of simple preparation, high yield, low cost, high feasibility and good application prospect.
Description
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a BCL-XL inhibitor and application thereof.
Background
Tumor development is associated with apoptosis and is a result of imbalance between cell proliferation and apoptosis. The BCL-2 family proteins play an important role in the apoptosis process and become a popular target for the research of anti-tumor drugs in recent years. BCL-XL anti-apoptotic proteins are a member of the BCL-2 family of proteins that are over-expressed as anti-apoptotic proteins in a variety of cancer cells.
Patent WO2005/049593 and WO 2005/024336 et al disclose that BCL-XL anti-apoptotic proteins are associated with bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic (lymphoblastic) leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, and the like.
In the treatment of cancer, cancer cells can utilize BCL-XL anti-apoptotic proteins to inhibit the therapeutic effects of traditional chemotherapy, affecting the therapeutic effects. It is also because cancer cells can utilize BCL-XL anti-apoptotic proteins to inhibit the therapeutic effects of traditional chemotherapy, so that the clinician has to increase the dose of chemotherapeutic drugs, which can lead to adverse effects such as nausea, hair loss, etc.
With the intensive research, the BCL-XL anti-apoptosis protein is found to be an anti-tumor therapeutic target with a definite effect. BCL-XL inhibitors can inhibit BCL-XL anti-apoptotic proteins from being over-expressed in a variety of cancer cells, thereby treating cancer.
Besides being used as a target point of anti-tumor treatment, the BCL-XL anti-apoptosis protein is also related to immune system diseases, and the literature Current Allergy & Asthma Reports 2003,3,378-38; british Journal of Haematology 2000,110, 2000,110 (3), 584-90; blood 2000,95 (4), 1283-9 and New England Journal of Medicine 2004,351 (14), 1409-1418 disclose that BCL-XL anti-apoptotic protein overexpression is associated with immune and autoimmune diseases. Thus, BCL-XL inhibitors can treat not only cancer, but also immune and autoimmune diseases.
Therefore, it is of great importance to study a BCL-XL inhibitor with excellent effect.
Disclosure of Invention
The invention aims to provide a BCL-XL inhibitor and application thereof. The BCL-XL inhibitor can inhibit the activity of the BCL-XL anti-apoptosis protein, thereby treating diseases related to the BCL-XL anti-apoptosis protein.
The present invention provides a compound of formula I, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitroxide thereof:
wherein,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 alkylene-O- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 alkylene-NH-CO) - (5-10 membered aromatic ring);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
R 3 selected from hydrogen, -C 1～10 Alkyl, halogen, hydroxy, carboxy, amino, cyano;
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocycle are substituted with 0-3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C) 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), -O- (5-to 10-membered aromatic ring), -C (O) - (5-to 10-membered aromatic ring); or two R's on the same carbon atom 13 Composition = O.
Further, the compound is represented by formula II:
wherein,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 alkylene-O- (5-10)Aromatic ring) -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 alkylene-NH-C (O) - (5-10 membered aromatic rings);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
R 3 selected from hydrogen, -C 1～10 Alkyl, halogen, hydroxy, carboxy, amino, cyano;
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocycle are substituted with 0-3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C) 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), -O- (5-to 10-membered aromatic ring), -C (O) - (5-to 10-membered aromatic ring); or two R's on the same carbon atom 13 Composition = O.
Further, the compound is represented by formula III:
wherein,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered hetero)Cycloalkyl) -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 alkylene-O- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 alkylene-NH-C (O) - (5-10 membered aromatic rings);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-10 membered cycloalkyl), -C 0～4 Alkylene- (3-10 membered heterocycloalkyl), -C 0～4 Alkylene- (5-10 membered aromatic ring), -C 0～4 Alkylene- (5-10 membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocycle are substituted with 0-3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C) 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), -O- (5-to 10-membered aromatic ring), -C (O) - (5-to 10-membered aromatic ring); or two R's on the same carbon atom 13 Composition = O.
Further, the method comprises the steps of,
R 1 selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene- (3-10 membered cycloalkyl), -C 0～2 Alkylene- (3-10 membered heterocycloalkyl), -C 0～2 Alkylene- (5-10 membered aromatic ring), -C 0～2 alkylene-O- (5-10 membered aromatic ring), -C 0～2 Alkylene- (5-10 membered aromatic heterocycle), -C 0～2 alkylene-NH-C (O) - (5-10 membered aromatic rings);
R 2 selected from hydrogen, -C 1～6 Alkyl group,-C 0～2 Alkylene- (3-10 membered cycloalkyl), -C 0～2 Alkylene- (3-10 membered heterocycloalkyl), -C 0～2 Alkylene- (5-10 membered aromatic ring), -C 0～2 Alkylene- (5-10 membered aromatic heterocycle), -C 0～2 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene- (3-10 membered cycloalkyl), -C 0～2 Alkylene- (3-10 membered heterocycloalkyl), -C 0～2 Alkylene- (5-10 membered aromatic ring), -C 0～2 Alkylene- (5-10 membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring is substituted with 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), -O- (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle); or two R's on the same carbon atom 13 Composition = O.
Further, the method comprises the steps of,
R 1 selected from-C 0～2 Alkylene- (3-10 membered cycloalkyl), -C 0～2 Alkylene- (3-10 membered heterocycloalkyl), -C 0～2 Alkylene- (5-10 membered aromatic ring), -C 0～2 alkylene-O- (5-10 membered aromatic ring), -C 0～2 Alkylene- (5-10 membered aromatic heterocycle), -C 0～2 alkylene-NH-C (O) - (5-10 membered aromatic rings);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring is substituted with 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), - (3-10-membered cycloalkyl), - (5-to 10-membered aromatic ring), -O- (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle);
preferably, the method comprises the steps of,
R 1 selected from phenyl group,
The phenyl group,By 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from-C 1～6 Alkyl, -O (C) 1～6 Alkyl), -O-phenyl.
Further, the method comprises the steps of,
R 2 selected from-C 0～2 alkylene-C (O) -R 21 ；
R 21 Selected from-C 1～6 Alkyl, -C 0～2 Alkylene- (3-10 membered cycloalkyl), -C 0～2 Alkylene- (3-10 membered heterocycloalkyl), -C 0～2 Alkylene- (5-10 membered aromatic ring), -C 0～2 Alkylene- (5-10 membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring is substituted with 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -a (3-to 10-membered cycloalkyl); or two R's on the same carbon atom 13 Composition = O;
preferably, the method comprises the steps of,
R 2 selected from the group consisting of-C (O) -R 21 ；
R 21 Selected from-C 1～6 Alkyl, phenyl,
The phenyl group,By 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, -C 1～6 Alkyl, -O (C) 1～6 Alkyl).
Further, the method comprises the steps of,
R 1 selected from the group consisting of
And/or R 2 Selected from the group consisting of
Preferably, the compound is of formula IV:
wherein R is 2 Selected from the group consisting of
Further, the structure of the compound is as follows:
the invention also provides application of the compound, or a salt, or a stereoisomer, or a hydrate, or a solvate, or a prodrug, or a nitrogen oxide of the compound in preparing a BCL-XL inhibitor or preparing a medicament for preventing and/or treating diseases related to the BCL-XL anti-apoptotic protein;
preferably, the disease is cancer, an immune disease or an autoimmune disease.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or nitrogen oxide thereof as an active substance and adding pharmaceutically acceptable auxiliary materials or auxiliary components.
The compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 Alkyl "refers to an alkyl group containing 1 to 4 carbon atoms.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of carbon atoms. For example, C 1～6 Alkyl means having 1 to 6 carbon atoms, e.g. 1, 2, 3,4. Alkyl groups of 5 or 6 carbon atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C 1～6 An alkoxy group.
"cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 10 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems). For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups comprising a multicycloalkyl ring system are dicyclohexyl, dicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:dicyclohexyl and->Dicyclohexyl group.
"heterocycloalkyl" refers to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; including single ring or multiple rings (including fused, bridged and spiro ring systems); wherein the hetero atom refers to nitrogen atom, oxygen atom and sulfur atom.
"aromatic ring" refers to an aromatic unsaturated containing group having 3 to 10 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems), such as phenyl.
"aromatic heterocycle" refers to an aromatic unsaturated ring comprising at least one heteroatom; including single ring or multiple rings (including fused, bridged and spiro ring systems); wherein the hetero atom refers to nitrogen atom, oxygen atom and sulfur atom.
"halogen" is fluorine, chlorine, bromine or iodine.
"halogen substituted alkyl" means that a hydrogen atom in the alkyl group may be substituted with one or more halogen atoms. For example halogen substituted C 1～4 Alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms.
“-C 0～4 Alkylene- (3-to 10-membered cycloalkyl) "means that 0 to 4 alkylene groups are attached to 3-to 10-membered cycloalkyl. Similarly, "-C 0～4 Alkylene- (3-10 membered heterocycloalkyl) "means that 0-4 alkylene groups are linked with 3-10 membered heterocycloalkyl groups; "-C 0～4 Alkylene- (5-10 membered aromatic ring) "means that 0-4 alkylene is connected with 5-10 membered aromatic ring; "-C 0～4 Alkylene- (5-10 membered aromatic heterocycle) "means that 0-4 alkylene is linked to 5-10 membered aromatic heterocycle.
“-C 0～4 alkylene-O- (5-10 membered aromatic ring) "means that after 0-4 alkylene groups are connected with one oxygen atom, the oxygen atom is connected with 5-10 membered aromatic ring; "-C (O) - (5-10 membered aromatic heterocycle)" means that a 5-10 membered aromatic heterocycle is attached to the carbonyl group.
“-C(O)-R 21 The structure of the' is
“-O(C 1～10 Alkyl) "means that C is attached to the oxygen atom 1～10 An alkyl group.
“-NH(C 1～10 Alkyl) "means that the nitrogen atoms are each attached to one hydrogen, one C 1～10 An alkyl group; "-N (C) 1～10 Alkyl) (C) 1～10 Alkyl) "means that the nitrogen atom is attached to two C's respectively 1～10 An alkyl group.
"stereoisomers" include enantiomers and diastereomers.
The salt is a "pharmaceutically acceptable salt" in the present invention.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
The terms "salts" and "pharmaceutically acceptable salts" refer to the acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.
In certain embodiments, one or more compounds of the present invention may be used in combination with one another. The compounds of the invention may alternatively be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to a subject simultaneously, separately or sequentially.
The compound can effectively bind with the BCL-XL anti-apoptosis protein and inhibit the activity of the BCL-XL anti-apoptosis protein; therefore, the anti-apoptosis protein can be used for preventing or treating diseases related to the BCL-XL anti-apoptosis protein, such as cancers, immune diseases, autoimmune diseases and the like. The compound can be used for preparing a BCL-XL inhibitor or preparing a medicine and a medicine composition for preventing or treating diseases related to BCL-XL anti-apoptosis proteins. In addition, the compound has good pharmacological characteristics, good stability and high possibility of patent medicine, and has the advantages of simple preparation, high yield, low cost, high feasibility and good application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a nuclear magnetic resonance apparatus (Bruker Avance III 400 and Bruker Avance 300) using deuterated dimethyl sulfoxide (DMSO-d 6) and deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) uses Gilson GX-281 reverse phase preparative chromatograph. The specification of the thin layer chromatography separation and purification product adopted by the smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from An Naiji chemical, chengkoulochemical, shaoshan chemical technology, carbofuran technology, and the like.
The reaction was carried out under nitrogen atmosphere without specific explanation in examples. The examples are not specifically described, and the solution refers to an aqueous solution. The temperature of the reaction was room temperature, unless otherwise specified in the examples. In the examples, M is mol per liter and% is mass percent, unless otherwise specified.
DCM: dichloromethane;
HATU:2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate;
DIPEA: n, N-diisopropylethylamine;
TFA: trifluoroacetic acid;
THF: tetrahydrofuran;
EDCI: 1-ethyl- (3-dimethylaminopropyl) carbodiimide;
HOBT: 1-hydroxybenzotriazole;
EA: ethyl acetate;
DMF: n, N-dimethylformamide.
Example 1 preparation of Compound A
The preparation and synthesis route of the compound A is as follows:
step 1: preparation of Compound 4
A50 mL reaction flask was charged with Compound 2 (240.00 mg, 998.94. Mu. Mol), compound 3 (185.00 mg, 998.80. Mu. Mol), compound 1 (300.00 mg, 998.80. Mu. Mol) and methanol (2.0 mL) sequentially. The reaction was quenched after stirring at room temperature for 5 hours (LC-MS monitoring). After the reaction solution was distilled under reduced pressure, a saturated NaCl solution (20.0 mL) was added to the system, followed by extraction with ethyl acetate (3X 20.0 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated, followed by purification by MPLC and concentration under reduced pressure to remove the solvent, whereby compound 4 (223.00 mg, 544.60. Mu. Mol, yield 54.53%) was obtained.
Characterization of the compound 4 produced: MS (ESI) M/z=410.2 (m+1) + 。
Step 2: preparation of Compound 5
Into a 50mL reaction flask was sequentially added Compound 4 (223.00 mg, 544.60. Mu. Mol), ac 2 O (55.60 mg, 544.60. Mu. Mol), DIPEA (148.40 mg,1.15 mmol) and dichloromethane (2.0 mL) were reacted with stirring at room temperature for 30 minutes, then the reaction was quenched (LC-MS monitoring), the pH of the system was adjusted to 6-7 with 1N hydrochloric acid solution, and the reaction solution was concentrated to give Compound 5 (245.89 mg, crude product) which was directly used in the next reaction.
Characterization of the compound 5 produced: MS (ESI) M/z=452.1 (m+1) + 。
Step 3: preparation of Compound 6
A50 mL reaction flask was charged with Compound 5 (245.89 mg, crude product), lithium hydroxide hydrate (180.00 mg, 540.00. Mu. Mol), methanol (2.0 mL) and water (2.0 mL) in this order, the reaction was quenched (LC-MS monitoring) after stirring at room temperature for 2 hours, the pH of the system was adjusted to 6.0 to 7.0 with a 1N hydrochloric acid solution, and the reaction mixture was concentrated to give Compound 6 (137.20 mg, 313.61. Mu. Mol, yield 58.08%).
Characterization of the compound 6 produced: MS (ESI) M/z= 438.2 (m+1) + 。
Step 4: preparation of Compound 8
To a 50mL reaction flask, compound 6 (137.20 mg, 313.61. Mu. Mol), DIPEA (222.60 mg,1.72mmol,0.3 mL), HATU (130.00 mg, 313.61. Mu. Mol) and DMF (2.0 mL) were added sequentially, and after the reaction system temperature had dropped to 0 ℃, compound 7 (78.80 mg, 285.12. Mu. Mol) was added, and the reaction was quenched after stirring under ice bath conditions for 1 hour (LC-MS monitoring). After distilling the reaction solution under reduced pressure, a saturated NaCl solution (20.0 mL) was added to the system, followed by extraction with ethyl acetate (3×20.0 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness, followed by concentration under reduced pressure to remove the solvent, whereby compound 8 (218.22 mg, crude product) was obtained.
Characterization of the compound 8 produced: MS (ESI) M/z= 696.3 (m+1) + 。
Step 5: preparation of Compound A
Compound 8 (218.22 mg, crude) was dissolved in a 50mL reaction flask in a mixed solution of 6N HCl and ethyl acetate (5.0 mL), and the mixture was reacted at room temperature for 0.5 hours with stirring, and the solvent was removed by concentration under reduced pressure to give Compound A (20.80 mg, 31.95. Mu. Mol, yield 10.17%).
Characterization of the compound a produced: MS (ESI) M/z= 596.4 (m+1) + 。
1 H NMR(400MHz,CD 3 OD)δ7.56-7.48(m,2H),7.46-7.42(m,2H),7.40-7.34(m,5H),7.29-7.25(m,3H),7.23-7.21(m,2H),7.17-7.09(m,2H),7.04-6.94(m,6H),5.00-4.93(m,2H),4.66-4.49(m,1H),3.39-3.16(m,1H),3.13-3.04(m,2H),3.01-2.96(m,2H),2.94-2.90(m,1H),2.79-2.38(m,2H),2.37-1.91(m,3H).
The beneficial effects of the present invention are demonstrated by specific test examples below.
Test example 1 detection of BCL-XL inhibitory Activity
1. Experimental instrument and reagents:
2. the experimental method comprises the following steps:
dry powder of the compound was dissolved in DMSO to a solution of 10.00mM, and the compound was diluted in a gradient using an instrument ECHO and added to 384-well reaction plates to give a final concentration of DMSO of less than 0.5% in the whole reaction system (12.0. Mu.L).
The BCL-XL and Tag2-BAK were diluted to 4 times the desired final concentration using a Diluent buffer in BCL-XL/BAK Binding Assay Kit, 3.0. Mu.L of BCL-XL and Tag2-BAK solutions were separately pipetted into 384-well reaction plates with the added compounds, centrifuged at 1000rpm for 1 min, and then placed on a microplate for constant volumeThe incubation was performed on a warm shaker at 25℃and 280rpm for 15 minutes. Then using Detection buffer (Lot 10A) in BCL-XL/BAK Binding Assay Kit to make 100X Anti-tag1-Eu 3+ (Lot 06A) and Anti-tag2-XL665 (Lot 104A) were diluted 1x respectively and formulated into Anti-tag1-Eu in a 1:1 ratio 3+ 6.0 mu L of the antibody mixture was pipetted into a 384-well reaction plate, centrifuged at 1000rpm for 1 min, placed on a microplate thermostatted shaker at 25℃at 280rpm and incubated for 2 hours. After the reaction, the microplate reader reads the fluorescence signal value (Flu) in 384-well reaction plates (ex=320 nm; em=665/620 nm; ex represents fluorescence excitation wavelength; em represents fluorescence collection wavelength).
Positive controls (positive controls contained DMSO only, BCL-XL solution, tag2-BAK solution prior to incubation) and negative controls (negative controls contained DMSO and Tag2-BAK solution only prior to incubation) were set.
3. Data analysis
The percent viability remaining for each concentration was calculated as follows:
residual viability (%) =100% × (Flu) Group of compounds -Flu Negative control )/(Flu Positive control -Flu Negative control )
IC was then calculated using GraphPad 5.0 Fit Effect curve 50 Values.
The compounds prepared in the examples and the compound ABT-263 were tested for BCL-XL inhibitory activity according to the methods described above, and the test results are shown in Table 1.
TABLE 1 inhibitory Activity of the Compounds against BCL-XL
The test shows that: the compounds of the invention have inhibitory activity against the BCL-XL protein.
Test example 2, detection of BCL-XL Surface Plasmon Resonance (SPR) binding experiment
1. Experimental instrument and reagents:
2. SPR test method
Preparing running buffer solution: the protein immobilization buffer and the running buffer A have the same composition, wherein NaH 2 PO 4 At a concentration of 10mM, na 2 HPO 4 The concentration is 40mM, the NaCl concentration is 150mM, the Tween20 content is 0.03%, and the pH is adjusted to 7.4; naH in running buffer B 2 OP 4 At a concentration of 10mM, na 2 HOP 4 The concentration was 40mM, the NaCl concentration was 150mM, the Tween20 content was 0.03%, the DMSO content was 5.00%, and the pH was adjusted to 7.4. The running buffer was prepared and filtered through a 0.22 μm filter.
BCL-XL protein immobilization: BCL-XL was immobilized on NTA chips by His capture and amino coupling using protein immobilization buffer. The NTA chip surface is respectively washed by 50mM NaOH and 350mM EDTA, the flow rate is 60.0 mu L/min, and each time is 60 seconds; then use 10mM NiCl 2 Activating for 1100 seconds, and activating for 650 seconds by using a mixture of EDC (75.00 mg/mL) and NHS (11.50 mg/mL) in a volume ratio of 1:1, wherein the activating flow rate is 10.0 mu L/min; BCL-XL (0.04 mg/mL) was then injected at 4.0. Mu.L/min for 850 seconds. After the end of BCL-XL injection, a 1:1 volume ratio of EDC (75.00 mg/mL) and NHS (11.50 mg/mL) mixture was crosslinked at a rate of 10.0. Mu.L/min for 200 seconds, and finally the chip surface was blocked by 1M ethanolamine (pH 8.5) injection at a rate of 6.0. Mu.L/min for 7 minutes. The final fixed amount of BCL-XL was 4690.00RU.
Compound dilution: test compounds were diluted with 100% dmso to 100 times the desired final concentration, mixed well and then pipetted into 4.0 μl and added to 396 μl running buffer a, and centrifuged at 15000rpm for 5 minutes to give a 1X compound solution containing 1% dmso for subsequent dilution. Compound a was serially diluted 2-fold for 9 concentrations starting from 50 μm (200 μl of compound solution was added to 200 μl of running buffer solution B for 2-fold dilution, for a total of 10 concentration gradients, containing 1 concentration 0 (replaced with running buffer solution B), starting at 50 μm). The diluted compounds were transferred to 96-well plates for sample introduction.
Running a program: the experiment was run at 25℃using run buffer B at a flow rate of 30.0. Mu.L/min. After the buffer B is run for 8 times to finish the balance, the compounds are sequentially injected from the lowest concentration to the highest concentration, the combination time and the dissociation time are 120 seconds, and the injection needle is cleaned by 50% DMSO after each injection. The solvent differences caused by DMSO were corrected by 0.50%,0.75%,1.00%,1.25% and 1.50% DMSO.
3. Data analysis
The response of the compounds to BCL-XL binding was analyzed after subtraction of the reference channel and 0 concentration, and affinity Kd was fitted by Biacore T200 Evaluation Software with steady state affinity model (1:1 binding model).
The SPR test was performed on the prepared compounds according to the above method, and the test results are shown in Table 2.
TABLE 2 binding response values of compounds to BCL-XL
The test shows that: the compounds of the invention have binding activity to the BCL-XL protein.
In conclusion, the compound disclosed by the invention can be effectively combined with the BCL-XL anti-apoptosis protein to inhibit the activity of the BCL-XL anti-apoptosis protein; therefore, the anti-apoptosis protein can be used for preventing or treating diseases related to the BCL-XL anti-apoptosis protein, such as cancers, immune diseases, autoimmune diseases and the like. The compound can be used for preparing a BCL-XL inhibitor or preparing a medicine and a medicine composition for preventing or treating diseases related to BCL-XL anti-apoptosis proteins. In addition, the compound has good pharmacological characteristics, good stability and high possibility of patent medicine, and has the advantages of simple preparation, high yield, low cost, high feasibility and good application prospect.
Claims (7)
1. A compound or salt thereof, characterized in that: the compound is shown in a formula III:
wherein,
R 1 selected from phenyl;
the phenyl group is substituted with 1R 13 Substitution;
R 13 selected from-O-phenyl;
R 2 selected from-C 0～2 alkylene-C (O) -R 21 ；
R 21 Selected from-C 1～6 An alkyl group.
2. A compound or salt thereof according to claim 1, wherein:
R 2 selected from the group consisting of-C (O) -R 21 ；
R 21 Selected from-C 1～6 An alkyl group.
3. A compound or salt thereof according to claim 1 or 2, characterized in that: the structure of the compound is as follows:
4. use of a compound according to any one of claims 1 to 3, or a salt thereof, for the preparation of a BCL-XL inhibitor.
5. Use of a compound according to any one of claims 1 to 3 or a salt thereof for the manufacture of a medicament for the prophylaxis and/or treatment of a disease associated with BCL-XL anti-apoptotic proteins.
6. Use according to claim 5, characterized in that: the disease is cancer, an immune disease or an autoimmune disease.
7. A pharmaceutical composition characterized by: a preparation prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components into the compound or salt thereof as an active substance in any one of claims 1 to 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110524420.XA CN115340499B (en) | 2021-05-13 | 2021-05-13 | BCL-XL inhibitors and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110524420.XA CN115340499B (en) | 2021-05-13 | 2021-05-13 | BCL-XL inhibitors and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115340499A CN115340499A (en) | 2022-11-15 |
| CN115340499B true CN115340499B (en) | 2024-02-23 |
Family
ID=83947143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110524420.XA Active CN115340499B (en) | 2021-05-13 | 2021-05-13 | BCL-XL inhibitors and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115340499B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6720338B2 (en) * | 2000-09-20 | 2004-04-13 | Abbott Laboratories | N-acylsulfonamide apoptosis promoters |
-
2021
- 2021-05-13 CN CN202110524420.XA patent/CN115340499B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL;Bruncko, Milan等;Journal of Medicinal Chemistry;第50卷(第4期);641-662 * |
| The ewing family of tumors relies on BCL-2 and BCL-XL to escape PARP inhibitor toxicity;Heisey, Daniel A. R.等;Clinical Cancer Research;第25卷(第5期);1664-1675 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115340499A (en) | 2022-11-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113563323B (en) | Benzothiazolyl biaryl compound, preparation method and application | |
| JP6913274B2 (en) | Crystal form of BTK kinase inhibitor and its production method | |
| CA3149963A1 (en) | Heterocyclic rip1 kinase inhibitors | |
| JPWO2018143315A1 (en) | Quinazoline compounds | |
| CN110092745B (en) | Compound containing aromatic ring and application thereof | |
| RU2633694C2 (en) | Dyetherned phenylaminopyrimidine and pharmaceutical composition containing such connection | |
| TWI788424B (en) | Receptor inhibitor | |
| CN113527299B (en) | Nitrogen-containing condensed ring compound, preparation method and application | |
| EP3661935B1 (en) | Substituted pyrazolopyrimidines useful as kinases inhibitors | |
| CN113683616A (en) | KRAS G12C mutein inhibitors | |
| WO2024040768A1 (en) | 5-pyridine-1h-indazole compound, pharmaceutical composition, and use | |
| CN115991706A (en) | PIM kinase inhibitors | |
| CN116375707A (en) | Menin inhibitors and uses thereof | |
| CN114591351B (en) | Polycyclic compound and preparation method and application thereof | |
| CN105503863A (en) | Novel anti-tumor compound | |
| CN110869371B (en) | 7-substituted pyrrolotriazine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof | |
| WO2021129841A1 (en) | Compound used as ret kinase inhibitor and application thereof | |
| CN115340499B (en) | BCL-XL inhibitors and uses thereof | |
| CN114907387B (en) | Pyrimido pyrrole KRAS inhibitor and preparation method and application thereof | |
| CN113979999B (en) | Compound for targeted ubiquitination degradation of BCR-ABL kinase and preparation method, composition and application thereof | |
| CN109081818B (en) | Novel indoleamine 2, 3-bis-oxidase inhibitors | |
| CN115340502B (en) | BCL-XL inhibitor and preparation method and application thereof | |
| CN111747927B (en) | Compounds as immunomodulators and uses thereof | |
| CN112020357B (en) | Salt of indazolyl-containing tricyclic derivative and crystal form thereof | |
| CN115340527B (en) | BCL-XL inhibitor and preparation method 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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |