CN114269753B - Nitrogen-containing bicyclic compound, pharmaceutical composition containing same, preparation method and application thereof - Google Patents
Nitrogen-containing bicyclic compound, pharmaceutical composition containing same, preparation method and application thereof Download PDFInfo
- Publication number
- CN114269753B CN114269753B CN202080055686.8A CN202080055686A CN114269753B CN 114269753 B CN114269753 B CN 114269753B CN 202080055686 A CN202080055686 A CN 202080055686A CN 114269753 B CN114269753 B CN 114269753B
- Authority
- CN
- China
- Prior art keywords
- compound
- membered
- formulsup
- alkyl
- pyrazol
- 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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 Nitrogen-containing bicyclic compound Chemical class 0.000 title claims description 161
- 150000001875 compounds Chemical class 0.000 claims abstract description 275
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 claims abstract description 55
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 claims abstract description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 162
- 125000000623 heterocyclic group Chemical group 0.000 claims description 135
- 238000006243 chemical reaction Methods 0.000 claims description 101
- 125000001424 substituent group Chemical group 0.000 claims description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 65
- 150000002431 hydrogen Chemical class 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 36
- 239000000460 chlorine Substances 0.000 claims description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 239000000556 agonist Substances 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 22
- 238000005859 coupling reaction Methods 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 238000005658 halogenation reaction Methods 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 4
- 238000006192 iodination reaction Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229940125670 thienopyridine Drugs 0.000 claims description 4
- 239000002175 thienopyridine Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- 206010005949 Bone cancer Diseases 0.000 claims 1
- 208000018084 Bone neoplasm Diseases 0.000 claims 1
- 208000003174 Brain Neoplasms Diseases 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 1
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 208000003445 Mouth Neoplasms Diseases 0.000 claims 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000000453 Skin Neoplasms Diseases 0.000 claims 1
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- 201000010881 cervical cancer Diseases 0.000 claims 1
- 208000029742 colonic neoplasm Diseases 0.000 claims 1
- 201000004101 esophageal cancer Diseases 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 201000010982 kidney cancer Diseases 0.000 claims 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 206010038038 rectal cancer Diseases 0.000 claims 1
- 201000001275 rectum cancer Diseases 0.000 claims 1
- 201000000849 skin cancer Diseases 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 14
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 150000001923 cyclic compounds Chemical class 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- 125000003545 alkoxy group Chemical group 0.000 description 117
- 125000003118 aryl group Chemical group 0.000 description 102
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 97
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 90
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 77
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 75
- 229910052736 halogen Inorganic materials 0.000 description 69
- 150000002367 halogens Chemical class 0.000 description 69
- 238000004949 mass spectrometry Methods 0.000 description 65
- 125000004093 cyano group Chemical group *C#N 0.000 description 64
- 238000003786 synthesis reaction Methods 0.000 description 62
- 230000015572 biosynthetic process Effects 0.000 description 61
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- 210000004027 cell Anatomy 0.000 description 44
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- 239000003480 eluent Substances 0.000 description 40
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 40
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 39
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 38
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 36
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 34
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
- 125000004432 carbon atom Chemical group C* 0.000 description 32
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- 238000002953 preparative HPLC Methods 0.000 description 28
- 239000002904 solvent Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 25
- 125000004122 cyclic group Chemical group 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000010438 heat treatment Methods 0.000 description 21
- 238000003818 flash chromatography Methods 0.000 description 20
- 229910052717 sulfur Inorganic materials 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000000753 cycloalkyl group Chemical group 0.000 description 18
- 125000002993 cycloalkylene group Chemical group 0.000 description 18
- 229910052760 oxygen Inorganic materials 0.000 description 18
- 125000004429 atom Chemical group 0.000 description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 17
- 239000001301 oxygen Chemical group 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 16
- 125000002947 alkylene group Chemical group 0.000 description 16
- 239000011593 sulfur Chemical group 0.000 description 16
- 125000004450 alkenylene group Chemical group 0.000 description 15
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 15
- 238000010828 elution Methods 0.000 description 15
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 15
- 125000006587 (C5-C10) heteroarylene group Chemical group 0.000 description 14
- 125000004419 alkynylene group Chemical group 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 13
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 13
- 125000000732 arylene group Chemical group 0.000 description 13
- 239000007810 chemical reaction solvent Substances 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 11
- 230000008484 agonism Effects 0.000 description 11
- 239000012091 fetal bovine serum Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 10
- 230000002757 inflammatory effect Effects 0.000 description 10
- 125000002950 monocyclic group Chemical group 0.000 description 10
- 125000003367 polycyclic group Chemical group 0.000 description 10
- 125000006413 ring segment Chemical group 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 229940125782 compound 2 Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000005089 Luciferase Substances 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 150000001204 N-oxides Chemical class 0.000 description 7
- 239000012980 RPMI-1640 medium Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 235000011056 potassium acetate Nutrition 0.000 description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 description 7
- 235000011009 potassium phosphates Nutrition 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- 102000003777 Interleukin-1 beta Human genes 0.000 description 6
- 108090000193 Interleukin-1 beta Proteins 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 6
- 238000006619 Stille reaction Methods 0.000 description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000004327 boric acid Substances 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 239000004031 partial agonist Substances 0.000 description 6
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 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 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 125000005605 benzo group Chemical group 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 4
- FNVOFDGAASRDQY-UHFFFAOYSA-N 3-amino-2,2-dimethylpropan-1-ol Chemical compound NCC(C)(C)CO FNVOFDGAASRDQY-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 4
- 108090000426 Caspase-1 Proteins 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000001464 adherent effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052785 arsenic Chemical group 0.000 description 4
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical group [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 4
- 229910052796 boron Inorganic materials 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- 208000026278 immune system disease Diseases 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 238000006317 isomerization reaction Methods 0.000 description 4
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 4
- 239000011574 phosphorus Chemical group 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 3
- ZZRFDLHBMBHJTI-UHFFFAOYSA-N 1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NN1C1OCCCC1 ZZRFDLHBMBHJTI-UHFFFAOYSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-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
- BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 3
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 3
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 3
- ZVQAOTYDHWJNCG-UHFFFAOYSA-N CC(C)(C)NC1=NC2=C(C(=C1)NCC3(COC3)CO)SC(=C2)C4=CC=NN4 Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCC3(COC3)CO)SC(=C2)C4=CC=NN4 ZVQAOTYDHWJNCG-UHFFFAOYSA-N 0.000 description 3
- CLIVTVVMXQJJCX-CYBMUJFWSA-N CC(C)C[C@H](CO)NC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NC(C)(C)C Chemical compound CC(C)C[C@H](CO)NC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NC(C)(C)C CLIVTVVMXQJJCX-CYBMUJFWSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 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 3
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 230000003698 anagen phase Effects 0.000 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 229940126208 compound 22 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 description 3
- 125000005549 heteroarylene group Chemical group 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 3
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 3
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- DYQNDIAFNAKKRC-UHFFFAOYSA-N 3-[[5-(tert-butylamino)-2-(6-methylpyridin-2-yl)thieno[3,2-b]pyridin-7-yl]amino]propan-1-ol Chemical compound CC1=NC(=CC=C1)C2=CC3=C(S2)C(=CC(=N3)NC(C)(C)C)NCCCO DYQNDIAFNAKKRC-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- GRKLVIJTAMVLJL-UHFFFAOYSA-N 7-bromo-N-tert-butyl-2-[2-(oxan-2-yl)pyrazol-3-yl]thieno[3,2-b]pyridin-5-amine Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)Br)SC(=C2)C3=CC=NN3C4CCCCO4 GRKLVIJTAMVLJL-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- UJWDDBLGXTYFGO-UHFFFAOYSA-N CC(C)(C)NC1=NC2=C(C(=C1)NCC(=O)NC3CC3)SC(=C2)C4=CC=NN4 Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCC(=O)NC3CC3)SC(=C2)C4=CC=NN4 UJWDDBLGXTYFGO-UHFFFAOYSA-N 0.000 description 2
- HLKOVCWAKBVYCV-UHFFFAOYSA-N CC(C)(C)NC1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3 Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3 HLKOVCWAKBVYCV-UHFFFAOYSA-N 0.000 description 2
- YDRWCUNLTIMHAB-UHFFFAOYSA-N CC(C)(C)NC1=NC2=C(C(=C1)NCC(CO)COC)SC(=C2)C3=CC=NN3 Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCC(CO)COC)SC(=C2)C3=CC=NN3 YDRWCUNLTIMHAB-UHFFFAOYSA-N 0.000 description 2
- XDQJQFGEXBIWFX-UHFFFAOYSA-N CC(C)(C)NC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 XDQJQFGEXBIWFX-UHFFFAOYSA-N 0.000 description 2
- GIDZNLGZXPVRIK-UHFFFAOYSA-N CC(C)(C)NC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3C4CCCCO4 Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3C4CCCCO4 GIDZNLGZXPVRIK-UHFFFAOYSA-N 0.000 description 2
- BNCOVEIBWXYLLW-UHFFFAOYSA-N CC(C)(C)NC1=NC2=C(C(=C1)NCCN3CCCC3=O)SC(=C2)C4=CC=NN4 Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCCN3CCCC3=O)SC(=C2)C4=CC=NN4 BNCOVEIBWXYLLW-UHFFFAOYSA-N 0.000 description 2
- UTENJBJNSZMUIZ-UHFFFAOYSA-N CC(C)(CNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)N4CCCC4)CO Chemical compound CC(C)(CNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)N4CCCC4)CO UTENJBJNSZMUIZ-UHFFFAOYSA-N 0.000 description 2
- LTOSAFKMIDPSIZ-UHFFFAOYSA-N CC(C)NC1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3 Chemical compound CC(C)NC1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3 LTOSAFKMIDPSIZ-UHFFFAOYSA-N 0.000 description 2
- 102100035904 Caspase-1 Human genes 0.000 description 2
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 101001109465 Homo sapiens NACHT, LRR and PYD domains-containing protein 3 Proteins 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 description 2
- 102000012064 NLR Proteins Human genes 0.000 description 2
- 108091005686 NOD-like receptors Proteins 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000001270 agonistic effect Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000013060 biological fluid Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229940078916 carbamide peroxide Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- KLVXXFGBNUEIES-UHFFFAOYSA-N thieno[3,2-b]pyridin-5-amine Chemical compound NC1=CC=C2SC=CC2=N1 KLVXXFGBNUEIES-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- LAJAFFLJAJMYLK-CVOKMOJFSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[[(7s)-4-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5h-benzo[7]annulen-3-yl]amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N1([C@H]2CCC3=CC=C(C(=C3CC2)OC)NC=2N=C(C(=CN=2)Cl)N[C@H]2[C@H]([C@@]3([H])C[C@@]2(C=C3)[H])C(N)=O)CCOCC1 LAJAFFLJAJMYLK-CVOKMOJFSA-N 0.000 description 1
- SRJUGZIEGNWPEX-LIXIDFRTSA-N (2R)-2-[[5-(tert-butylamino)-2-[2-(oxan-2-yl)pyrazol-3-yl]thieno[3,2-b]pyridin-7-yl]amino]-4-methylpentan-1-ol Chemical compound CC(C)C[C@H](CO)NC1=CC(=NC2=C1SC(=C2)C3=CC=NN3C4CCCCO4)NC(C)(C)C SRJUGZIEGNWPEX-LIXIDFRTSA-N 0.000 description 1
- NXMXETCTWNXSFG-SCSAIBSYSA-N (2r)-1-methoxypropan-2-amine Chemical compound COC[C@@H](C)N NXMXETCTWNXSFG-SCSAIBSYSA-N 0.000 description 1
- VPSSPAXIFBTOHY-ZCFIWIBFSA-N (2r)-2-amino-4-methylpentan-1-ol Chemical compound CC(C)C[C@@H](N)CO VPSSPAXIFBTOHY-ZCFIWIBFSA-N 0.000 description 1
- RXEGAVWOPSLNLG-UHFFFAOYSA-N (3-methylpyridin-2-yl)methanamine;hydrochloride Chemical compound Cl.CC1=CC=CN=C1CN RXEGAVWOPSLNLG-UHFFFAOYSA-N 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- XHSGIZRXEBIOFC-UHFFFAOYSA-N (6-methylpyridin-2-yl)boronic acid Chemical compound CC1=CC=CC(B(O)O)=N1 XHSGIZRXEBIOFC-UHFFFAOYSA-N 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- WZHOBXRNVCZJGB-UHFFFAOYSA-N 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CN1N=C(C)C=C1B1OC(C)(C)C(C)(C)O1 WZHOBXRNVCZJGB-UHFFFAOYSA-N 0.000 description 1
- HHEKNWQXFVOUNJ-UHFFFAOYSA-N 1-(2-aminoethyl)pyrrolidin-2-one Chemical compound NCCN1CCCC1=O HHEKNWQXFVOUNJ-UHFFFAOYSA-N 0.000 description 1
- ARUCEOOEVJYWKL-UHFFFAOYSA-N 1-[2-[[5-(tert-butylamino)-2-[2-(oxan-2-yl)pyrazol-3-yl]thieno[3,2-b]pyridin-7-yl]amino]ethyl]pyrrolidin-2-one Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCCN3CCCC3=O)SC(=C2)C4=CC=NN4C5CCCCO5 ARUCEOOEVJYWKL-UHFFFAOYSA-N 0.000 description 1
- ZFNNBIMQDHBELV-UHFFFAOYSA-N 1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(3-cyclohexylpropoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;dihydrochloride Chemical compound Cl.Cl.CC(C)C=1C=C(N)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C(C=1)=CC=CC=1OCCCC1CCCCC1 ZFNNBIMQDHBELV-UHFFFAOYSA-N 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical compound CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 description 1
- YXJQNNIQEUQOPV-UHFFFAOYSA-N 2-[[5-(tert-butylamino)-2-[2-(oxan-2-yl)pyrazol-3-yl]thieno[3,2-b]pyridin-7-yl]-methylamino]ethanol Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)N(C)CCO)SC(=C2)C3=CC=NN3C4CCCCO4 YXJQNNIQEUQOPV-UHFFFAOYSA-N 0.000 description 1
- YWSVVGHXDFDLLC-UHFFFAOYSA-N 2-[[5-(tert-butylamino)-2-[2-(oxan-2-yl)pyrazol-3-yl]thieno[3,2-b]pyridin-7-yl]amino]-N-cyclopropylacetamide Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCC(=O)NC3CC3)SC(=C2)C4=CC=NN4C5CCCCO5 YWSVVGHXDFDLLC-UHFFFAOYSA-N 0.000 description 1
- CAYSWNDCZRTXGL-UHFFFAOYSA-N 2-amino-n-cyclopropylacetamide Chemical compound NCC(=O)NC1CC1 CAYSWNDCZRTXGL-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- HCLQARMRCPEALF-DNQXCXABSA-N 3-[[(2r)-2-[(1r)-2-[[1-(1-benzothiophen-2-yl)-2-methylpropan-2-yl]amino]-1-hydroxyethyl]pyrrolidin-1-yl]methyl]benzonitrile Chemical compound C([C@@H]1[C@H](O)CNC(C)(CC=2SC3=CC=CC=C3C=2)C)CCN1CC1=CC=CC(C#N)=C1 HCLQARMRCPEALF-DNQXCXABSA-N 0.000 description 1
- PMTZNINCNYCSGH-UHFFFAOYSA-N 3-[[5-(tert-butylamino)-2-[2-(oxan-2-yl)pyrazol-3-yl]thieno[3,2-b]pyridin-7-yl]amino]-2,2-dimethylpropan-1-ol Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3C4CCCCO4 PMTZNINCNYCSGH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- JHNLZOVBAQWGQU-UHFFFAOYSA-N 380814_sial Chemical compound CS(O)(=O)=O.O=P(=O)OP(=O)=O JHNLZOVBAQWGQU-UHFFFAOYSA-N 0.000 description 1
- IMLXLGZJLAOKJN-UHFFFAOYSA-N 4-aminocyclohexan-1-ol Chemical compound NC1CCC(O)CC1 IMLXLGZJLAOKJN-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- TWSVRCKEKXQBIG-UHFFFAOYSA-N 7-bromo-2-iodo-4-oxidothieno[3,2-b]pyridin-4-ium Chemical compound C1=C[N+](=C2C=C(SC2=C1Br)I)[O-] TWSVRCKEKXQBIG-UHFFFAOYSA-N 0.000 description 1
- WVBQGXIQHADWQB-UHFFFAOYSA-N 7-bromo-2-iodothieno[3,2-b]pyridine Chemical compound C1=CN=C2C=C(SC2=C1Br)I WVBQGXIQHADWQB-UHFFFAOYSA-N 0.000 description 1
- VSURMXXZFVIXEC-UHFFFAOYSA-N 7-bromo-N-tert-butyl-2-(6-methylpyridin-2-yl)thieno[3,2-b]pyridin-5-amine Chemical compound CC1=NC(=CC=C1)C2=CC3=C(S2)C(=CC(=N3)NC(C)(C)C)Br VSURMXXZFVIXEC-UHFFFAOYSA-N 0.000 description 1
- CHEUHZVDYAOOPF-UHFFFAOYSA-N 7-bromo-N-tert-butyl-2-iodothieno[3,2-b]pyridin-5-amine Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)Br)SC(=C2)I CHEUHZVDYAOOPF-UHFFFAOYSA-N 0.000 description 1
- NLHODWKWTMTFEN-UHFFFAOYSA-N 7-bromothieno[3,2-b]pyridine Chemical compound BrC1=CC=NC2=C1SC=C2 NLHODWKWTMTFEN-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 102100029647 Apoptosis-associated speck-like protein containing a CARD Human genes 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- IZODQFZXPZJSOA-UHFFFAOYSA-N C1=C(NN=C1)C2=CC3=C(S2)C(=CC(=N3)NCC(=O)O)NCC(F)F Chemical compound C1=C(NN=C1)C2=CC3=C(S2)C(=CC(=N3)NCC(=O)O)NCC(F)F IZODQFZXPZJSOA-UHFFFAOYSA-N 0.000 description 1
- SDLFGIZSEGLAPJ-UHFFFAOYSA-N C1=C(NN=C1)C2=CC3=C(S2)C(=CC(=N3)NCCO)NCC(F)F Chemical compound C1=C(NN=C1)C2=CC3=C(S2)C(=CC(=N3)NCCO)NCC(F)F SDLFGIZSEGLAPJ-UHFFFAOYSA-N 0.000 description 1
- LTTIMPNPJHNWGN-UHFFFAOYSA-N C1=C(NN=C1)C2=CC3=C(S2)C(=CC(=N3)NCCO)NCCCO Chemical compound C1=C(NN=C1)C2=CC3=C(S2)C(=CC(=N3)NCCO)NCCCO LTTIMPNPJHNWGN-UHFFFAOYSA-N 0.000 description 1
- BHNIBMKCWNUUCF-UHFFFAOYSA-N C1CC1CNC2=CC(=NC3=C2SC(=C3)C4=CC=NN4)NCC(=O)O Chemical compound C1CC1CNC2=CC(=NC3=C2SC(=C3)C4=CC=NN4)NCC(=O)O BHNIBMKCWNUUCF-UHFFFAOYSA-N 0.000 description 1
- UJEFMSLAMIKRPU-UHFFFAOYSA-N C1CC1CNC2=CC(=NC3=C2SC(=C3)C4=CC=NN4)NCCO Chemical compound C1CC1CNC2=CC(=NC3=C2SC(=C3)C4=CC=NN4)NCCO UJEFMSLAMIKRPU-UHFFFAOYSA-N 0.000 description 1
- LHNISQAPVMKSLS-UHFFFAOYSA-N C1CC1NC2=NC3=C(C(=C2)NCCCO)SC(=C3)C4=CC=NN4 Chemical compound C1CC1NC2=NC3=C(C(=C2)NCCCO)SC(=C3)C4=CC=NN4 LHNISQAPVMKSLS-UHFFFAOYSA-N 0.000 description 1
- XYKYYGFUBJFSLW-UHFFFAOYSA-N C1CCN(C1)C2=NC3=C(C(=C2)Br)SC(=C3)I Chemical compound C1CCN(C1)C2=NC3=C(C(=C2)Br)SC(=C3)I XYKYYGFUBJFSLW-UHFFFAOYSA-N 0.000 description 1
- OZFKIEAFUSCNED-UHFFFAOYSA-N C1CCN(C1)C2=NC3=C(C(=C2)NCC(F)F)SC(=C3)C4=CC=NN4 Chemical compound C1CCN(C1)C2=NC3=C(C(=C2)NCC(F)F)SC(=C3)C4=CC=NN4 OZFKIEAFUSCNED-UHFFFAOYSA-N 0.000 description 1
- FKJGTRHPHKWICK-UHFFFAOYSA-N CC(C)(C)NC1=NC2=C(C(=C1)NCCC(C)(C)O)SC(=C2)C3=CC=NN3 Chemical compound CC(C)(C)NC1=NC2=C(C(=C1)NCCC(C)(C)O)SC(=C2)C3=CC=NN3 FKJGTRHPHKWICK-UHFFFAOYSA-N 0.000 description 1
- RDUSIGCYMBKSCP-BYULHYEWSA-N CC(C)(C)[C@@](C1)([C@H]2CN1C(O)=O)[C@H]2N Chemical compound CC(C)(C)[C@@](C1)([C@H]2CN1C(O)=O)[C@H]2N RDUSIGCYMBKSCP-BYULHYEWSA-N 0.000 description 1
- WMFJXPHYQQRDEU-UHFFFAOYSA-N CC(C)(CNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)N(C)C)CO Chemical compound CC(C)(CNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)N(C)C)CO WMFJXPHYQQRDEU-UHFFFAOYSA-N 0.000 description 1
- GRERYRKLAPJPOW-UHFFFAOYSA-N CC(C)(CNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NC)CO Chemical compound CC(C)(CNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NC)CO GRERYRKLAPJPOW-UHFFFAOYSA-N 0.000 description 1
- URZMGJCJOORCOM-UHFFFAOYSA-N CC(C)(CNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NC4CC4)CO Chemical compound CC(C)(CNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NC4CC4)CO URZMGJCJOORCOM-UHFFFAOYSA-N 0.000 description 1
- MIQDLEUSZULLGV-UHFFFAOYSA-N CC(C)NC(C=C1Br)=NC2=C1SC(C1=CC=NN1C1OCCCC1)=C2 Chemical compound CC(C)NC(C=C1Br)=NC2=C1SC(C1=CC=NN1C1OCCCC1)=C2 MIQDLEUSZULLGV-UHFFFAOYSA-N 0.000 description 1
- MCBKWBRTWCLRKM-UHFFFAOYSA-N CC(C)NC1=NC2=C(C(=C1)Br)SC(=C2)I Chemical compound CC(C)NC1=NC2=C(C(=C1)Br)SC(=C2)I MCBKWBRTWCLRKM-UHFFFAOYSA-N 0.000 description 1
- LQWRAKZHWTXPSR-UHFFFAOYSA-N CC(C)NC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 Chemical compound CC(C)NC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 LQWRAKZHWTXPSR-UHFFFAOYSA-N 0.000 description 1
- FJLWQIXBFHCILG-UHFFFAOYSA-N CC1=NN(C(=C1)C2=CC3=C(S2)C(=CC(=N3)NC(C)(C)C)Br)C Chemical compound CC1=NN(C(=C1)C2=CC3=C(S2)C(=CC(=N3)NC(C)(C)C)Br)C FJLWQIXBFHCILG-UHFFFAOYSA-N 0.000 description 1
- VHCOYFMFCXGJTI-UHFFFAOYSA-N CC1=NN(C(=C1)C2=CC3=C(S2)C(=CC(=N3)NC(C)(C)C)NCCCO)C Chemical compound CC1=NN(C(=C1)C2=CC3=C(S2)C(=CC(=N3)NC(C)(C)C)NCCCO)C VHCOYFMFCXGJTI-UHFFFAOYSA-N 0.000 description 1
- BOJRATQGNWKMJR-UHFFFAOYSA-N CCN(CC)C1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3 Chemical compound CCN(CC)C1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3 BOJRATQGNWKMJR-UHFFFAOYSA-N 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
- HGMUBRXZNRXLSR-UHFFFAOYSA-N CCNC1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3 Chemical compound CCNC1=NC2=C(C(=C1)NCC(C)(C)CO)SC(=C2)C3=CC=NN3 HGMUBRXZNRXLSR-UHFFFAOYSA-N 0.000 description 1
- YDEJACOVMZGTBA-UHFFFAOYSA-N CCNC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 Chemical compound CCNC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 YDEJACOVMZGTBA-UHFFFAOYSA-N 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- YJKNKBCLDYJVKZ-UHFFFAOYSA-N CN(C)C1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 Chemical compound CN(C)C1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 YJKNKBCLDYJVKZ-UHFFFAOYSA-N 0.000 description 1
- MDDHRXVXAMWKQX-UHFFFAOYSA-N CNC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 Chemical compound CNC1=NC2=C(C(=C1)NCCCO)SC(=C2)C3=CC=NN3 MDDHRXVXAMWKQX-UHFFFAOYSA-N 0.000 description 1
- UICNPFWUBITUMN-UHFFFAOYSA-N COCCNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)N4CCCC4 Chemical compound COCCNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)N4CCCC4 UICNPFWUBITUMN-UHFFFAOYSA-N 0.000 description 1
- VKRKSJIISYZTRM-UHFFFAOYSA-N COCCNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NCC(=O)O Chemical compound COCCNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NCC(=O)O VKRKSJIISYZTRM-UHFFFAOYSA-N 0.000 description 1
- INGDCEGZSRVXQV-UHFFFAOYSA-N COCCNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NCCO Chemical compound COCCNC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NCCO INGDCEGZSRVXQV-UHFFFAOYSA-N 0.000 description 1
- JOVHJSKYMAFZPA-LLVKDONJSA-N C[C@H](COC)NC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NC(C)(C)C Chemical compound C[C@H](COC)NC1=CC(=NC2=C1SC(=C2)C3=CC=NN3)NC(C)(C)C JOVHJSKYMAFZPA-LLVKDONJSA-N 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- 238000002965 ELISA Methods 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 1
- 101001074035 Homo sapiens Zinc finger protein GLI2 Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010027457 Metastases to liver Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108010044012 STAT1 Transcription Factor Proteins 0.000 description 1
- 102100029904 Signal transducer and activator of transcription 1-alpha/beta Human genes 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005529 alkyleneoxy group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000008485 antagonism Effects 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
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- KKTCWAXMXADOBB-UHFFFAOYSA-N azanium;hydrogen carbonate;hydrate Chemical compound [NH4+].O.OC([O-])=O KKTCWAXMXADOBB-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- AJRQIXBBIDPNGK-BVSLBCMMSA-N benzyl n-[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(=O)OCC1=CC=CC=C1 AJRQIXBBIDPNGK-BVSLBCMMSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000004976 cyclobutylene group Chemical group 0.000 description 1
- LQNHRNOPWKZUSN-UHFFFAOYSA-N cyclobutylmethanamine Chemical compound NCC1CCC1 LQNHRNOPWKZUSN-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004977 cycloheptylene group Chemical group 0.000 description 1
- 125000005725 cyclohexenylene group Chemical group 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
- 125000004956 cyclohexylene group Chemical group 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([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
- 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
- 125000004978 cyclooctylene group Chemical group 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
- 125000004979 cyclopentylene group Chemical group 0.000 description 1
- 125000004980 cyclopropylene group Chemical group 0.000 description 1
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 102000045720 human TLR8 Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229940088592 immunologic factor Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000012336 iodinating agent Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 238000000048 melt cooling Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- WGLUNLJVYNJMBU-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]-n-[(3-methyl-1-oxo-2,4-dihydroisoquinolin-3-yl)methyl]decanamide Chemical compound C1=CC=C2C(=O)NC(CN(CCN(C)C)C(=O)CCCCCCCCC)(C)CC2=C1 WGLUNLJVYNJMBU-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- IPBPLHNLRKRLPJ-UHFFFAOYSA-N oxan-4-ylmethanamine Chemical compound NCC1CCOCC1 IPBPLHNLRKRLPJ-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- OJEOJUQOECNDND-UHFFFAOYSA-N oxetan-3-amine Chemical compound NC1COC1 OJEOJUQOECNDND-UHFFFAOYSA-N 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004351 phenylcyclohexyl group Chemical group C1(=CC=CC=C1)C1(CCCCC1)* 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 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
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 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
- 230000028327 secretion Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- LZCVVMQABORALM-UHFFFAOYSA-N spiro[2.5]octyl Chemical group [CH]1CC11CCCCC1 LZCVVMQABORALM-UHFFFAOYSA-N 0.000 description 1
- GAJDDVONBAWAGB-UHFFFAOYSA-N spiro[2.6]nonyl Chemical group [CH]1CC11CCCCCC1 GAJDDVONBAWAGB-UHFFFAOYSA-N 0.000 description 1
- LMUMMJCCZMWLEN-UHFFFAOYSA-N spiro[3.3]heptyl Chemical group [CH]1CCC11CCC1 LMUMMJCCZMWLEN-UHFFFAOYSA-N 0.000 description 1
- 210000001324 spliceosome Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the field of pharmaceutical chemistry, and relates to a nitrogen-containing and cyclic compound, a pharmaceutical composition containing the same, a preparation method and application thereof. Specifically, the invention provides a compound with a structure shown in a formula II, which has a remarkable NLRP3 regulating effect, can be used as a high-efficiency NLRP3 regulator, and has anti-tumor activity.
Description
Citation of related application
The present invention claims that was filed in china on the date 9 and 29 of 2019, entitled "a nitrogen-containing and cyclic compound, pharmaceutical compositions containing the same, methods for preparing the same, and uses thereof," priority of the inventive patent application of application number 201910932795.2, the entire contents of which are incorporated herein by reference.
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a novel nitrogen-containing fused ring compound with NLRP3 regulation activity, a preparation method thereof, a pharmaceutical composition containing the same and medical application thereof.
Background
NLRP3 (NLR family pyrin domain containing 3) belongs to the NLR (NOD-like receptors) family, and is an intracellular mode recognition receptor which has been most studied in recent years, and is mainly expressed in macrophages and neutrophils, and participates in the innate immunity of the organism, and resists pathogen infection and stress injury. The role of NLRP3 inflammatory bodies in inflammatory and metabolic diseases is well established, and their overactivation can lead to immune diseases such as type 2 diabetes, rheumatoid arthritis and atherosclerosis. However, recent studies have shown that NLRP3 has anti-tumor effects in inhibiting tumor growth and metastasis.
After recognizing PAMP (pathway-associated molecular patterns) or DAMP (damage-associated molecular patterns), the NOD domain of NLRP3 protein is oligomerized and recruits proteins such as ASC and pro-caspase-1 to form functional NLRP3 inflammatory corpuscles. After the pro-caspase-1 is cleaved and activated to caspase-1, the caspase-1 cleaves the pro-IL-1β and pro-IL-18 in large amounts, converting them into active forms IL-1β and IL-18 and releasing them extracellular, amplifying the inflammatory response. The excited NLRP3 inflammatory corpuscles can obviously improve the level of immune factors IL-1 beta and IL-18 in tumor microenvironment, and start natural immune killing and subsequent acquired immune response so as to play an anti-tumor role. Specifically, IL-1. Beta. Can induce CD8+ T cells to secrete interferon gamma (IFN-gamma), and also can induce CD4+ T cells to secrete IL-17, so that an effective anti-tumor immune effect is caused; IL-18 can promote NK cell maturation, activate STAT1 downstream signal channels in immune cells, and enhance the killing function of the immune cells. Clinical studies have shown that down-regulation of NLRP3 is significantly inversely related to prognosis in liver cancer patients. Preclinical studies also show that NLRP3 deficient mice have higher colorectal tumor formation rates and worsen colorectal liver metastases. Therefore, NLRP3 plays an important role in tumor microenvironment, and can be used as a key target point of tumor immunotherapy and a tumor prognosis marker.
WO2017184746, WO2017184735, WO2018152396 and WO2019014402 disclose NLRP3 modulators. Despite the potential for NLRP3 agonists for tumor immunotherapy, only one compound is currently in clinical phase I studies. Thus, there is a need to develop new, high-potency, low-toxicity NLRP3 agonists to meet clinical therapeutic needs.
Disclosure of Invention
Problems to be solved by the invention
The invention aims to provide novel nitrogen-containing parallel ring compounds with a regulating effect on NLRP3, which can directly bind to or modify NLRP3 at the protein level, and enhance the functions of NLRP3 inflammatory corpuscles by means of activating, stabilizing, changing NLRP3 distribution and the like.
Solution for solving the problem
In a first aspect, the present invention provides a compound having the structure of formula II or a pharmaceutically acceptable form thereof,
wherein,
X 1 selected from-C (R) 6 ) =sum-n=;
X 2 selected from-C (-L-R) 3 ) =sum-n=; when a plurality of L and R are present at the same time 3 When each L or R 3 The same or different from each other;
R 1 selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl and 9-12 membered aryl-heterocyclo, wherein said C 1-8 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, and 9-12 membered aryl-heterocyclo are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-OR 37 and-SR 37 ;
R 4 Is NR (NR) 41a R 41b ;R 41a And R is 41b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, or R 41a And R is 41b Along with the connection theretoN atoms together form a 4-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 4-7 membered heterocyclyl, cyano, nitro, -OR 37 、-SR 37 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-C(=O)OR 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 and-NR 31 R 32 And R is 41a And R is 41b Are not hydrogen at the same time;
R 6 selected from hydrogen, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and-NR 31 R 32 ;
L is- (L) 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 、L 2 And L 3 Each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -NR 33 -、-S(=O)-、-S(=O) 2 -, -C (=O) -and-CR 36a R 36b -, wherein the C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene and 5-10 membered heteroarylene are each optionally substituted with one or more substituents, each of which is substitutedEach independently selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and-NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the n, p and q are each independently 0, 1 or 2;
R 3 selected from hydrogen, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-C(=NR 38 )NR 31 R 32 、-NR 33 C(=NR 38 )NR 31 R 32 、-P(R 39 ) 2 、-P(OR 39 ) 2 、-P(=O)R 39 R 40 、-P(=O)(OR 39 )OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylalkylheterocyclyl, 9-12 membered arylalkylheteroaryl, and 9-12 membered arylalkylcycloalkyl are each optionally substituted with one or more substituents, each of which is independently selected from halogen, cyano, nitro, hydroxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-OR 37 、-SR 37 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-C(=NR 38 )NR 31 R 32 、-NR 33 C(=NR 38 )NR 31 R 32 、-N=NR 38 、-P(R 39 ) 2 、-P(OR 39 ) 2 、-P(=O)R 39 R 40 and-P (=o) (OR 39 )OR 30 ;
R 30 、R 37 、R 39 And R is 40 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl), wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl) each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 Haloalkoxy, -C (=o) O (C) 1-6 Alkyl), -C (=O) NR 31 R 32 、-NR 31 R 32 、-NR 33 C(=O)R 34 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 ;
R 35 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl), wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 Haloalkoxy, -C (=o) O (C) 1-6 Alkyl), -C (=O) NR 31 R 32 、-NR 31 R 32 、-NR 33 C(=O)R 34 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 ;
R 31 、R 32 、R 33 And R is 34 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-to 10-membered heteroaryl, or R 31 And R is 32 Together with the N atom to which it is attached form a 4-8 membered heterocyclic group, or R 33 And R is 34 Together with the N atom and the C atom to which they are correspondingly attached form a 4-8 membered heterocyclic group, wherein the C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, halogen, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl;
R 36a and R is 36b Each independently selected from hydrogen, C 1-8 Alkyl and C 1-8 Alkoxy, wherein said C 1-8 Alkyl and C 1-8 Alkoxy groups each optionally being substituted with one or moreA plurality of substituents each independently selected from hydroxy, cyano, halogen, amino, methylamino and dimethylamino, or R 36a And R is 36b Together with the C atom to which it is attached form a 3-7 membered cycloalkyl or heterocyclyl;
R 38 selected from hydrogen, hydroxy, cyano, nitro, -S (=o) R 35 and-S (=o) 2 R 35 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
When a plurality of R are simultaneously present 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36a 、R 36b 、R 37 、R 38 、R 39 And/or R 40 When each R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 a、R 36b 、R 37 、R 38 、R 39 Or R is 40 The same or different from each other;
the pharmaceutically acceptable form is selected from the group consisting of pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, co-crystals, solvates, N-oxides, isotopic labels, metabolites and prodrugs.
In Sup>A second aspect, the present invention provides Sup>A specific compound having the structure of formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, comprising:
(1) 4- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2-methyl-2-butanol;
(2) 3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(3) 3- (5- (tert-butylamino) -2- (1, 3-dimethyl-1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(4)N 5 -tert-butyl-N 7 - (oxetan-3-yl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(5)N 5 -tert-butyl-N 7 - (cyclobutylmethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(6)(R)-N 5 -tert-butyl-N 7 - (1-methoxypropan-2-yl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(7)N 5 -tert-butyl-N 7 - ((3-methylpyridin-2-yl) methyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(8)N 5 -tert-butyl-N 7 - (2-morpholinoethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(9) 1- (2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) ethyl) -2-pyrrolidone;
(10)N 5 -tert-butyl-N 7 - (cyclopropylmethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(11) 3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol;
(12)N 5 -tert-butyl-N 7 - (2, 2-difluoroethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(13)N 5 -tert-butyl-N 7 -isobutyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(14) 3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2- (methoxymethyl) -1-propanol;
(15) (3- ((5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) methyl) oxetan-3-yl) methanol;
(16) 2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -N-cyclopropylacetamide;
(17) 2- ((5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-yl) (methyl) amino) ethanol;
(18)N 5 -tert-butyl-N 7 - (2-methoxyethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(19)N 7 - ((1R, 5S,6 s) -3-azabicyclo [ 3.1.0)]Hex-6-yl) -N 5 -tertiary (t)Butyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(20) (R) -2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -4-methyl-1-pentanol;
(21) (1 r,4 r) -4- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) cyclohexanol;
(22)N 5 -tert-butyl-N 7 - ((3-Methyloxetan-3-yl) methyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(23) 3- (5- (tert-butylamino) -2- (6-methylpyridin-2-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(24)N 5 -tert-butyl-2- (1H-pyrazol-5-yl) -N 7 - ((tetrahydro-2H-pyran-4-yl) methyl) thieno [3,2-b]Pyridine-5, 7-diamine;
(25) 2, 2-dimethyl-3- (5- (methylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(26) 3- (5- (methylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(27)N 7 - (2, 2-difluoroethyl) -N 5 -methyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(28)N 7 - (cyclopropylmethyl) -N 5 -methyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(29)N 7 - (2-methoxyethyl) -N 5 -methyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(30) 3- (5- (ethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol;
(31) 3- (5- (ethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(32)N 7 - (2, 2-difluoroethyl) -N 5 -ethyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(33)N 7 - (cyclopropylmethyl) -N 5 -ethyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(34)N 5 -ethyl-N 7 - (2-methoxyethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(35) 3- (5- (isopropylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol;
(36) 3- (5- (isopropylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(37)N 7 - (2, 2-difluoroethyl) -N 5 -isopropyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(38)N 7 - (cyclopropylmethyl) -N 5 -isopropyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(39)N 5 -isopropyl-N 7 - (2-methoxyethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(40) 3- (5- (cyclopropylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol;
(41) 3- (5- (cyclopropylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(42)N 5 -cyclopropyl-N 7 - (2, 2-difluoroethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(43)N 5 -cyclopropyl-N 7 - (cyclopropylmethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(44)N 5 -cyclopropyl-N 7 - (2-methoxyethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(45) 3- (5- (dimethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol;
(46) 3- (5- (dimethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(47)N 7 - (2, 2-difluoroethyl))-N 5 ,N 5 -dimethyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(48)N 7 - (cyclopropylmethyl) -N 5 ,N 5 -dimethyl-2- (1H-pyrazol-5-yl) thieno [3,2-b ]Pyridine-5, 7-diamine;
(49)N 7 - (2-methoxyethyl) -N 5 ,N 5 -dimethyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(50) 3- (5- (diethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol;
(51) 3- (5- (diethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(52)N 7 - (2, 2-difluoroethyl) -N 5 ,N 5 -diethyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(53)N 7 - (cyclopropylmethyl) -N 5 ,N 5 -diethyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(54)N 5 ,N 5 -diethyl-N 7 - (2-methoxyethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(55) 3- (2- (1H-pyrazol-5-yl) -5- (pyrrolidin-1-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol;
(56) 3- (2- (1H-pyrazol-5-yl) -5- (pyrrolidin-1-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(57) N- (2, 2-difluoroethyl) -2- (1H-pyrazol-5-yl) -5- (pyrrolidin-1-yl) thieno [3,2-b ] pyridin-7-amine;
(58) N- (cyclopropylmethyl) -2- (1H-pyrazol-5-yl) -5- (pyrrolidin-1-yl) thieno [3,2-b ] pyridin-7-amine;
(59) N- (2-methoxyethyl) -2- (1H-pyrazol-5-yl) -5- (pyrrolidin-1-yl) thieno [3,2-b ] pyridin-7-amine;
(60) 2- (7- (3-hydroxy-2, 2-dimethylpropanamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-ylamino) acetic acid;
(61) 2- (7- (3-hydroxypropanamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-ylamino) acetic acid;
(62) 2- (7- (2, 2-difluoroethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-ylamino) acetic acid;
(63) 2- (7- (cyclopropylmethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-ylamino) acetic acid;
(64) 2- (7- (2-methoxyethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-ylamino) acetic acid;
(65) 3- (5- (2-hydroxyethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol;
(66) 3- (5- (2-hydroxyethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(67) 2- (7- (2, 2-difluoroethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-ylamino) ethanol;
(68) 2- (7- (cyclopropylmethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-ylamino) ethanol;
(69) 2- (7- (2-methoxyethylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-ylamino) ethanol;
(70) 2, 2-dimethyl-3- (5- (1-methylcyclopropylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(71) 3- (5- (1-methylcyclopropylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol;
(72)N 7 - (2, 2-difluoroethyl) -N 5 - (1-methylcyclopropyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(73)N 7 - (cyclopropylmethyl) -N 5 - (1-methylcyclopropyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(74)N 7 - (2-methoxyethyl) -N 5 - (1-methylcyclopropyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine;
(75) 3- (2- (1H-pyrazol-5-yl) -5- (2, 4-trimethylpent-2-ylamino) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol; and
(76) 3- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol.
In Sup>A third aspect, the present invention provides Sup>A compound of formulSup>A IV-A and Sup>A compound of formulSup>A IV-B (when X in formulSup>A IV 1 For-ch=the compounds of formulSup>A IV-Sup>A-1 and IV-B-1, respectively), comprising the steps of:
step 1: the compound IV-1 is subjected to halogenation reaction to generate a compound IV-2;
x represents a halogen atom selected from chlorine and bromine;
step 2: the compound IV-2 is subjected to iodination reaction to generate a compound IV-3;
step 3: the compound IV-3 is subjected to oxidation reaction to generate a compound IV-4;
Step 4: compounds IV-4 and R 4 H reaction to give compound IV-5, wherein R 4 Is connected with thienopyridine through a nitrogen atom;
step 5: the compound IV-5 is subjected to a coupling reaction to generate a compound IV-6;
step 6-1: the compound IV-6 is subjected to substitution reaction to generate Sup>A compound IV-A-1;
step 6-2: the compound IV-6 is subjected to a coupling reaction to generate a compound IV-B-1;
wherein R is 1 、R 3a 、R 3b 、R 4 、L a And L b As defined herein.
The present invention also provides compounds of formulSup>A IV-A and compounds of formulSup>A IV-B (when X in formulSup>A IV 1 Is-ch=and R 1 In the case of 1H-pyrazol-5-yl, the compounds of formulSup>A IV-A-2 and of formulSup>A IV-B-2, respectively), comprising the following steps:
step 7: the compound IV-A-1 'and the compound IV-B-1' are respectively subjected to deprotection reaction to generate Sup>A compound IV-A-2 and Sup>A compound IV-B-2;
wherein R is 3a 、R 3b 、R 4 、L a And L b As defined herein; PG 1 And PG 2 Represents a protecting group, each independently selected from the group consisting of tetrahydro-2H-pyran-2-yl, t-butoxycarbonyl and benzyloxycarbonyl.
In a fourth aspect, the present invention provides a process for the preparation of a compound of formula V comprising the steps of:
step 1: the compound IV-6 is subjected to substitution or coupling reaction to generate a compound V;
wherein R is 1 、R 3 、R 4 、R 33 、L 2 、L 3 P and q are as defined herein.
In Sup>A fifth aspect, the invention provides Sup>A pharmaceutical composition comprising Sup>A compound having the structure of formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, or Sup>A pharmaceutically acceptable form thereof, and Sup>A pharmaceutically acceptable carrier.
In Sup>A sixth aspect, the invention provides Sup>A compound having the structure of formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, or Sup>A pharmaceutically acceptable form or pharmaceutical composition thereof, for use as an NLRP3 modulator, preferably as an NLRP3 agonist.
In Sup>A seventh aspect, the present application provides the use of Sup>A compound having the structure of formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, or Sup>A pharmaceutically acceptable form or pharmaceutical composition thereof, in the manufacture of Sup>A medicament for the prevention and/or treatment of Sup>A disease mediated at least in part by NLRP 3.
In an eighth aspect, the present invention provides a method for preventing and/or treating a disease mediated at least in part by NLRP3, comprising the steps of: sup>A prophylactically and/or therapeutically effective amount of Sup>A compound having the structure of formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, or Sup>A pharmaceutically acceptable form or pharmaceutical composition thereof, is administered to Sup>A subject in need thereof.
In Sup>A ninth aspect, the invention provides Sup>A pharmaceutical combination composition comprising Sup>A compound having the structure of formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, or Sup>A pharmaceutically acceptable form or pharmaceutical composition thereof, and at least one other co-directional NLRP3 modulator.
In a tenth aspect, the present invention provides a method for preventing and/or treating cancer, comprising the steps of: sup>A prophylactically and/or therapeutically effective amount of Sup>A compound having the structure of formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition or pharmaceutical combination composition, as an NLRP3 agonist is administered to Sup>A subject in need thereof.
In an eleventh aspect, the present invention provides a method for preventing and/or treating an immune disease, comprising the steps of: sup>A prophylactically and/or therapeutically effective amount of Sup>A compound having the structure of formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition or pharmaceutical combination composition, as an NLRP3 antagonist is administered to an individual in need thereof.
ADVANTAGEOUS EFFECTS OF INVENTION
The compound has obvious agonist activity to NLRP3 and a signal path thereof, has no obvious toxic or side effect, and can be used for treating abnormal cell proliferation diseases (such as cancers).
Detailed Description
Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[ definition of terms ]
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The terms "comprising," "including," "having," or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion, either inclusive or open-ended. For example, a composition, method, or apparatus that comprises a list of elements is not necessarily limited to only those elements explicitly listed, but may also include other elements not explicitly listed or inherent to such composition, method, or apparatus.
By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention that is substantially non-toxic to an organism. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed from the compounds of the present invention by reaction with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases, such salts also being referred to as acid addition salts or base addition salts. Examples of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: properties, selection, and Use [ M ], wiley-VCH,2002.
The term "isomer" refers to a compound that has the same molecular weight due to the same number and type of atoms, but differs in the spatial arrangement or configuration of the atoms.
The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular plane of asymmetry due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby enabling rotation of plane polarized light. The present invention also includes stereoisomers and mixtures thereof, due to the presence of asymmetric centers and other chemical structures which may lead to stereoisomers. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, mixtures of enantiomers and diastereomers. In general, these compounds can be prepared in the form of racemates. However, if desired, such compounds can be prepared or separated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures in which the single stereoisomers are enriched (purity +.gtoreq.98%,. Gtoreq.95%,. Gtoreq.93%,. Gtoreq.90%,. Gtoreq.88%,. Gtoreq.85% or. Gtoreq.80%). As described below, individual stereoisomers of the compounds are prepared synthetically from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds having specific stereochemistry are either commercially available or prepared according to the methods described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-overlapping mirror images of each other. The term "diastereoisomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal portions of individual enantiomers. All stereoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerisation, imine-enamine isomerisation, nitroso-oxime isomerisation, amide-imine alcohol isomerisation, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "cis-trans isomer" refers to stereoisomers formed by atoms (or groups) located on either side of a double bond or ring system due to different positions relative to a reference plane; in the cis isomer the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer the atoms (or groups) are on the opposite side of the double bond or ring system. All cis and trans isomeric forms of the compounds of the present invention are within the scope of the present invention unless otherwise indicated.
The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex, which may be a single polymorph or a mixture of more than one polymorph in any proportion. Polymorphs can be obtained by known methods by those skilled in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. In addition, polymorphs can be detected, classified and identified using well known techniques including, but not limited to, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SCXRD), solid state Nuclear Magnetic Resonance (NMR), infrared spectroscopy (IR), raman spectroscopy, scanning Electron Microscopy (SEM), and the like.
The term "solvate" refers to a substance formed by the association of a compound of the invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule by non-covalent intermolecular forces. Common solvates include, but are not limited to, hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, and the like), ethanolates, acetonates, and the like.
The term "N-oxide" refers to compounds formed by oxidation of a nitrogen atom in the structure of tertiary amines or nitrogen-containing (aromatic) heterocycles. Common N-oxides include, but are not limited to, trimethylamine-N-oxide, 4-methylmorpholine-N-oxide, pyridine-N-oxide, and the like. The 1a position in the parent nucleus of the compound of the formula I is tertiary amine nitrogen atom, and corresponding N-oxide can be formed; in addition, when the group directly attached to the nitrogen atom at the 3-position in the parent nucleus is not a (sulfonyl) group, the 3-position is also a tertiary amine nitrogen atom, and the corresponding N-oxide can be formed as well.
The term "isotopic label" refers to a derivative compound from which a specific atom in a compound of the present invention is replaced by its isotopic atom (having the same atomic number, but different atomic masses or mass numbers). Unless otherwise indicated, the compounds of the invention include various isotopes of H, C, N, O, F, P, S, cl, e.g 2 H(D)、 3 H(T)、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 18 F、 31 p、 32 p、 35 S、 36 S、 37 Cl、 123 I and 125 I。
the term "metabolite" refers to a derivative compound of the present invention which is formed after metabolism. For examples of metabolites see Goodman and Gilman's: the Pharmacological Basis of Therapeutics (9) th ed.)[M],McGraw-Hill International Editions,1996。
The term "prodrug" refers to a derivative compound that is capable of providing a compound of the invention directly or indirectly after administration to a subject. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to an individual, may increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood) or promote delivery of the parent compound to the site of action (e.g., the lymphatic system). All prodrug forms of the compounds of the invention are within the scope of the invention unless otherwise indicated, and the various prodrug forms are well known in the art. Additional information regarding prodrugs can be found in Pro-drugs as Novel Drug Delivery Systems (14 th ed.)[M]ACS Symposium Series,1975 and Bioreversible Carriers in Drug Design [ M ]],Pergamon Press,1987。
The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, examples of suitable protecting groups being found in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie [ M ], plenum Press,1973 and Protective Groups in Organic Synthesis [ M ], john Wiley & Sons,1991. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The term "independently" means that at least two groups (or ring systems) present in the structure that are the same or similar in value range may have the same or different meanings in the particular case. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, then when substituent X is hydrogen, substituent Y may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl.
The term "each optionally" means that at least two groups (or ring systems) present in the structure may have the same or different treatments in a particular situation. For example, each of substituents X and Y is optionally substituted with an alkyl group, then in practice the following various treatments are included: (1) only X is substituted with alkyl; (2) only Y is substituted with alkyl; (3) X and Y are both substituted with alkyl; (4) X and Y are both unsubstituted.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The term "halo" refers to substitution with a halogen atom.
The term "cyano" refers to a-CN group.
The term "nitro" refers to-NO 2 A group.
The term "hydroxy" refers to an-OH group.
The term "alkyl" refers to a straight or branched monovalent saturated aliphatic hydrocarbon radical. The term "C 1-15 Alkyl "," C 1-8 Alkyl "," C 1-6 Alkyl "and" C 1-4 Alkyl "refers to straight or branched alkyl groups having 1 to 15 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively. Common alkyl groups include, but are not limited to, methyl (-CH) 3 ) Ethyl (-CH) 2 CH 3 ) N-propyl (-CH) 2 CH 2 CH 3 ) Isopropyl (-CH (CH) 3 ) 2 ) N-butyl (-CH) 2 CH 2 CH 2 CH 3 ) Sec-butyl (-CH (CH) 3 )CH 2 CH 3 ) Isobutyl (-CH) 2 CH(CH 3 ) 2 ) Tert-butyl (-C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) Neopentyl (-CH) 2 C(CH 3 ) 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) Etc.
The term "alkylene" refers to a divalent saturated aliphatic hydrocarbon group obtained by removing two hydrogen atoms from a straight-chain or branched saturated aliphatic hydrocarbon group. Common alkylene groups include, but are not limited to, methylene (-CH) 2 (-), 1, 2-ethylene (-CH) 2 CH 2 (-), 1, 3-propylene (-CH) 2 CH 2 CH 2 (-), 1-methyl1, 2-ethylene group (-CH (CH) 3 )CH 2 (-), 1, 4-butylene (-CH) 2 CH 2 CH 2 CH 2 (-), 1-methyl-1, 3-propylene (-CH (CH) 3 )CH 2 CH 2 (-), 1-dimethyl-1, 2-ethylene (-C (CH) 3 ) 2 CH 2 (-), 1, 2-dimethyl-1, 2-ethylene (-CH (CH) 3 )CH(CH 3 ) (-), etc.
The term "haloalkyl" refers to a straight or branched chain alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. The term "C 1-8 Haloalkyl "," C 1-6 Haloalkyl groups "and" C 1-4 Haloalkyl "refers to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms, respectively. Common haloalkyl groups include, but are not limited to, fluoromethyl (-CH) 2 F) Difluoromethyl (-CHF) 2 ) Trifluoromethyl (-CF) 3 ) 1-fluoroethyl (-CHFCH) 3 ) 2-fluoroethyl (-CH) 2 CH 2 F) 1, 2-difluoroethyl (-CHFCH) 2 F) 2, 2-difluoroethyl (-CH) 2 CHF 2 ) 1, 2-trifluoroethyl (-CHFCHF) 2 ) 2, 2-trifluoroethyl group (-CH) 2 CF 3 ) 1, 2-pentafluoroethyl (-CF) 2 CF 3 ) 3, 3-trifluoropropyl (-CH) 2 CH 2 CF 3 ) Chloromethyl (-CH) 2 Cl), and the like.
The term "hydroxyalkyl" refers to a straight or branched chain alkyl group substituted with one or more (such as 1 to 3) hydroxyl groups. The term "C 1-4 Hydroxyalkyl groups "and" C 1-3 Hydroxyalkyl "refers to hydroxyalkyl groups having 1 to 4 carbon atoms and 1 to 3 carbon atoms, respectively. Common hydroxyalkyl groups include, but are not limited to, hydroxymethyl (-CH) 2 OH), 2-hydroxyethyl (-CH 2 CH 2 OH), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 4-hydroxybutyl (-CH 2 CH 2 CH 2 CH 2 OH), 1-hydroxyethyl (-CH (OH) CH 3 ) Etc.
The term "alkenyl" refers to a straight or branched chain monovalent aliphatic hydrocarbon radical containing one or more (such as 1 to 3) carbon-carbon double bonds. Common olefinsRadicals include, but are not limited to, vinyl (-ch=ch) 2 ) 2-propen-1-yl (-CH) 2 CH=CH 2 ) 1-methyl-1-vinyl (-C (CH) 3 )=CH 2 ) 2-buten-1-yl (-CH) 2 -CH=CH-CH 3 ) Etc.
The term "alkenylene" refers to a straight or branched chain divalent aliphatic hydrocarbon radical containing one or more (such as 1 to 3) carbon-carbon double bonds. Common alkenylenes include, but are not limited to, 1, 2-ethenylene (-ch=ch-), 1, 3-ethenylene-1-propenyl (-CH) 2 Ch=ch-), 1, 2-sub-1-propenyl (-C (CH) 3 ) =ch-) and the like.
The term "alkynyl" refers to a straight or branched chain monovalent aliphatic radical having one or more (such as 1 to 3) carbon-carbon triple bonds. Common alkenylenes include, but are not limited to, ethynyl2-propyn-1-yl->2-butyn-1-yl->1, 3-butanediynyl->Etc.
The term "alkynylene" refers to a straight or branched chain divalent aliphatic hydrocarbon radical having one or more (such as 1 to 3) carbon-carbon triple bonds. Common alkynylene groups include, but are not limited to, 1, 2-ethynylene groups1, 3-sub-1-propynyl1, 3-sub-1-butynyl->1, 4-sub-2-butynyl->Etc.
The term "alkoxy" refers to a monovalent, linear or branched alkyl-O-group, and is attached to the other group by a single bond to an oxygen atom. Common alkoxy groups include, but are not limited to, methoxy (-OCH) 3 ) Ethoxy (-OCH) 2 CH 3 ) N-propoxy (-OCH) 2 CH 2 CH 3 ) Isopropoxy (-OCH (CH) 3 ) 2 ) N-butoxy (-OCH) 2 CH 2 CH 2 CH 3 ) Sec-butoxy (-OCH (CH) 3 )CH 2 CH 3 ) Isobutoxy (-OCH) 2 CH(CH 3 ) 2 ) T-butoxy (-OC (CH) 3 ) 3 ) N-pentyloxy (-OCH) 2 CH 2 CH 2 CH 2 CH 3 ) Neopentyloxy (-OCH) 2 C(CH 3 ) 3 ) N-hexyloxy (-OCH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) Etc.
The term "alkylene" refers to a divalent straight or branched chain alkylene-O-group and is linked to the other group by one single bond to an oxygen atom and another single bond to an alkylene group. Common alkyleneoxy groups include, but are not limited to, OCH 2 -、-OCH(CH 3 )CH 2 -、-CH 2 CH 2 O-, and the like.
The term "fused ring" or "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
The term "spiro" refers to a ring system formed by two or more cyclic structures sharing one ring atom with each other.
The term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly attached to each other.
The term "cycloalkyl" refers to a monovalent non-aromatic cyclic hydrocarbon radical that is saturated or unsaturated, monocyclic or polycyclic (such as bicyclic). Common cycloalkyl groups include, but are not limited to, monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like; and cyclic (condensed ring) cycloalkanes such as decalin (also referred to as decalin, decalin), bicyclo [2.1.0] pentyl, bicyclo [3.1.0] hexyl, bicyclo [5.1.0] octyl, bicyclo [2.2.0] hexyl, bicyclo [4.2.0] octyl, etc.; spirocycloalkyl radicals, such as the spiropentyl, spiro [2.4] heptyl, spiro [2.5] octyl, spiro [2.6] nonyl, spiro [3.3] heptyl, spiro [3.5] nonyl and the like; bridged cycloalkyl groups such as adamantyl and the like. The carbon atom on the cycloalkyl group in the present invention is optionally oxo, i.e. forms a cyclic carbonyl group (c=o).
The term "cycloalkylene" refers to a saturated or unsaturated, monocyclic or polycyclic (such as bicyclic) divalent non-aromatic cyclic hydrocarbon radical having two monovalent radical centers resulting from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent cycloalkyl radical. Common cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, cyclohexenylene, and the like. The carbon atom on the cycloalkylene group in the present invention is optionally oxo, i.e. forms a cyclic carbonyl group (c=o).
The term "heterocyclyl" refers to a monovalent, non-aromatic ring system of saturated or unsaturated, mono-or polycyclic (including fused, bridged, spiro) character, the ring atoms of which consist of carbon atoms and heteroatoms selected from the group consisting of boron, nitrogen, oxygen, sulfur, phosphorus and arsenic. The term "3-14 membered heterocyclic group" means a heterocyclic group having 3 to 14 ring atoms, including, but not limited to, 4-10 membered heterocyclic groups, 4-7 membered heterocyclic groups (e.g., 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups), 5-6 membered heterocyclic groups (e.g., 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups), etc., and "nitrogen-containing heterocyclic groups", "oxygen-containing heterocyclic groups", "sulfur-containing heterocyclic groups", each optionally containing one or more heteroatoms selected from nitrogen, oxygen, sulfur. Common monocyclic heterocyclic groups include, but are not limited to, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, Thiomorpholino, dithianyl, trithianyl, and the like; common heterocycloalkyls include, but are not limited to, heterocycloalkyls, monocycloheterocycloalkyls, and the like, such as pyrrolidinyl-cyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-cyclohexyl, cyclopentylazacyclopropyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, pyrrolidinyl-morpholinyl, piperidinyl-morpholinyl, and the like; common bridged heterocyclic groups include, but are not limited to Etc.; common spiro heterocyclyl groups include, but are not limited to-> Etc. The carbon atoms on the heterocyclyl in the present invention are optionally oxo, i.e. form a cyclic carbonyl group (c=o). The nitrogen atom on the heterocyclic group in the present invention is optionally oxidized, that is, nitrogen oxide (nh→o) is formed. The sulfur atom on the heterocyclyl in the present invention is optionally oxidized, i.e. forms a sulfoxide (s=o) or a sulfone (S (=o) 2 )。
The term "heterocyclylene" refers to a saturated or unsaturated, monocyclic or polycyclic (such as bicyclic) divalent non-aromatic ring system, the ring atoms of which are composed of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus and arsenic, having two monovalent radical centers derived from the removal of two hydrogen atoms from two carbon atoms, two heteroatoms or one carbon atom and one heteroatom of a parent heterocyclic group. Often times The heterocyclylene groups that may be used include, but are not limited to, oxetan-2, 2-subunit, oxetan-2, 3-subunit, azetidin-2, 2-subunit, azetidin-2, 3-subunit, azetidin-2, 4-subunit, tetrahydrofuran-2, 5-subunit, tetrahydro-2H-pyran-2, 3-subunit, tetrahydro-2H-pyran-2, 4-subunit, tetrahydro-2H-pyran-2, 5-subunit, tetrahydro-2H-pyran-2, 6-subunit, pyrrolidin-1, 2-subunit, pyrrolidin-1, 3-subunit, pyrrolidin-2, 5-subunit, piperidin-1, 2-subunit, piperidin-1, 3-subunit, piperidin-1, 4-subunit, piperidin-2, 3-subunit, piperidin-2, 4-subunit, piperidin-2, 5-subunit, piperidine-6-subunit, and the like. The carbon atoms on the heterocyclylene in the present invention are optionally oxo, i.e. form a cyclic carbonyl group (c=o). The nitrogen atom on the heterocyclylene group in the present invention is optionally oxidized, i.e., forms a nitrogen oxide (nh→o). The sulfur atom on the heterocyclylene in the present invention is optionally oxidized, i.e. forms a sulfoxide (s=o) or sulfone (S (=o) 2 )。
The term "aryl" refers to an all-carbon monocyclic or fused polycyclic monovalent aromatic ring system having a conjugated pi-electron system. The term "C 6-12 Aryl "and" C 6-10 Aryl "refers to aryl groups containing 6 to 12 and 6 to 10 carbon atoms, respectively. Common aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.
The term "arylene" refers to an all-carbon monocyclic or fused polycyclic divalent aromatic ring system having a conjugated pi-electron system with two monovalent radical centers derived from the removal of two hydrogen atoms from two carbon atoms of the parent aryl group. Common aryl groups include, but are not limited to, phenylene, naphthylene, and the like.
The term "aryl-cycloalkyl" refers to a monovalent, cyclic group formed by aryl and cycloalkyl groups (e.g., monocyclic cycloalkyl groups) sharing two adjacent atoms with each other, the attachment site of which to other groups (or ring systems) may be on the aryl or on the cycloalkyl. The term "9-12 membered arylcycloalkyl" refers to arylcycloalkyl groups containing 9-12 ring atoms. Common aryl-cycloalkyl groups include, but are not limited to, phenyl-cyclopentyl, phenyl-cyclohexyl, and the like. The carbon atom on the cycloalkyl group in the aryl-cycloalkyl group in the present invention is optionally oxo, i.e. forms a cyclic carbonyl group (c=o).
The term "aryl-heterocyclyl" refers to a monovalent, fused ring radical formed by aryl and heterocyclyl groups (e.g., monocyclic heterocyclyl groups) sharing two adjacent atoms with each other, the point of attachment to other groups (or ring systems) being on either the aryl or the heterocyclyl. The term "9-12 membered arylalkylheterocyclyl" refers to a radical of an arylalkylheterocyclyl containing 9-12 ring members, such as a benzo 5-6 membered nitrogen-containing heterocyclyl, a benzo 5-6 membered oxygen-containing heterocyclyl, a benzo 5-6 membered sulfur-containing heterocyclyl, and the like, the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl", "sulfur-containing heterocyclyl" each optionally containing one or more heteroatoms selected from nitrogen, oxygen, sulfur. Common arylcycloalkyl groups include, but are not limited to, indazolyl, benzomorpholinyl, dihydroisoquinolinone, benzo [1,4 ] ]Dioxane group and dihydrobenzofuranyl group. The carbon atoms on the heterocyclyl in the present invention are optionally oxo, i.e. form a cyclic carbonyl group (c=o). The nitrogen atom on the heterocyclic group in the present invention is optionally oxidized, that is, nitrogen oxide (nh→o) is formed. The sulfur atom on the heterocyclyl in the present invention is optionally oxidized, i.e. forms a sulfoxide (s=o) or a sulfone (S (=o) 2 )。
The term "heteroaryl" refers to a mono-or fused polycyclic monovalent aromatic ring system having a conjugated pi-electron system with ring atoms consisting of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus and arsenic, preferably mono-or fused polycyclic groups having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms. The term "5-10 membered heteroaryl" refers to heteroaryl groups containing 5 to 10 ring atoms, including 5-10 membered nitrogen containing heteroaryl, 5-10 membered oxygen containing heteroaryl, 5-10 membered sulfur containing heteroaryl, preferably 5-6 membered nitrogen containing heteroaryl, 5-6 membered oxygen containing heteroaryl, 5-6 membered sulfur containing heteroaryl, more preferably 5-6 membered nitrogen containing mono-heteroaryl, 5-6 membered oxygen containing mono-heteroaryl, 5-6 membered sulfur containing mono-heteroaryl. "Nitrogen-containing heteroaryl", "oxygen-containing heteroaryl", "sulfur-containing heteroaryl" each optionally contain one or more heteroatoms selected from oxygen, nitrogen, sulfur. Common heterocyclic groups include, but are not limited to, acridinyl, carbazolyl, indazolyl, indolizinyl, indolyl, thienyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, phenazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, purinyl, and the like.
The term "heteroarylene" refers to a monocyclic or fused polycyclic divalent aromatic ring system having a conjugated pi-electron system, the ring atoms of which are composed of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus and arsenic, preferably a monocyclic or fused polycyclic group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms, with two monovalent radical centers resulting from the removal of two hydrogen atoms from two carbon atoms or one carbon atom and one heteroatom of the parent heteroaryl. Common heteroarylenes include, but are not limited to, pyrazolylene, imidazolylene, and the like.
The term "aryl-heteroaryl" refers to a monovalent, fused ring group formed by an aryl group (e.g., phenyl) and a heteroaryl group (e.g., a 5-6 membered monocyclic heteroaryl) sharing two adjacent atoms with each other, the point of attachment to the other group (or ring system) may be on an aromatic or heteroaromatic ring. The term "9-12 membered arylalkylheteroaryl" refers to arylalkylheteroaryl groups containing 9-12 ring atoms, such as benzo 5-6 membered nitrogen containing monocyclic heteroaryl.
The term "heteroarylcycloalkyl" refers to heteroaryl (e.g., 5-6 membered monocyclic heteroaryl) and cycloalkyl (e.g., C 4-6 Cycloalkyl) share two adjacent atoms with each other to form a monovalent and cyclic group, the point of attachment to other groups (or ring systems) may be on the heteroaryl or cycloalkyl group. The term "9-10 membered heteroarylcycloalkyl" refers to heteroarylcycloalkyl containing 9-10 ring atoms, e.g., 4-6 membered nitrogen-containing monocyclic heteroaryl and C 4-6 A monocyclic cycloalkyl group.
The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on the designated atom (or group) are replaced by other atoms (or groups), provided that the normal valency of the designated atom in the present case is not exceeded and a stable compound is formed. If a substituent is described as "optionally substituted (by)", the substituent may be (1) unsubstituted or (2) substituted. If a substituent is described as "each independently selected from the group consisting of", "then any one of the plurality of substituents that are present at the same time is selected independently of the other; in other words, one of the plurality of substituents may be the same as or different from another. The term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 under reasonable conditions.
As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
[ Compounds of the general formula ]
The present invention provides a compound of formula X or a pharmaceutically acceptable form thereof,
A-L-R 3
X
wherein,
a is selected from
·X 2 Selected from-C (-L-R) 3 ) =sum-n=; when a plurality of L and R are present at the same time 3 When each L or R 3 The same or different from each other;
·R 1 selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl and 9-12 membered aryl-heterocyclo, wherein said C 1-8 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, and 9-12 membered aryl-heterocyclo are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-OR 37 and-SR 37 ;
··R 2 is-NR 41a R 41b ;
R. 5 Each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and-NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the m is 0, 1 or 2;
··X 1 selected from-C (R) 6 ) =sum-n=;
··R 4 is-NR 41a R 41b ;
··R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and-NR 31 R 32 ;
·R 41a And R is 41b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, or R 41a And R is 41b Together with the N atom to which it is attached form a 4-7 membered heterocyclic group, wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 4-7 membered heterocyclyl, cyano, nitro, -OR 37 、-SR 37 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-C(=O)OR 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 and-NR 31 R 32 And R is 41a And R is 41b Are not hydrogen at the same time;
l is- (L) 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 、L 2 And L 3 Each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -NR 33 -、-S(=O)-、-S(=O) 2 -, -C (=O) -and-CR 36a R 36b -, wherein the C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene and 5-10 membered heteroarylene are each optionally substituted with one or more substituents, each independently selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and-NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the n, p and q are each independently 0, 1 or 2;
R 3 selected from hydrogen, halogen, cyano, nitro, C 1-8 Alkyl group,C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-C(=NR 38 )NR 31 R 32 、-NR 33 C(=NR 38 )NR 31 R 32 、-P(R 39 ) 2 、-P(OR 39 ) 2 、-P(=O)R 39 R 40 、-P(=O)(OR 39 )OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylalkylheterocyclyl, 9-12 membered arylalkylheteroaryl, and 9-12 membered arylalkylcycloalkyl are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, hydroxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-OR 37 、-SR 37 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-C(=NR 38 )NR 31 R 32 、-NR 33 C(=NR 38 )NR 31 R 32 、-N=NR 38 、-P(R 39 ) 2 、-P(OR 39 ) 2 、-P(=O)R 39 R 40 and-P (=o) (OR 39 )OR 30 ;
R 30 、R 37 、R 39 And R is 40 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl), wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl) each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 Haloalkoxy, -C (=o) O (C) 1-6 Alkyl), -C (=O) NR 31 R 32 、-NR 31 R 32 、-NR 33 C(=O)R 34 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 ;
R 35 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl), wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents, eachThe substituents are each independently selected from hydroxy, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 Haloalkoxy, -C (=o) O (C) 1-6 Alkyl), -C (=O) NR 31 R 32 、-NR 31 R 32 、-NR 33 C(=O)R 34 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 ;
R 31 、R 32 、R 33 And R is 34 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-to 10-membered heteroaryl, or R 31 And R is 32 Together with the N atom to which it is attached form a 4-8 membered heterocyclic group, or R 33 And R is 34 Together with the N atom and the C atom to which they are correspondingly attached form a 4-8 membered heterocyclic group, wherein the C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, halogen, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl;
R 36a and R is 36b Each independently selected from hydrogen, C 1-8 Alkyl and C 1-8 Alkoxy, wherein said C 1-8 Alkyl and C 1-8 Alkoxy groups are each optionally substituted with one or more substituents, each of which is independently selected from hydroxy, cyano, halogen, amino, methylamino and dimethylamino, or R 36a And R is 36b Together with the C atom to which it is attached form a 3-7 membered cycloalkyl or heterocyclyl;
R 38 Selected from hydrogen, hydroxy, cyano, nitro, -S (=o) R 35 and-S (=o) 2 R 35 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
When a plurality of R are simultaneously present 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36a 、R 36b 、R 37 、R 38 、R 39 And/or R 40 When each R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36a 、R 36b 、R 37 、R 38 、R 39 Or R is 40 The same or different from each other;
the pharmaceutically acceptable form is selected from the group consisting of pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, co-crystals, solvates, N-oxides, isotopic labels, metabolites and prodrugs.
In some embodiments of the invention, the compound of formula X described above is a compound of formula I,
wherein,
X 2 selected from-C (-L-R) 3 ) =sum-n=; when a plurality of L and R are present at the same time 3 When each L or R 3 The same or different from each other;
R 1 selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl and 9-12 membered aryl-heterocyclo, wherein said C 1-8 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, and 9-12 membered aryl-heterocyclo are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-OR 37 and-SR 37 ;
R 2 Is NR (NR) 41a R 41b ;R 41a And R is 41b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, or R 41a And R is 41b Together with the N atom to which it is attached form a 4-7 membered heterocyclic group, wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 4-7 membered heterocyclyl, cyano, nitro, -OR 37 、-SR 37 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-C(=O)OR 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 and-NR 31 R 32 And R is 41a And R is 41b Are not hydrogen at the same time;
each R is 5 Each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and-NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the m is 0, 1 or 2;
l is- (L) 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 、L 2 And L 3 Each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -NR 33 -、-S(=O)-、-S(=O) 2 -, -C (=O) -and-CR 36a R 36b -, wherein the C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene and 5-10 membered heteroarylene are each optionally substituted with one or more substituents, each independently selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and-NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the n, p and q are each independently 0, 1 or 2;
R 3 selected from hydrogen, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-C(=NR 38 )NR 31 R 32 、-NR 33 C(=NR 38 )NR 31 R 32 、-P(R 39 ) 2 、-P(OR 39 ) 2 、-P(=O)R 39 R 40 、-P(=O)(OR 39 )OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylalkylheterocyclyl, 9-12 membered arylalkylheteroaryl, and 9-12 membered arylalkylcycloalkyl are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, hydroxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-OR 37 、-SR 37 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-C(=NR 38 )NR 31 R 32 、-NR 33 C(=NR 38 )NR 31 R 32 、-N=NR 38 、-P(R 39 ) 2 、-P(OR 39 ) 2 、-P(=O)R 39 R 40 and-P (=o) (OR 39 )OR 30 ;
R 30 、R 37 、R 39 And R is 40 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl), wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroarylRadical, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl) each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 Haloalkoxy, -C (=o) O (C) 1-6 Alkyl), -C (=O) NR 31 R 32 、-NR 31 R 32 、-NR 33 C(=O)R 34 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 ;
R 35 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl), wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 Haloalkoxy, -C (=o) O (C) 1-6 Alkyl), -C (=O) NR 31 R 32 、-NR 31 R 32 、-NR 33 C(=O)R 34 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 ;
R 31 、R 32 、R 33 And R is 34 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-to 10-membered heteroaryl, or R 31 And R is 32 Together with the N atom to which it is attached form a 4-8 membered heterocyclic group, or R 33 And R is 34 Together with and connect withWhich together form a 4-8 membered heterocyclic group with the corresponding attached N atom and C atom, wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, halogen, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl;
R 36a and R is 36b Each independently selected from hydrogen, C 1-8 Alkyl and C 1-8 Alkoxy, wherein said C 1-8 Alkyl and C 1-8 Alkoxy groups are each optionally substituted with one or more substituents, each of which is independently selected from hydroxy, cyano, halogen, amino, methylamino and dimethylamino, or R 36a And R is 36b Together with the C atom to which it is attached form a 3-7 membered cycloalkyl or heterocyclyl;
R 38 Selected from hydrogen, hydroxy, cyano, nitro, -S (=o) R 35 and-S (=o) 2 R 35 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
When a plurality of R are simultaneously present 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36a 、R 36b 、R 37 、R 38 、R 39 And/or R 40 When each R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36a 、R 36b 、R 37 、R 38 、R 39 Or R is 40 The same as or different from each other.
In some embodiments of the invention, the compound of formula X or formula I described above is a compound of formula III,
wherein R is 1 、R 2 、R 3 、R 5 L and m are as defined above.
In some embodiments of the invention, the compounds of formula X, formula I or formula III described above are compounds of formula III-A,
wherein,
R 1 and R is 2 As defined hereinabove;
R 5a selected from hydrogen, C 1-3 Alkyl, fluorine and chlorine;
L a is-L 1a -(L 2 ) p -(L 3 ) q -, wherein L 1a Selected from the group consisting of-O-, -S-and-NR 33 -, and L 2 、L 3 P and q are as defined above;
R 3a selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylalkylheterocyclyl, 9-12 membered arylalkylheteroaryl, and 9-12 membered arylalkylcycloalkyl are each optionally substituted with one or more substituents, each independently selected from the group consisting of halogen, Cyano, nitro, hydroxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-OR 37 、-SR 37 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 and-NR 33 C(=O)OR 30 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 30 、R 31 、R 32 、R 33 、R 34 、R 35 And R is 37 As defined hereinabove.
In some embodiments of the invention, the compounds of formula X, formula I or formula III described above are compounds of formula III-B,
wherein,
R 1 and R is 2 As defined hereinabove;
R 5a selected from hydrogen, C 1-3 Alkyl, fluorine and chlorine;
L b is- (L) 1b ) n -(L 2b ) p -(L 3b ) q -, wherein L 1b 、L 2b And L 3b Each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -NR 33 -、-S(=O)-、-S(=O) 2 -、-C(=O) -and-CR 36a R 36b -, wherein the C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene and 5-10 membered heteroarylene are each optionally substituted with one or more substituents, each independently selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 1-4 An alkoxy group; n, p and q are each independently 0 or 1;
R 3b selected from hydrogen, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylalkylheterocyclyl, 9-12 membered arylalkylheteroaryl, and 9-12 membered arylalkylcycloalkyl are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, hydroxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-OR 37 、-SR 37 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 and-NR 33 C(=O)OR 30 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
The conditions are as follows:
when n+p+q is greater than or equal to 1, - (L) 1b ) n -(L 2b ) p -(L 3b ) q L in connection with quinoline in formula III-B 1b Or L 2b Or L 3b not-O-, -S-, -NR 33 -、-S(=O)-、-S(=O) 2 -or-C (=o) -;
when n+p+q=0, R 3b Not hydrogen, halogen, cyano, nitro, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 or-S (=o) 2 NR 31 R 32 。
In some embodiments of the invention, the compound of formula X above is a compound of formula II,
/>
wherein,
X 1 selected from-C (R) 6 ) =sum-n=;
X 2 selected from-C (-L-R) 3 ) =sum-n=; when a plurality of L and R are present at the same time 3 When each L or R 3 The same or different from each other;
R 1 selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl and 9-12 membered aryl-heterocyclo, wherein said C 1-8 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, and 9-12 membered aryl-heterocyclo are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-OR 37 and-SR 37 ;
R 4 Is NR (NR) 41a R 41b ;R 41a And R is 41b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, or R 41a And R4 1b Together with the N atom to which it is attached form a 4-7 membered heterocyclic group, wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 4-7 membered heterocyclyl, cyano, nitro, -OR 37 、-SR 37 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-C(=O)OR 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 and-NR 31 R 32 And R is 41a And R is 41b Are not hydrogen at the same time;
R 6 selected from hydrogen, halogen, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 1-4 Alkoxy, C 38 Cycloalkyl and 4-10 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and-NR 31 R 32 ;
L is- (L) 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 、L 2 And L 3 Each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -NR 33 -、-S(=O)-、-S(=O) 2 -, -C (=O) -and-CR 36a R 36b -, wherein the C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene and 5-10 membered heteroarylene are each optionally substituted with one or more substituents, each independently selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and-NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the n, p and q are each independently 0, 1 or 2;
R 3 selected from hydrogen, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, -C(=O)OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-C(=NR 38 )NR 31 R 32 、-NR 33 C(=NR 38 )NR 31 R 32 、-P(R 39 ) 2 、-P(OR 39 ) 2 、-P(=O)R 39 R 40 、-P(=O)(OR 39 )OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylalkylheterocyclyl, 9-12 membered arylalkylheteroaryl, and 9-12 membered arylalkylcycloalkyl are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, hydroxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-OR 37 、-SR 37 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-C(=NR 38 )NR 31 R 32 、-NR 33 C(=NR 38 )NR 31 R 32 、-N=NR 38 、-P(R 39 ) 2 、-P(OR 39 ) 2 、-P(=O)R 39 R 40 and-P (=o) (OR 39 )OR 30 ;
R 30 、R 37 、R 39 And R is 40 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl), wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl) each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 Haloalkoxy, -C (=o) O (C) 1-6 Alkyl), -C (=O) NR 31 R 32 、-NR 31 R 32 、-NR 33 C(=O)R 34 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 ;
R 35 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 Aryl and C 1-8 Alkylene- (5-10 membered heteroaryl), wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 Haloalkoxy, -C (=o) O (C) 1-6 Alkyl), -C (=O) NR 31 R 32 、-NR 31 R 32 、-NR 33 C(=O)R 34 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 ;
R 31 、R 32 、R 33 And R is 34 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-to 10-membered heteroaryl, or R 31 And R is 32 Together with the N atom to which it is attached form a 4-8 membered heterocyclic group, or R 33 And R is 34 Together with the N atom and the C atom to which they are correspondingly attached form a 4-8 membered heterocyclic group, wherein the C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from hydroxy, cyano, halogen, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl and 5-10 membered heteroaryl;
R 36a and R is 36b Each independently selected from hydrogen, C 1-8 Alkyl and C 1-8 Alkoxy, wherein said C 1-8 Alkyl and C 1-8 Alkoxy groups are each optionally substituted with one or more substituents, each of which is independently selected from hydroxy, cyano, halogen, amino, methylamino and dimethylamino, or R 36a And R is 36b Together with the C atom to which it is attached form a 3-7 membered cycloalkyl or heterocyclyl;
R 38 selected from hydrogen, hydroxy, cyano, nitro, -S (=o) R 35 and-S (=o) 2 R 35 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
When a plurality of R are simultaneously present 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36a 、R 36b 、R 37 、R 38 、R 39 And/or R 40 When each R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36a 、R 36b 、R 37 、R 38 、R 39 Or R is 40 The same as or different from each other.
In some embodiments of the invention, the compound of formula X or formula II described above is a compound of formula IV,
wherein R is 1 、R 3 、R 4 、X 1 And L is as defined above.
In some embodiments of the invention, the compound of formulSup>A X, formulSup>A II or formulSup>A IV above is Sup>A compound of formulSup>A IV-A,
wherein,
R 1 、R 4 and R is 6 As defined hereinabove;
L a is-L 1a -(L 2 ) p -(L 3 ) q -, wherein L 1a Selected from the group consisting of-O-, -S-and-NR 33 -, and L 2 、L 3 P and q are as defined above;
R 3a selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylalkylheterocyclyl, 9-12 membered arylalkylheteroaryl, and 9-12 membered arylalkylcycloalkyl are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, nitro, hydroxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-OR 37 、-SR 37 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 and-NR 33 C(=O)OR 30 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 30 、R 31 、R 32 、R 33 、R 34 、R 35 And R is 37 As defined hereinabove.
In some embodiments of the invention, the compound of formula X, formula II or formula IV above is a compound of formula IV-B,
wherein,
R 1 、R 4 and R is 6 As defined hereinabove;
L b is- (L) 1b ) n -(L 2b ) p -(L 3b ) q -, wherein L 1b 、L 2b And L 3b Each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -NR 33 -、-S(=O)-、-S(=O) 2 -, -C (=O) -and-CR 36a R 36b -, wherein the C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene and 5-10 membered heteroarylene are each optionally substituted with one or more substituents, each independently selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 1-4 An alkoxy group; n, p and q are each independently 0 or 1;
R 3b selected from hydrogen, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroarylEach of the 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroarylo and 9-12 membered aryl-cycloalkyl is optionally substituted with one or more substituents, each of which is independently selected from halogen, cyano, nitro, hydroxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O)R 35 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-S(=O) 2 NR 31 R 32 、-OR 37 、-SR 37 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 and-NR 33 C(=O)OR 30 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
The conditions are as follows:
when n+p+q is greater than or equal to 1, - (L) 1b ) n -(L 2b ) p -(L 3b ) q L in connection with thienopyridines of the formula IV-B 1b Or L 2b Or L 3b not-O-, -S-, -NR 33 -、-S(=O)-、-S(=O) 2 -or-C (=o) -;
when n+p+q=0, R 3b Not hydrogen, halogen, cyano, nitro, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-OC(=O)NR 31 R 32 、-NR 33 C(=O)NR 31 R 32 、-NR 33 C(=O)OR 30 、-S(=O)R 35 、-S(=O)NR 31 R 32 or-S (=o) 2 NR 31 R 32 。
In some embodiments of the invention, the compound of formulSup>A X, formulSup>A II, formulSup>A IV or formulSup>A IV-A described above is Sup>A compound of formulSup>A V,
wherein,
R 1 、R 3 、R 4 、L 2 、L 3 p and q are as defined above;
R 33 selected from hydrogen and C 1-6 An alkyl group.
In some preferred embodiments of the invention, R in a compound of formula I, formula II, formula III, formula IV or formula V 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl, -C (=o) OR 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-OR 37 、-SR 37 、-C(=O)R 30 、-OC(=O)R 30 、-NR 33 C(=O)NR 31 R 32 and-S (=o) 2 NR 31 R 32 Wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, C 6-10 Aryl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, hydroxy, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-7 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl, -C (=o) OR 30 、-C(=O)R 30 、-C(=O)NR 31 R 32 、-NR 33 C(=O)R 34 、-NR 31 R 32 、-S(=O) 2 R 35 、-S(=O)NR 31 R 32 、-OR 37 、-SR 37 and-NR 33 C(=O)OR 30 。
In some preferred embodiments of the invention, R in a compound of formula I, formula II, formula III, formula IV or formula V 3 Selected from cyclobutyl, hydroxy, oxetan-3-ylMethoxy, methyl, morpholin-4-yl->2-oxo-pyrrolidin-1-yl->Cyclopropyl, cyclopropylamino, difluoromethyl, fluoro, isopropyl, (1R, 5S,6 s) -1, 5-dimethyl-3-azabicyclo [3.1.0 ]Hex-6-yl->Isobutyl, hydroxymethyl and tetrahydro-2H-pyran-4-yl +.>
In some preferred embodiments of the invention, L in the compounds of formula I, formula II, formula III or formula IV is- (L) 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 、L 2 And L 3 Each independently selected from-NR 33 -, -C (=O) -, 5-to 10-membered heteroarylene, C 1-6 Alkylene and C 3-6 Cycloalkylene group, wherein the 5-10 membered heterocyclylene group, C 1-6 Alkylene and C 3-6 Cycloalkylene radicals are each optionally substituted with one or more substituents, each independently selected from hydroxy, C 1-6 Alkyl, C 1-4 Hydroxyalkyl and C 1-4 An alkoxy group.
In some preferred embodiments of the invention, L in the compound of formula V 2 And L 3 Each independently selected from C 1-6 Alkylene, C 3-6 Cycloalkylene, 5-10 membered heteroarylene, 4-10 membered heterocyclylene, -C (=o)) -and-NR 33 -, wherein the C 1-6 Alkylene, C 3-6 Each of the cycloalkylene, 5-10 membered heteroarylene, and 4-10 membered heterocyclylene is optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 1-4 An alkoxy group.
In some more preferred embodiments of the invention, the formula I, formula II, formula III or formula IV compounds in the form of-L-R 3 or-L in Sup>A compound of formulSup>A III-A or formulSup>A IV-A a -R 3a or-L in the compounds of the formula III-B or of the formula IV-B b -R 3b or-N (R) in the compound of formula V 33 )-(L 2 ) p -(L 3 ) q -R 3 Selected from:
preferably:
in some preferred embodiments of the invention, R in Sup>A compound of formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-A, formulSup>A IV-A, formulSup>A III-B, formulSup>A IV-B or formulSup>A V 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, C 6-10 Aryl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents, each independently selected from halogen, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl and C 1-4 Hydroxyalkyl groups.
In some more preferred embodiments of the invention, R in Sup>A compound of formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-A, formulSup>A IV-A, formulSup>A III-B, formulSup>A IV-B or formulSup>A V 1 Selected from 5-6 membered heteroaryl and 4-7 membered heterocyclyl, especially 5-6 membered nitrogen containing heteroaryl (e.g. pyrazolyl or pyridinyl) and 6 membered oxygen containing heterocyclyl (e.g. tetrahydro-2H-pyran-2-yl), optionally substituted with one or more substituents, each independently selected from halogen (preferably fluoro), C 1-3 Alkyl (preferably methyl) and 4-7 membered heterocyclyl (preferably tetrahydro-2H-pyran-2-yl).
In some more preferred embodiments of the invention, R in Sup>A compound of formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-A, formulSup>A IV-A, formulSup>A III-B, formulSup>A IV-B or formulSup>A V 1 Is a 5-6 membered heteroaryl (preferably a 5-6 membered nitrogen containing heteroaryl, more preferably a pyrazolyl or pyridinyl) optionally substituted with one or more substituents, each independently selected from halogen (preferably fluoro), C 1-3 Alkyl (preferably methyl) and 4-7 membered heterocyclyl (preferably tetrahydro-2H-pyran-2-yl).
In some more preferred embodiments of the invention, R in Sup>A compound of formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-A, formulSup>A IV-A, formulSup>A III-B, formulSup>A IV-B or formulSup>A V 1 Selected from pyrazolyl, 1, 3-dimethyl-1H-pyrazolyl, methylpyridinyl, and 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolyl; preferably, R 1 Selected from the group consisting of 1H-pyrazol-5-yl, 1, 3-dimethyl-1H-pyrazol-5-yl, 2-methylpyridin-6-yl, and 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-2-yl; more preferably, R 1 Selected from the group consisting of 1H-pyrazol-5-yl and 2-methylpyridin-6-yl.
In some preferred embodiments of the invention, R in the compounds of formula I, formula III-A or formula III-B 2 is-NR 41a R 41b Wherein R is 41a And R is 41b Each independently selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl, and R 41a And R is 41b Not both hydrogen, or R 41a And R is 41b Together with the N atom to which it is attached form a 4-6 membered heterocyclic group, wherein said C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from C 1-4 Alkyl, C 1-4 Hydroxyalkyl and-C (=o)OH。
In some preferred embodiments of the invention, R in Sup>A compound of formulSup>A II, formulSup>A IV-A, formulSup>A IV-B or formulSup>A V 4 is-NR 41a R 41b Wherein R is 41a And R is 41b Each independently selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl, and R 41a And R is 41b Not both hydrogen, or R 41a And R is 41b Together with the N atom to which it is attached form a 4-6 membered heterocyclic group, wherein said C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl are each optionally substituted with one or more substituents each independently selected from C 1-4 Alkyl, C 1-4 Hydroxyalkyl and carboxyl.
In some more preferred embodiments of the invention, R4 in the compounds of formulSup>A II, formulSup>A IV-A, formulSup>A IV-B or formulSup>A V is-NR 41a R 41b Wherein R is 41a And R is 41b Each independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl and cyclopropyl, and R 41a And R is 41b Not both hydrogen, or R 41a And R is 41b Together with the N atom to which it is attached, form pyrrolidin-1-yl, wherein the methyl, ethyl, isopropyl, tert-butyl, cyclopropyl and pyrrolidin-1-yl are each optionally substituted with one or more substituents, each of which is independently selected from methyl, tert-butyl, hydroxymethyl and carboxyl.
In some more preferred embodiments of the invention, R in Sup>A compound of formulSup>A II, formulSup>A IV-A, formulSup>A IV-B or formulSup>A V 4 Selected from-N (H) -C (CH) 3 ) 3 、-N(H)-CH 3 、-N(H)-C 2 H 5 -N (H) -isopropyl, -N (H) -cyclopropyl, -N (CH) 3 ) 2 、-N(C 2 H 5 ) 2 、-N(H)-CH 2 -COOH、-N(H)-C 2 H 4 -OH, -N (H) -1-methylcyclopropyl, -N (H) -C (CH) 3 ) 2 -CH 2 -C(CH 3 ) 3 And pyrrolidin-1-yl; preferably, R 4 is-N (H) -C (CH) 3 ) 3 。
In the present inventionIn some preferred embodiments, m in the compound of formula I or formula III is 0 or 1, R 5 Selected from hydrogen, halogen, C 1-4 Alkyl and C 3-6 Cycloalkyl, wherein said C 1-4 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxy, cyano, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and-NR 31 R 32 。
In some preferred embodiments of the invention, R in Sup>A compound of formulSup>A II, formulSup>A IV-A, formulSup>A IV-B or formulSup>A V 6 Selected from hydrogen, halogen (preferably chlorine), C 1-4 Alkyl (preferably methyl) and C 3-6 Cycloalkyl groups. In some more preferred embodiments of the invention, R in Sup>A compound of formulSup>A II, formulSup>A IV-A, formulSup>A IV-B or formulSup>A V 6 Is hydrogen.
In some preferred embodiments of the invention, R in the compound of formula V 33 Selected from hydrogen, methyl and or ethyl; preferably; r is R 33 Is hydrogen.
In addition, the present invention provides specific compounds having the structure of formulSup>A X, formulSup>A II, formulSup>A IV-Sup>A or formulSup>A V, or pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs thereof, including but not limited to compounds having the structure and designations shown in the following table:
/>
/>
/>
/>
/>
/>
/>
/>
/>
[ preparation method ]
The present invention provides the above compound of formula III-A and compound of formula III-B (when R in formula III 5 In the case of hydrogen, a compound of formula III-A-1 and a compound of formula III-B-1), respectively), comprising the steps of:
step 1: carrying out halogenation reaction on the compound III-1 to generate a compound III-2;
x represents a halogen atom selected from chlorine, bromine and iodine;
step 2: oxidizing the compound III-2 to generate a compound III-3;
step 3: compounds III-3 and R 2 H reaction to give compound III-4, wherein R 2 Is connected with quinoline through nitrogen atom;
step 4: the compound III-4 is subjected to a coupling reaction to generate a compound III-5;
step 5-1: the compound III-5 is subjected to substitution reaction to generate a compound III-A-1;
step 5-2: the compound III-5 is subjected to a coupling reaction to generate a compound III-B-1;
wherein R is 1 、R 2 、R 3a 、R 3b 、L a And L b As defined hereinabove.
In some preferred embodiments of the present invention, the halogenating agent that may be used in the halogenation reaction in step 1 comprises phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, hydrogen bromide, and the like; solvents that may be used include 1, 4-dioxane, N-dimethylformamide, ethyl acetate, and the like; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, the oxidizing agent that can be used for the oxidation reaction in step 2 includes m-chloroperoxybenzoic acid, hydrogen peroxide, carbamide peroxide, and the like; solvents that may be used include methylene chloride, chloroform, 1, 2-dichloroethane, 1, 4-dioxane, etc.; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, solvents that may be used for the reaction in step 3 include tetrahydrofuran, 1, 4-dioxane, toluene, and the like; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, the coupling reaction in step 4 comprises a Suzuki reaction, a Stille reaction, and the like, R 1 By boric acid (e.g. R) 1 -B(OH) 2 ) Boric acid esters (e.g) Or organotin compounds (e.g. R 1 -Sn(n-Bu) 3 ) Participating in the reaction; catalysts that may be used include Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 ·CH 2 Cl 2 Etc.; alkaline agents that may be used include cesium carbonate (Cs) 2 CO 3 ) Potassium phosphate (K) 3 PO 4 ) Sodium carbonate (Na) 2 CO 3 ) Potassium acetate (AcOK), sodium bicarbonate (NaHCO) 3 ) Potassium carbonate (K) 2 CO 3 ) Etc.; solvents that can be used are 1, 4-dioxane/water (a combination of both of the slash expressions), N-dimethylformamide/water, dimethyl sulfoxide/water, acetonitrile/water, toluene/water, and the like; the reaction temperature is 60 ℃ to 180 ℃. />
In some preferred embodiments of the present invention, the solvent that can be used for the substitution reaction in step 5-1 is N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, or the like; basic reagents that may be used include triethylamine, N-diisopropylethylamine, potassium carbonate, potassium t-butoxide, sodium hydroxide, and the like; the reaction temperature is-20 ℃ to 180 ℃.
In some preferred embodiments of the present invention, the coupling reaction in step 5-2 comprises a Suzuki reaction, a Stille reaction, and the like, R 3b -L b By boric acid (e.g. R) 3b -L b -B(OH) 2 ) Boric acid esters (e.g) Or organotin compounds (e.g. R 3b -L b -Sn(n-Bu) 3 ) Participating in the reaction; catalysts that may be used include Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 ·CH 2 Cl 2 Etc.; alkaline agents that may be used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, and the like; solvents that can be used are 1, 4-dioxane/water, N-dimethylformamide/water, dimethyl sulfoxide/water, acetonitrile/water, toluene/water, etc.; the reaction temperature is 60 ℃ to 180 ℃.
The present invention provides the above compound of formula III-A and compound of formula III-B (when R in formula III 5 When fluorine and m is 1, respectively a compound of formula III-A-2 and a compound of formula III-B-2), comprising the steps of:
step 1: reacting the compound III-6 with Meldrum's acid under the catalysis of Lewis acid to generate a compound III-7;
step 2: the compound III-7 is subjected to condensation reaction to generate a compound III-8;
wherein Y represents a sulfonyl group selected from the group consisting of methanesulfonyl (Ms), p-toluenesulfonyl (Ts) and trifluoromethanesulfonyl (Tf);
step 3-1: the compound III-8 is subjected to substitution reaction to generate a compound III-9-1;
Step 3-2: the compound III-8 is subjected to a coupling reaction to generate a compound I-9-2;
step 4: the compounds III-9-1 and III-9-2 are respectively subjected to halogenation reaction to generate the compounds III-10-1 and III-10-2;
wherein X represents a halogen atom selected from chlorine, bromine and iodine;
step 5: compounds III-10-1 and III-10-2 are reacted with R2H to give compounds III-11-1 and III-11-2, respectively, where R 2 Is connected with quinoline through nitrogen atom;
step 6: the compounds III-11-1 and III-11-2 are respectively subjected to coupling reaction to generate the compounds III-A-2 and III-B-2;
wherein R is 1 、R 2 、R 3a 、R 3b 、L a And L b As defined hereinabove.
In some preferred embodiments of the present invention, the Lewis acid that may be used for the reaction in step 1 includes Eaton's reagent, aluminum trichloride, boron trifluoride, ferric bromide, etc.; solvents that may be used include tetrahydrofuran, 1, 4-dioxane, toluene, and the like; the reaction temperature is 20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, the basic reagents that may be used for the substitution reaction in step 2 include triethylamine, N-diisopropylethylamine, potassium carbonate, and the like; solvents which may be used are tetrahydrofuran, 1, 4-dioxane, toluene, etc.; the reaction temperature is 20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, solvents that may be used for the substitution reaction in steps 3-1 include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, and the like; basic reagents that may be used include triethylamine, N-diisopropylethylamine, potassium carbonate, potassium t-butoxide, sodium hydroxide, and the like; the reaction temperature is-20 ℃ to 180 ℃.
In some preferred embodiments of the present invention, the coupling reaction in step 3-2 comprises a Suzuki reaction, a Stille reaction, and the like, R 3b -L b By boric acid (e.g. R) 3b -L b -B(OH) 2 ) Boric acid esters (e.g) Or organotin compounds (e.g. R 3b -L b -Sn(n-Bu) 3 ) Participating in the reaction; catalysts that may be used include Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 ·CH 2 Cl 2 Etc.; alkaline agents that may be used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, and the like; solvents that can be used are 1, 4-dioxane/water (a combination of both of the slash expressions), N-dimethylformamide/water, dimethyl sulfoxide/water, acetonitrile/water, toluene/water, and the like; the reaction temperature is 60 ℃ to 180 ℃.
In some preferred embodiments of the present invention, the halogenating agent that may be used in the halogenation reaction in step 4 includes phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, hydrogen bromide, and the like; solvents that may be used include 1, 4-dioxane, N-dimethylformamide, ethyl acetate, and the like; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, solvents that may be used for the reaction in step 5 include tetrahydrofuran, 1, 4-dioxane, toluene, and the like; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, the coupling reaction in step 6 comprises a Suzuki reaction, a Stille reaction, and the like, R 1 By boric acid (e.g. R) 1 -B(OH) 2 ) Boric acid esters (e.g) Or organotin compounds (e.g. R 1 -Sn(n-Bu) 3 ) Participating in the reaction; catalysts that may be used include Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 ·CH 2 Cl 2 Etc.; alkaline agents that may be used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, and the like; solvents that can be used are 1, 4-dioxane/water, N-dimethylformamide/water, dimethyl sulfoxide/water, acetonitrile/water, toluene/water, etc.; the reaction temperature is 60 ℃ to 180 ℃.
The present invention provides the above compound of formulSup>A IV-A and compound of formulSup>A IV-B (when X in formulSup>A IV 1 For-ch=the compounds of formulSup>A IV-Sup>A-1 and IV-B-1, respectively), comprising the steps of:
step 1: the compound IV-1 is subjected to halogenation reaction to generate a compound IV-2;
x represents a halogen atom selected from chlorine and bromine;
step 2: the compound IV-2 is subjected to iodination reaction to generate a compound IV-3;
step 3: the compound IV-3 is subjected to oxidation reaction to generate a compound IV-4;
step 4: compounds IV-4 and R 4 H reaction to give compound IV-5, wherein R 4 Is connected with thienopyridine through a nitrogen atom;
step 5: the compound IV-5 is subjected to a coupling reaction to generate a compound IV-6;
step 6-1: the compound IV-6 is subjected to substitution reaction to generate Sup>A compound IV-A-1;
Step 6-2: the compound IV-6 is subjected to a coupling reaction to generate a compound IV-B-1;
wherein R is 1 、R 3a 、R 3b 、R 4 、L a And L b As defined hereinabove.
In some preferred embodiments of the present invention, the halogenating agent that may be used in the halogenation reaction in step 1 comprises phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, hydrogen bromide, and the like; solvents which can be used are 1, 4-dioxane, N-dimethylformamide, ethyl acetate, etc.; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, iodinating agents that may be used in the iodination reaction in step 2 include elemental iodine, N-iodosuccinimide (NIS), hydrogen iodide, and the like; solvents that may be used include acetic acid, 1, 4-dioxane, N-dimethylformamide, ethyl acetate, and the like; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, the oxidizing agent that can be used for the oxidation reaction in step 3 includes m-chloroperoxybenzoic acid, hydrogen peroxide, carbamide peroxide, and the like; solvents which can be used are methylene chloride, chloroform, 1, 2-dichloroethane, 1, 4-dioxane, etc.; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, solvents that may be used for the reaction in step 4 are tetrahydrofuran, 1, 4-dioxane, toluene, etc.; the reaction temperature is-20 ℃ to 100 ℃.
In some preferred embodiments of the present invention, the coupling reaction in step 5 comprises a Suzuki reaction, a Stille reaction, and the like, R 1 By boric acid (e.g. R) 1 -B(OH) 2 ) Boric acid esters (e.g) Or organotin compounds (e.g. R 1 -Sn(n-Bu) 3 ) Participating in the reaction; catalysts that may be used include Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 ·CH 2 Cl 2 Etc.; alkaline agents that may be used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, and the like; solvents that can be used are 1, 4-dioxane/water, N-dimethylformamide/water, dimethyl sulfoxide/water, acetonitrile/water, toluene/water, etc.; the reaction temperature is 60 ℃ to 180 ℃.
In some preferred embodiments of the present invention, solvents that may be used for the substitution reaction in step 6-1 include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, and the like; basic reagents that may be used include triethylamine, N-diisopropylethylamine, potassium carbonate, potassium t-butoxide, sodium hydroxide, and the like; the reaction temperature is-20 ℃ to 180 ℃.
In some preferred embodiments of the present invention, the coupling reaction in step 6-2 comprises a Suzuki reaction, a Stille reaction, and the like, R 3b -L b By boric acid (e.g. R) 3b -L b -B(OH) 2 ) Boric acid esters (e.g ) Or organotin compounds (e.g. R 3b -L b -Sn(n-Bu) 3 ) Participating in the reaction; catalysts that may be used include Pd (PPh) 3 ) 4 、Pd(dppf)Cl 2 ·CH 2 Cl 2 Etc.; alkaline agents that may be used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, and the like; solvents which can be used are1, 4-dioxane/water (a combination of both of the slash expressions), N-dimethylformamide/water, dimethyl sulfoxide/water, acetonitrile/water, toluene/water, and the like; the reaction temperature is 40 ℃ to 180 ℃.
The present invention provides the above compound of formulSup>A IV-A and compound of formulSup>A IV-B (when X in formulSup>A IV 1 Is-ch=and R 1 In the case of 1H-pyrazol-5-yl, the compounds of formulSup>A IV-A-2 and of formulSup>A IV-B-2, respectively), comprising the following steps:
step 7: the compound IV-A-1 'and the compound IV-B-1' are respectively subjected to deprotection reaction to generate Sup>A compound IV-A-2 and Sup>A compound IV-B-2;
wherein R is 3a 、R 3b 、R 4 、L a And L b As defined hereinabove; PG 1 And PG 2 Represents a protecting group, each independently selected from tetrahydro-2H-pyran-2-yl (THP), t-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
In some preferred embodiments of the present invention, acids that may be used for the deprotection reactions in steps 7-1 and 7-2 include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aluminum chloride (Lewis acid), p-toluenesulfonic acid, and the like; the solvents that can be used are dichloromethane, ethyl acetate, 1, 4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, etc.; the reaction temperature is-10 ℃ to 180 ℃.
The invention provides Sup>A preparation method of the compound of the formulSup>A V, which takes an intermediate compound IV-6 in the preparation method of the compound of the formulSup>A IV-A and the compound of the formulSup>A IV-B as Sup>A raw material, and specifically comprises the following steps:
step 1: the compound IV-6 is subjected to substitution or coupling reaction to generate a compound V;
wherein R is 1 、R 3 、R 4 、R 33 、L 2 、L 3 P and q are as defined above.
In some preferred embodiments of the present invention, solvents that may be used for the substitution reaction in step 1 include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, and the like; basic reagents that may be used include triethylamine, N-diisopropylethylamine, potassium carbonate, potassium t-butoxide, sodium hydroxide, and the like; the reaction temperature is-20 ℃ to 180 ℃.
In some preferred embodiments of the present invention, the coupling reaction in step 1 comprises a Buchwald-Hartwig reaction; catalysts that may be used include Pd (PPh) 3 ) 4 、Pd 2 (dba) 3 、Pd(OAc) 2 、Pd(dppf)Cl 2 ·CH 2 Cl 2 Etc.; ligands that may be used include PPh 3 BINAP, xphos, davephos, brettphos, etc.; alkaline agents that may be used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium t-butoxide, triethylamine, N-diisopropylethylamine, sodium hydroxide, and the like; solvents which can be used are 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, toluene, etc.; the reaction temperature is 40 ℃ to 180 ℃.
[ pharmaceutical composition ]
The term "pharmaceutical composition" refers to a composition that can be used as a medicament comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to a pharmaceutical adjuvant that is compatible with the pharmaceutically active ingredient and is not harmful to the subject, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. Common pharmaceutically acceptable carriers include, but are not limited to, diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, smelling agents, preservatives, antioxidants, pH adjusting agents, solvents, co-solvents, surfactants, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences [ M ], mack Printing Company,1990.
The present invention provides Sup>A pharmaceutical composition comprising Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-A, formulSup>A III-B, formulSup>A IV-A, formulSup>A IV-B or formulSup>A V, or Sup>A pharmaceutically acceptable form thereof, as described above.
In some embodiments of the invention, the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
[ medical use ]
The term "agonist" refers to a compound that binds to and activates a receptor to elicit a downstream biological effect (biological effect) or response (response), including full agonist and partial agonist. Full agonists activate the receptor and produce the greatest effect (maximal effect or Emax). Partial agonists can bind to and activate receptors, but produce only partial effects (partial effects) relative to full agonists. When a full agonist and a partial agonist coexist, the partial agonist may sometimes become a partial antagonist by competing with the full agonist for a binding site or other mechanism at the receptor. The potency (measurable by EC 50) of a partial agonist is likely to be higher or lower than the potency of a full agonist. The NLRP3 agonists of the invention include NLRP3 full agonists and NLRP3 partial agonists.
The term "NLRP3" is generally known as NLR family pyrin domain containing 3 and is an inflammatory body. In the present invention, when referring to "NLRP3", the meaning includes nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, short peptides, polypeptides, proteins, homologous or heterologous molecules, subtypes, precursors, mutants, variants, derivatives, various spliceosomes, alleles, different species, and activation fragments, etc. of NLRP 3.
Whether Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-A, formulSup>A III-B, formulSup>A IV-A, formulSup>A IV-B or formulSup>A V or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition as described above, is capable of exhibiting Sup>A modulating effect (particularly agonistic activity) on NLRP3 and is useful as an NLRP3 modulator. Accordingly, the present invention provides the use of Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-Sup>A, formulSup>A III-B, formulSup>A IV-Sup>A, formulSup>A IV-B or formulSup>A V above, or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition as described above, as Sup>A modulator of NLRP 3.
In addition, the application also provides the use of the compound of the formulSup>A X, the formulSup>A I, the formulSup>A II, the formulSup>A III, the formulSup>A IV, the formulSup>A III-A, the formulSup>A III-B, the formulSup>A IV-A, the formulSup>A IV-B or the formulSup>A V or Sup>A pharmaceutically acceptable form thereof or the pharmaceutical composition in the preparation of Sup>A medicament for preventing and/or treating diseases mediated at least in part by NLRP 3.
The term "disease mediated at least in part by NLRP 3" refers to a disease in which the pathogenesis includes at least a portion of the factors associated with NLRP3, including, but not limited to, cancers (e.g., leukemia, lymphoma, myeloma, breast, ovarian, cervical, prostate, bladder, colon, rectal, colorectal, gastric, esophageal, oral, pancreatic, liver, lung, kidney, skin, bone, brain, glioma, melanoma, etc.).
[ method of treatment ]
The present invention provides a method for preventing and/or treating a disease mediated at least in part by NLRP3, comprising the steps of: sup>A prophylactically and/or therapeutically effective amount of Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-Sup>A, formulSup>A III-B, formulSup>A IV-Sup>A, formulSup>A IV-B or formulSup>A V above, or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition as described above, is administered to Sup>A subject in need thereof.
The term "prophylactically and/or therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient capable of eliciting a biological or medical response in a cell, tissue, organ or organism (e.g., an individual) to achieve a prophylactic and/or therapeutic effect.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered or several divided doses may be administered over time. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg, for example about 0.01 to about 10 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg human, the total is about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is divided into several smaller doses beforehand and administered in portions throughout the day.
The compounds of the present invention may be present in the pharmaceutical composition in an amount or amount of about 0.01 mg to about 1000mg.
Unless otherwise indicated, the term "treating" refers to reversing, alleviating, inhibiting the disorder or condition for which it is intended, or the progression of one or more symptoms of such disorder or condition. The term "administering" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the invention) to a subject or a cell, tissue, organ, biological fluid, etc. thereof, such that the pharmaceutically active ingredient or pharmaceutical composition is in contact with the subject or a cell, tissue, organ, biological fluid, etc. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like. For the above administration (administration) route, the pharmaceutical composition of the present invention may be used by a suitable dosage form. Suitable dosage forms include, but are not limited to, tablets, capsules, troches, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, suspensions, injections, elixirs, syrups and the like.
The term "in need thereof" refers to a judgment of a physician or other caregiver as to the need of an individual or as to the impending benefit from the prevention and/or treatment process based on various factors of the physician or other caregiver in their area of expertise.
The term "individual" (or subject) refers to a human or non-human animal (e.g., mammal). Exemplary human subjects include both human subjects suffering from a disease and normal human subjects. Exemplary animal subjects include all vertebrates, such as non-mammals (e.g., amphibians, reptiles, birds, etc.) and mammals (non-human primates, rodents, domestic animals, and/or domesticated animals, etc.).
[ Combined drug administration ]
The invention provides Sup>A pharmaceutical combination composition comprising Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A IH-A, formulSup>A III-B, formulSup>A IV-A, formulSup>A IV-B or formulSup>A V or Sup>A pharmaceutically acceptable form thereof or the pharmaceutical composition, and at least one other homodromous NLRP3 modulator.
The term "co-directional" means that when at least two modulators are administered to a target, their modulation directions should be substantially the same, either simultaneously exhibiting agonism, or simultaneously exhibiting antagonism. In particular, when the above pharmaceutical combination composition comprises Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-Sup>A, formulSup>A III-B, formulSup>A IV-Sup>A, formulSup>A IV-B or formulSup>A V, or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition, as an NLRP3 agonist, it further comprises at least one additional NLRP3 agonist, which pharmaceutical combination composition is suitable for the prevention and/or treatment of cancer; similarly, when the above pharmaceutical combination composition comprises Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-Sup>A, formulSup>A III-B, formulSup>A IV-Sup>A, formulSup>A IV-B or formulSup>A V, or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition, as an NLRP3 antagonist, it further comprises at least one additional NLRP3 antagonist, which pharmaceutical combination composition is suitable for use in the prevention and/or treatment of an immune disorder.
The present invention provides a method for preventing and/or treating cancer, comprising the steps of: sup>A prophylactically and/or therapeutically effective amount of Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-Sup>A, formulSup>A III-B, formulSup>A IV-Sup>A, formulSup>A IV-B or formulSup>A V above, or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition or pharmaceutical combination composition as described above, as an NLRP3 agonist is administered to Sup>A subject in need thereof.
The present invention provides a method for preventing and/or treating an immune disease, comprising the steps of: sup>A prophylactically and/or therapeutically effective amount of Sup>A compound of formulSup>A X, formulSup>A I, formulSup>A II, formulSup>A III, formulSup>A IV, formulSup>A III-Sup>A, formulSup>A III-B, formulSup>A IV-Sup>A, formulSup>A IV-B or formulSup>A V above, or Sup>A pharmaceutically acceptable form thereof, or Sup>A pharmaceutical composition or pharmaceutical combination composition as described above, and as an NLRP3 antagonist, is administered to Sup>A subject in need thereof.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention. If the experimental methods in the following examples do not specify specific conditions, the conditions are generally conventional or recommended by the manufacturer (e.g., room temperature of 20 to 30 ℃). The reagents used were purchased from Acros Organics, aldrich Chemical Company, shanghai Tebert chemical technologies Co., ltd. The percentages and parts appearing in the following examples are by weight unless otherwise indicated.
Abbreviations in the context of the present invention have the following meanings:
the structure of the compound of the invention is characterized by nuclear magnetic resonance hydrogen spectrum 1 H-NMR) and/or Mass Spectrometry (MS).
1 The H-NMR chemical shifts (δ) are reported in parts per million (ppm). 1 H-NMR was determined by AVANCE III HD-400 MHz nuclear magnetic resonance apparatus with deuterated methanol (CD) 3 OD), deuterated chloroform (CDCl 3) or deuterated dimethyl sulfoxide (DMSO-d) 6 ) The internal standard is Tetramethylsilane (TMS). Common abbreviations have the following meanings: s: single peak; d: a double peak; t: a triplet;q: a quartet; dd: a double peak; qd: four doublets; m: multiple peaks; br: broad peak (broad); j: coupling constants; hz: hertz.
The reaction was monitored by TLC or LC-MS.
TLC uses silica gel GF 254 (peninsula ocean) as the stationary phase.
LC-MS used an Aglient 1260 affinity/Aglient 6120 Quadrapol mass spectrometer.
The compounds of the present invention may be isolated and purified by preparative TLC, silica gel column chromatography, prep-HPLC and/or Flash column chromatography (Flash column chromatography).
Prep-HPLC using Agilent 1260 preparative liquid chromatograph with detection wavelength 214nm or 254nm; the column was Waters SunFire Prep C OBD (19 mm. Times.150 mm. Times.5.0. Mu.rm); the column temperature was 25 ℃, and the elution conditions were as follows:
Condition 1:10% -90% acetonitrile and 90% -10% ammonium formate aqueous solution (0.05%, w/v), 0-16min; flow rate: 24mL/min;
condition 2:10% -46% acetonitrile and 90% -54% ammonium bicarbonate water solution (0.05%, w/v) for 0-7.2min; flow rate: 24mL/min;
condition 3:10% -90% acetonitrile and 90% -10% formic acid water solution (0.05%, w/v) for 0-16min; flow rate: 28mL/min;
condition 4:10% -90% acetonitrile and 90% -10% ammonium bicarbonate aqueous solution (0.05%, w/v) for 0-16min; flow rate: 28mL/min;
condition 5:30% -90% acetonitrile and 70% -10% ammonium bicarbonate aqueous solution (0.05%, w/v) for 0-16min; flow rate: 24mL/min;
condition 6:10% -70% acetonitrile and 90% -30% ammonium bicarbonate aqueous solution (0.05%, w/v) for 0-18min; flow rate: 24mL/min.
Column chromatography generally uses 200-300 mesh silica gel (Qingdao ocean) as the stationary phase. Eluent system a: dichloromethane and methanol; eluent system B: petroleum ether and ethyl acetate. The volume ratio of the two eluent systems is adjusted according to the polarity of the compounds.
Flash column chromatography using a Biotage flash column chromatograph.
The microwave reaction was performed using a Biotage Initiator + microwave reactor.
In the following examples, the reaction temperature was room temperature (15℃to 30 ℃) unless otherwise specified.
The reagents used in this application are available from Acros Organics, aldrich Chemical Company or tertbe chemistry, among others.
Intermediate preparation example 1: (7-bromo-N-tert-butyl-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-amine (compound 2 f).
Step 1: synthesis of 7-bromothieno [3,2-b ] pyridine (Compound 2 b).
Phosphorus oxybromide (158.90 g,555.61 mmol) was heated to 60℃to a molten state, and compound 1a (14 g,92.60 mmol) was added thereto, and the temperature was raised to 100℃for 2 hours. The reaction solution was slowly poured into ice water and pH > 8 was adjusted with sodium hydroxide. The organic layer was dried and concentrated. Purification by column chromatography (eluent system B) afforded compound 2B (18.5 g).
MS(ESI):m/z 213.9[M+H] + 。
Step 2: synthesis of 7-bromo-2-iodothieno [3,2-b ] pyridine (Compound 2 c).
LDA (4M, 14.2 mL) was slowly added to a solution of compound 2b (10 g,46.71 mmol) in THF (100 mL) at-65℃and the reaction was stirred at low temperature for 1 hour. A solution of elemental iodine (14.18 g,56.05 mmol) in THF (80 mL) was slowly added to the reaction system and reacted at low temperature for 2 hours. The reaction was allowed to slowly warm to room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride. EA extraction, drying and concentrating the organic layer. Purification by column chromatography (eluent system B) afforded compound 2c (13.5 g).
MS(ESI):m/z 339.9[M+H] + 。
Step 3: synthesis of 7-bromo-2-iodothieno [3,2-b ] pyridine 4-oxide (Compound 2 d).
Metroproperoxide benzoic acid (3.57 g,17.65 mmol) was added to a solution of compound 2c (4.08 g,11.77 mmol) in DCM (50 mL) at room temperature and reacted for 4 hours at room temperature. The reaction was quenched with saturated aqueous sodium carbonate and extracted with DCM. The organic layer was dried, concentrated, slurried with DCM, and filtered to give compound 2d (3.0 g).
MS(ESI):m/z 355.9[M+H] + 。
Step 4: synthesis of 7-bromo-N-tert-butyl-2-iodothieno [3,2-b ] pyridin-5-amine (Compound 2 e).
Tert-butylamine (3.22 g,44.12 mmol), p-toluenesulfonic anhydride (7.19 g,22.06 mmol) were added sequentially to a solution of compound 2d (3.0 g,8.82 mmol) in chloroform (15 mL)/benzotrifluoride (15 mL) at 0deg.C. The reaction was carried out at 0℃for 1 hour. The reaction solution was filtered and the mother liquor was concentrated. Purification by column chromatography (eluent system B) afforded compound 2e (2.3 g).
MS(ESI):m/z 435.0[M+Na] + 。
Step 5: synthesis of 7-bromo-N-tert-butyl-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-amine (Compound 2 f).
Potassium carbonate (1.54 g,11.19 mmol), pd (dppf) Cl were added sequentially at room temperature 2 (204.49 mg, 279.74. Mu. Mol) was added to a solution of compound 1f (1.87 g,6.71 mmol) and compound 2e (2.3 g,5.59 mmol) in 1, 4-dioxane (20 mL)/water (2 mL), and then the reaction was stirred at 50℃for 8 hours. The reaction was quenched with water and extracted with EA (40 mL. Times.3). The organic layer was concentrated by drying and purified by column chromatography (PE: ea=5:1) to give compound 2f (2.0 g).
MS(ESI):m/z 435.0[M+H] + 。
Example 1:3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (compound 2).
The first step: synthesis of 3- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (1 b).
3-aminopropanol (69 mg))、2f(200mg)、Brettphos(49.31mg)、Pd 2 (dba) 3 (42.07 mg) and potassium t-butoxide (154.64 mg) were added to 1, 4-dioxane (8 mL), and the mixture was stirred at 110℃for 10 hours under nitrogen. Cooled, filtered, and the filtrate concentrated and purified by chromatography on a silica gel plate (eluent system B) to give 1B (23 mg).
MS(ESI):m/z 430.2[M+H] + 。
And a second step of: synthesis of 3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (Compound 2).
1b (15 mg) and p-toluenesulfonic acid (8 mg) were added to methanol (5 mL), stirred at 25℃for 3 hours, concentrated under reduced pressure, purified by Prep-HPLC (elution condition 2), and lyophilized to give compound 2 (12 mg).
MS(ESI):m/z 346.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.91(s,1H),7.79(s,1H),7.36(s,1H),6.77(s,1H),5.96(s,1H),5.68-5.71(m,2H),4.53-4.55(m,1H),3.51-3.52(m,2H),3.16-3.35(m,2H),1.75-1.76(m,2H),1.41(s,9H)。
Example 2:3- (5-tert-butylamino) -2- (1, 3-dimethyl-1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (compound 3).
The first step: synthesis of 7-bromo-N-tert-butyl-2- (1, 3-dimethyl-1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-amine (2 a).
2e (71.31 mg), 1, 3-dimethyl-1H-pyrazole-5-boronic acid pinacol ester (35.59 mg), potassium carbonate (73.85 mg), pd (dppf) Cl 2 (21.83 mg) was added to a mixed system of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 The reaction was carried out at 50℃for 4 hours after the displacement. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and subjected to thin layer chromatography (eluent system B) to give 2a (90 mg).
MS(ESI):m/z 379[M+H] + 。
And a second step of: synthesis of 3- (5-tert-butylamino) -2- (1, 3-dimethyl-1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (Compound 3).
3-amino-1-propanol (128.71 mg), 2a (130 mg), pd 2 (dba) 3 (62.77 mg), brettPhos (73.58 mg), potassium tert-butoxide (115.37 mg) were added to 1, 4-dioxane (5 mL), N 2 The reaction was carried out at 110℃for 5 hours after the displacement. The mixture was filtered, the cake was washed with dioxane, and the filtrate was concentrated under reduced pressure, and then purified by Prep-HPLC (elution condition 4) and lyophilized to give compound 3 (30 mg).
MS(ESI):m/z 374.1[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ7.25(s,1H),6.30(s,1H),6.11-6.08(m,1H),5.83(s,1H),5.73(s,1H),4.52(t,J=5.0Hz,1H),3.92(s,3H),3.52(dd,J=11.3,6.1Hz,2H),3.18(dd,J=12.6,6.7Hz,2H),2.16(s,3H),1.80-1.72(m,2H),1.41(s,9H)。
Example 3: n (N) 5 -tert-butyl-N 7 - (oxetan-3-yl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 4).
The first step: n (N) 5 -tert-butyl-N 7 - (oxetan-3-yl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (3 a).
Oxetan-3-amine (67 mg), 2f (200 mg), brettphos (49.31 mg), pd 2 (dba) 3 (42.07 mg) and potassium t-butoxide (154.64 mg) were added to 1, 4-dioxane (8 mL), and the mixture was stirred at 110℃for 10 hours under nitrogen. Cooled, filtered, and the filtrate concentrated and purified by chromatography on a silica gel plate (eluent system B) to give 3a (30 mg).
MS(ESI):m/z 428.2[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 - (oxetan-3-yl)) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 4).
3a (30 mg) and p-toluenesulfonic acid (16 mg) were added to methanol (5 mL), stirred at 25℃for 3 hours, concentrated under reduced pressure, purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 4 (4 mg).
MS(ESI):m/z 344.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.93(s,1H),7.80(s,1H),7.38(s,1H),6.71-6.79(m,2H),5.78(s,1H),5.39(s,1H),4.82-4.84(m,2H),4.51-4.58(m,3H),1.40(s,9H)。
Example 4: n (N) 5 -tert-butyl-N 7 - (cyclobutylmethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 5).
The first step: n (N) 5 -tert-butyl-N 7 - (cyclobutylmethyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (4 a).
2f (70 mg), cyclobutylmethylamine (68.5 mg), pd 2 (dba) 3 (30.3 mg), brettPhos (30.3 mg), and potassium t-butoxide (83 mg) were added to 1, 4-dioxane (3 mL), and the mixture was heated to 120℃for 4 hours after nitrogen substitution. The system was filtered, and the filtrate was concentrated and diluted with a small amount of methanol, followed by thin layer chromatography (eluent system a) to give 4a (62 mg).
MS(ESI):m/z 440.2[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 - (cyclobutylmethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 5).
4a (62 mg) was added to anhydrous methanol (3 mL), p-toluenesulfonic acid (73 mg) was added, and the reaction was reacted at room temperature for 0.5 hours, and the reaction solution was purified by Prep-HPLC (elution condition 2) and lyophilized to give compound 5 (16 mg).
MS(ESI):m/z 356.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.91(s,1H),7.79(s,1H),7.35(s,1H),6.77(s,1H),6.01(s,1H),5.72(s,1H),5.67(s,1H),3.57(t,J=6.4Hz,2H),2.71-2.60(m,1H),2.09-1.99(m,2H),1.91-1.81(m,2H),1.76-1.65(m,2H),1.40(s,9H)。
Example 5: (R) -N 5 -tert-butyl-N 7 - (1-methoxypropan-2-yl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 6).
The first step: n (N) 5 -tert-butyl-N 7 - ((R) -1-methoxypropan-2-yl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (5 a).
2f (70 mg), (R) -1-methoxy-2-propylamine (71.7 mg), pd 2 (dba) 3 (30.3 mg), brettPhos (30.3 mg), and potassium t-butoxide (83 mg) were added to 1, 4-dioxane (3 mL), and the mixture was heated to 120℃for 4 hours after nitrogen substitution. The system was filtered, and the filtrate was concentrated and diluted with a small amount of methanol, followed by thin layer chromatography (eluent system a) to give 5a (25 mg).
MS(ESI):m/z 444.2[M+H] + 。
And a second step of: (R) -N 5 -tert-butyl-N 7 - (1-methoxypropan-2-yl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 6).
5a (25 mg) was added to anhydrous methanol (3 mL), p-toluenesulfonic acid (29 mg) was added, and the reaction was reacted at room temperature for 0.5 hours, and the reaction solution was purified by Prep-HPLC (elution condition 2) and lyophilized to give compound 6 (10 mg).
MS(ESI):m/z 360.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.92(s,1H),7.80(s,1H),7.36(s,1H),6.78(s,1H),5.74(s,2H),5.64(s,1H),3.74-3.62(m,1H),3.50-3.43(m,1H),3.31-3.27(m,4H),1.41(s,9H),1.19(d,J=6.4Hz,3H)。
Example 6: n (N) 5 -tert-butyl-N 7 - ((3-methylpyridin-2-yl) methyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 7).
The first step: n (N) 5 -tert-butyl-N 7 - ((3-methylpyridin-2-yl) methyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (6 a).
2f (70 mg), 2-aminomethyl-3-methylpyridine hydrochloride (30.14 mg), potassium tert-butoxide (54.12 mg), pd (OAc) 2 (7.22 mg), BINAP (40.04 mg) was added to toluene (2 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 6a (50 mg).
MS(ESI):m/z 477.1[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 - ((3-methylpyridin-2-yl) methyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 7).
6a (20 mg) and p-toluenesulfonic acid (8.66 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 12 hours. Concentrating under reduced pressure, separating and purifying by Prep-HPLC (eluting condition 5), and lyophilizing to obtain compound 7.
MS(ESI):m/z 393.1[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.96(s,1H),8.44-8.42(m,1H),7.81(s,1H),7.65-7.62(m,1H),7.41(s,1H),7.28-7.25(m,1H),6.81(s,1H),6.44(s,1H),5.80(s,2H),4.45(d,J=4.4Hz,2H),2.36(s,3H),1.41(s,9H)。
Example 7: n (N) 5 -tert-butyl-N 7 - (2-morpholinoethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamines (Compounds8)。
The first step: n (N) 5 -tert-butyl-N 7 - (2-morpholinoethyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (7 a).
2f (70 mg), N- (2-aminoethyl) morpholine (24.7 mg), potassium tert-butoxide (54.12 mg), pd (OAc) 2 (7.22 mg), BINAP (40.04 mg) was added to toluene (2 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 7a (50 mg).
MS(ESI):m/z 485.1[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 - (2-morpholinoethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 8).
7a (20 mg) and p-toluenesulfonic acid (8.66 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 12 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 8 (3 mg).
MS(ESI):m/z 401.1[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.92(s,1H),7.79(s,1H),7.37(s,1H),6.78(s,1H),5.81-5.76(m,2H),5.70(s,1H),3.61-3.58(m,4H),3.26-3.22(m,2H),2.57-2.51(m,2H),2.49-2.43(m,4H),1.41(s,9H)。
Example 8:1- (2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) ethyl) -2-pyrrolidone (compound 9).
The first step: synthesis of 1- (2- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) ethyl) -2-pyrrolidone (8 a).
2f (100 mg), 1- (2-aminoethyl) -2-pyrrolidone (88.32 mg), potassium tert-butoxide (77.32 mg), pd (OAc) 2 (10.31 mg), BINAP (5721 mg) was added to toluene (3 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 8a (50 mg).
MS(ESI):m/z 483.2[M+H] + 。
And a second step of: synthesis of 1- (2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) ethyl) -2-pyrrolidone (Compound 9).
8a (30 mg) and p-toluenesulfonic acid (11.77 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 9 (12 mg).
MS(ESI):m/z 399.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.95(s,1H),7.79(s,1H),7.37(s,1H),6.77(s,1H),6.07(s,1H),5.72(d,J=5.2Hz,2H),3.44-3.38(m,4H),3.27(dd,J=11.8,5.9Hz,2H),2.23(t,J=8.1Hz,2H),1.97-1.87(m,2H),1.41(s,9H)。
Example 9: n (N) 5 -tert-butyl-N 7 - (cyclopropylmethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 10).
The first step: n (N) 5 -tert-butyl-N 7 - (cyclopropylmethyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (9 a).
2f (70 mg), cyclopropylmethylamine (57.99 mg), potassium tert-butoxide (54.90 mg), pd 2 (dba) 3 (29.42 mg), brettPhos (34.47 mg) was added to 1, 4-dioxane (2 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Spin-drying reaction solutionThe preparation was subjected to flash column chromatography (eluent system A) to give 9a (45 mg).
MS(ESI):m/z 426.2[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 - (cyclopropylmethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 10).
9a (45 mg) and p-toluenesulfonic acid (20.03 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 10 (15 mg).
MS(ESI):m/z 342.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.69(s,1H),7.56(s,1H),7.13(s,1H),6.54(s,1H),5.87(s,1H),5.50(s,2H),2.77(t,J=6.1Hz,2H),1.17(s,9H),0.96-0.87(m,1H),0.27-0.20(m,2H),0.02(q,J=4.8Hz,2H)。
Example 10:3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (compound 11).
The first step: synthesis of 3- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (10 a).
2f (70 mg), 3-amino-2, 2-dimethyl-1-propanol (49.76 mg), pd (OAc) 2 (3.61 mg), BINAP (20.02 mg), potassium t-butoxide (54.12 mg) were added to toluene (7 mL), N 2 Protection, heating to 120 ℃ and reacting for 5 hours. The system was filtered, and the filtrate was concentrated and diluted with a small amount of methanol, followed by thin layer chromatography (eluent system a) to give 10a (45 mg).
MS(ESI):m/z 458.2[M+H] + 。
And a second step of: synthesis of 3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (Compound 11).
10a (34 mg) was added to methanol (6 mL), p-toluenesulfonic acid (20.02 mg) was added, the reaction was allowed to react at 25℃for 2 hours, the reaction system was spin-dried, purified by Prep-HPLC (elution condition 4), and freeze-dried to give compound 11 (15 mg).
MS(ESI):m/z 374.2[M+H] + 。
1 H-NMR(400MHz,DMSO-d 6 ):δ12.93(s,1H),7.79(s,1H),7.37(s,1H),6.78(s,1H),5.79-5.65(m,3H),4.84(t,J=5.2Hz,1H),3.27(d,J=5.2Hz,2H),3.03(d,J=5.9Hz,2H),1.40(s,9H),0.90(s,6H)。
Example 11: n (N) 5 -tert-butyl-N 7 - (2, 2-difluoroethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 12).
The first step: n (N) 5 -tert-butyl-N 7 - (2, 2-difluoroethyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ]Pyridine-5, 7-diamine (11 a).
2f (70 mg), 2-difluoroethylamine (39.10 mg), pd (OAc) 2 (3.61 mg), BINAP (20.02 mg), potassium t-butoxide (54.12 mg) were added to toluene (7 mL), N 2 Protection, heating to 120 ℃ and reacting for 5 hours. The system was filtered, and the filtrate was concentrated and diluted with a small amount of methanol, followed by thin layer chromatography (eluent system a) to give 11a (55 mg).
MS(ESI):m/z 436.3[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 - (2, 2-difluoroethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 12).
11a (55 mg) was added to methanol (4 mL), reacted at 25℃for 2 hours, after the completion of the reaction, the system was concentrated and purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 12 (29 mg).
MS(ESI):m/z 352.1[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.95(s,1H),7.82(s,1H),7.41(s,1H),6.81(s,1H),6.39(t,J=7.3Hz,1H),6.17(tt,J=4.1Hz,1H),5.83(s,1H),5.79(s,1H),3.60-3.50(m,2H),1.43(s,9H)。
Example 12: n (N) 5 -tert-butyl-N 7 -isobutyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 13).
The first step: n (N) 5 -tert-butyl-N 7 -isobutyl-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (12 a).
2f (80 mg), isobutyl amine (40.28 mg), pd (OAc) 2 (4.12 mg), BINAP (22.88 mg), potassium t-butoxide (61.85 mg) were added to toluene (10 mL), N 2 Protecting, heating to 120 ℃ and reacting for 5 hours. The system was filtered, and the filtrate was concentrated and diluted with a small amount of methanol, followed by thin layer chromatography (eluent system a) to give 12a (50 mg).
MS(ESI):m/z 428.1[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 -isobutyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 13).
12a (35 mg) was added to methanol (5 mL), reacted at 25℃for 2 hours, and after concentration of the system, purified by Prep-HPLC (elution condition 4) and freeze-dried to give compound 13 (4 mg).
MS(ESI):m/z 344.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.91(s,1H),7.79(s,1H),7.36(s,1H),6.77(s,1H),6.09(s,1H),5.72(s,1H),5.66(s,1H),2.91(t,J=6.0Hz,2H),1.99-1.91(m,1H),1.40(s,9H),0.92(d,J=6.6Hz,6H)。
Example 13:3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2- (methoxymethyl) -1-propanol (compound 14).
The first step: n (N) 5 -tert-butyl-N 7 - (oxetan-3-ylmethyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (13 a).
2f (100 mg), 3-aminomethyl-1-oxetane (24.01 mg), potassium tert-butoxide (77.32 mg), pd (OAc) 2 (10.02 mg), BINAP (57.21 mg) was added to toluene (3 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 13a (80 mg).
MS(ESI):m/z 442.1[M+H] + 。
And a second step of: synthesis of 3- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2- (methoxymethyl) -1-propanol (Compound 14).
13a (20 mg) and p-toluenesulfonic acid (8.66 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 12 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 6), and lyophilized to give compound 14 (5 mg).
MS(ESI):m/z 390.1[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.91(s,1H),7.79(s,1H),7.36(s,1H),6.77(s,1H),5.95-5.92(m,1H),5.70-5.67(m,2H),4.59-4.57(m,1H),3.51-3.47(m,2H),3.44-3.35(m,2H),3.31(s,3H),3.14-3.11(m,2H),2.11-2.04(m,1H),1.41(s,9H)。
Example 14: (3- ((5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) methyl) oxetan-3-yl) methanol (compound 15).
The first step: synthesis of (3- ((5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) methyl) oxetan-3-yl) methanol (14 a).
2f (60 mg), 3-aminomethyl-3-hydroxymethyl-1-oxetane (64.58 mg), potassium tert-butoxide (46.39 mg), pd 2 (dba) 3 (25.24 mg), brettPhos (29.59 mg) was added to 1, 4-dioxane (2 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 14a (35 mg).
MS(ESI):m/z 472.2[M+H] + 。
And a second step of: synthesis of (3- ((5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) methyl) oxetan-3-yl) methanol (Compound 15).
14a (35 mg) and p-toluenesulfonic acid (14.06 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 15 (12 mg).
MS(ESI):m/z 388.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.93(s,1H),7.80(s,1H),7.37(s,1H),6.78(s,1H),6.04(t,J=5.7Hz,1H),5.73(d,J=11.9Hz,2H),5.06(t,J=5.1Hz,1H),4.39(d,J=5.9Hz,2H),4.34(d,J=5.9Hz,2H),3.71(d,J=5.0Hz,2H),3.39(d,J=5.7Hz,2H),1.41(s,9H)。
Example 15:2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -N-cyclopropylacetamide (Compound 16).
The first step: synthesis of 2- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -N-cyclopropylacetamide (15 a).
2f (100 mg), 2-amino-N-cyclopropylacetamide (78.65 mg), potassium tert-butoxide (77.32 mg), pd (OAc) 2 (10.31 mg), BINAP (57.21 mg) was added to toluene (3 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 15a (70 mg).
MS(ESI):m/z 469.3[M+H] + 。
And a second step of: synthesis of 2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -N-cyclopropylacetamide (Compound 16).
15a (35 mg) and p-toluenesulfonic acid (14.15 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 16 (15 mg).
MS(ESI):m/z 399.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.93(s,1H),7.98(d,J=4.1Hz,1H),7.80(s,1H),7.38(s,1H),6.79(s,1H),6.10(s,1H),5.79(s,1H),5.52(s,1H),3.69(d,J=5.8Hz,2H),2.67(tq,J=7.8,4.0Hz,1H),1.40(s,9H),0.62(td,J=7.0,4.7Hz,2H),0.48-0.42(m,2H)。
Example 16:2- ((5-tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-yl) (methyl) amino) ethanol (compound 17).
The first step: synthesis of 2- ((5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-yl) (methyl) amino) ethanol (16 a).
2f (100 mg), N-methyl-2-hydroxyethylamine (24.36 mg), potassium tert-butoxide (77.32 mg), pd (OAc) 2 (10.02 mg), BINAP (57.21 mg) was added to toluene (2 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. The spin-dried reaction solvent was subjected to flash column chromatography (eluent system A) to give 16a (50 mg).
MS(ESI):m/z 430.1[M+H] + 。
And a second step of: synthesis of 2- ((5-tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-yl) (methyl) amino) ethanol (Compound 17).
16a (20 mg) and p-toluenesulfonic acid (11.4 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 12 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 17 (3 mg).
MS(ESI):m/z 346.1[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.94(s,1H),7.79(s,1H),7.39(s,1H),6.79(s,1H),5.86-5.82(m,2H),4.78-4.76(m,1H),3.63-3.56(m,2H),3.55-3.34(m,2H),3.02(s,3H),1.41(s,9H)。
Example 17: n (N) 5 -tert-butyl-N 7 - (2-methoxyethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 18).
The first step: n (N) 5 -tert-butyl-N 7 - (2-methoxyethyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (17 a).
2f (400 mg), 2-methoxyethylamine (345 mg), pd 2 (dba) 3 (173 mg), brettPhos (73 mg), potassium t-butoxide (474 mg) were added to 1, 4-dioxane (18 mL), and the mixture was heated to 120℃for 4 hours after nitrogen substitution. The system was filtered, and the filtrate was concentrated and diluted with a small amount of methanol, followed by thin layer chromatography (eluent system a) to give 17a (400 mg).
MS(ESI):m/z 430.2[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 - (2-methoxyethyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 18).
17a (27 mg) was added to anhydrous methanol (3 mL), p-toluenesulfonic acid (32.5 mg) was added, and the mixture was reacted at room temperature for 0.5 hour, and the reaction mixture was purified by Prep-HPLC (elution condition 4) and lyophilized to give compound 18 (7 mg).
MS(ESI):m/z 346.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.96(s,1H),7.81(s,1H),7.40(s,1H),6.78(s,1H),6.45-5.50(m,3H),3.53(t,J=5.6Hz,2H),3.31-3.27(m,5H),1.41(s,9H)。
Example 18: n (N) 7 - ((1R, 5S,6 s) -3-azabicyclo [ 3.1.0)]Hex-6-yl) -N 5 -tert-butyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 19).
The first step: synthesis of (1R, 5S,6 s) -tert-butyl 6- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -3-azabicyclo [3.1.0] hexane-3-carboxylate (18 a).
2f (120 mg), (1R, 5S,6 s) -tert-butyl 6-amino-3-azabicyclo [3.1.0]Hexane-3-carboxylic acid ester (163.94 mg), potassium tert-butoxide (92.78 mg), pd (OAc) 2 (12.38 mg), BINAP (68.65 mg) was added to toluene (3 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 18a (110 mg).
MS(ESI):m/z 553.3[M+H] + 。
And a second step of: n (N) 7 - ((1R, 5S,6 s) -3-azabicyclo [ 3.1.0)]Hex-6-yl) -N 5 -tert-butyl-2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 19).
18a (60 mg) was added to a 2M dioxane solution (2 mL) of hydrochloric acid, and the reaction was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure to pH 9 with sodium hydroxide, purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 19 (10 mg).
MS(ESI):m/z 368.9[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.91(s,1H),7.76(s,1H),7.36(d,J=5.3Hz,1H),6.74(s,1H),6.37(d,J=65.1Hz,1H),5.94(d,J=37.6Hz,1H),5.85(d,J=8.3Hz,1H),3.71(d,J=10.7Hz,1H),3.40(d,J=9.0Hz,2H),3.12(d,J=11.0Hz,1H),2.77(d,J=10.6Hz,1H),2.18(d,J=68.0Hz,1H),1.66(d,J=75.1Hz,2H),1.43(s,9H)。
Example 19: (R) -2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -4-methyl-1-pentanol (compound 20).
The first step: synthesis of (2R) -2- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -4-methyl-1-pentanol (19 a).
2f (80 mg), (R) -2-amino-4-methyl-1-pentanol (56.52 mg), pd (OAc) 2 (3.61 mg), BINAP (20.02 mg), potassium t-butoxide (54.12 mg) were added to toluene (7 mL), N 2 Protection, heating to 120 ℃ and reacting for 5 hours. The system was filtered, and the filtrate was concentrated and diluted with a small amount of methanol, followed by thin layer chromatography (eluent system a) to give 19a (40 mg).
MS(ESI):m/z 472.3[M+H] + 。
And a second step of: synthesis of (R) -2- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -4-methyl-1-pentanol (Compound 20).
19a (35 mg) was added to methanol (5 mL), reacted at 25℃for 2 hours, and after concentration of the system, purified by Prep-HPLC (elution condition 4) and lyophilized to give compound 20 (20 mg).
MS(ESI):m/z 388.0[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.92(s,1H),7.84-7.74(m,1H),7.35(s,1H),6.77(t,J=2.0Hz1H),5.74(s,1H),5.68(s,1H),5.41(d,J=8.3Hz,1H),4.71(t,J=5.2Hz,1H),3.49-3.45(m,2H),3.35-3.33(m,1H),1.76-1.69(m,1H),1.52-1.44(m,2H),1.41(s,9H),0.93(d,J=6.6Hz,3H),0.86(d,J=6.5Hz,3H)。
Example 20: (1 r,4 r) -4- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) cyclohexanol (compound 21).
The first step: synthesis of (((1 r,4 r) -4- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) cyclohexanol (20 a).
2f (100 mg), trans-4-aminocyclohexanol (79.36 mg), potassium tert-butoxide (77.32 mg), pd (OAc) 2 (10.31 mg), BINAP (57.21 mg) was added to toluene (3 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 20a (80 mg).
MS(ESI):m/z 470.3[M+H] + 。
And a second step of: synthesis of (1 r,4 r) -4- (5- (tert-butylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) cyclohexanol (Compound 21).
20a (30 mg) and p-toluenesulfonic acid (12.10 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 21 (16 mg).
MS(ESI):m/z 386.0[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.93(s,1H),7.76(s,1H),7.35(s,1H),6.74(s,1H),5.72(d,J=6.4Hz,2H),5.63(d,J=7.8Hz,1H),4.60(d,J=3.1Hz,1H),3.46-3.39(m,1H),3.26-3.16(m,1H),1.99-1.83(m,4H),1.41(s,9H),1.37-1.22(m,4H)。
Example 21: n (N) 5 -tert-butyl-N 7 - ((3-Methyloxetan-3-yl) methyl) -2- (1H-pyrazole-5-yl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 22).
The first step: n (N) 5 -tert-butyl-N 7 - ((3-methyl oxetan-3-yl) methyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ]Synthesis of pyridine-5, 7-diamine (21 a).
2f (300 mg), 3-methyl-3-aminomethyl-1-oxetane (289 mg), pd 2 (dba) 3 (76 mg), brettPhos (77 mg), potassium t-butoxide (232 mg) were added to 1, 4-dioxane (10 mL), N 2 After displacement, the reaction was carried out for 4 hours by heating to 120 ℃. The system was filtered, and the filtrate was concentrated and diluted with a small amount of methanol, followed by thin layer chromatography (eluent system a) to give 21a (240 mg).
MS(ESI):m/z 456.2[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-N 7 - ((3-Methyloxetan-3-yl) methyl) -2- (1H-pyrazol-5-yl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (Compound 22).
21a (40 mg) was added to anhydrous methanol (3 mL), p-toluenesulfonic acid (45 mg) was added, and the mixture was reacted at room temperature for 0.5 hour, and the mixture was purified by Prep-HPLC (elution condition 4) and lyophilized to give compound 22 (9 mg).
MS(ESI):m/z 372.0[M+H]+。
1 H-NMR(DMSO-d 6 ,400MHz):δ13.03(s,1H),7.83(s,1H),7.44(s,1H),6.81(s,1H),6.40-5.70(m,2H),4.48(d,J=6.0Hz,2H),4.25(d,J=5.6Hz,2H),3.47-3.35(m,2H),1.42(s,9H),1.34(s,3H)。
Example 22:3- (5- (tert-butylamino) -2- (6-methylpyridin-2-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (compound 23).
The first step: synthesis of 7-bromo-N-tert-butyl-2- (6-methylpyridin-2-yl) thieno [3,2-b ] pyridin-5-amine (22 a).
2e (500 mg), 6-methylpyridin-2-ylboronic acid (249.84 mg), pdCl 2 (dppf)·CH 2 Cl 2 (99.32 mg), potassium carbonate (322.31 mg) and water (5 mL), N 2 Heating to 80 ℃ under protection for reaction for 6 hours. The system was filtered, concentrated and then chromatographed on thin layer (eluent system B) to give 22a (170 mg).
MS(ESI):m/z 376.0[M+H] + 。
And a second step of: synthesis of 3- (5- (tert-butylamino) -2- (6-methylpyridin-2-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (Compound 23).
22a (160 mg), 3-aminopropanol (63.87 mg), pd (OAc) 2 (9.55 mg), BINAP (52.95 mg), potassium tert-butoxide (119.27 mg) were added to toluene (6 mL), N 2 Protection, heating to 120 ℃ and reacting for 5 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and thin layer chromatography (eluent system a) gave crude product, which was purified by Prep-HPLC (elution condition 2) and lyophilized to give compound 23 (53 mg).
MS(ESI):m/z 371.0[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ7.89(d,J=7.9Hz,1H),7.75(s,1H),7.72(t,J=7.8Hz,1H),7.16(d,J=7.6Hz,1H),6.10(t,J=5.4Hz,1H),5.80(s,1H),5.70(s,1H),4.54(t,J=5.0Hz,1H),3.53(d,J=5.5Hz,2H),3.18(d,J=6.1Hz,2H),2.48(s,3H),1.77(t,J=6.7Hz,2H),1.42(s,9H)。
Example 23: n (N) 5 -tert-butyl-2- (1H-pyrazol-5-yl) -N 7 - ((tetrahydro-2H-pyran-4-yl) methyl) thieno [3,2-b]Pyridine-5, 7-diamine (compound 24).
The first step: n (N) 5 -tert-butyl-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -N 7 - ((tetrahydro-2H-pyran-4-yl) methyl) thieno [3,2-b]Synthesis of pyridine-5, 7-diamine (23 a).
2f (70 mg), 4-aminomethyltetrahydro-2H-pyran (21.88 mg), potassium tert-butoxide (54.12 mg), pd (OAc) 2 (7.22 mg), BINAP (40.04 mg) was added to toluene (2 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 23a (30 mg).
MS(ESI):m/z 470.1[M+H] + 。
And a second step of: n (N) 5 -tert-butyl-2- (1H-pyrazol-5-yl) -N 7 Synthesis of (- ((tetrahydro-2H-pyran-4-yl) methyl) thieno [3,2-b1 pyridine-5, 7-diamine (compound 24).
23a (200 mg) and p-toluenesulfonic acid (86.6 mg) were added to methanol (20 mL), and the reaction was stirred at room temperature for 12 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 2), and lyophilized to give compound 24 (55 mg).
MS(ESI):m/z 386.1[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.91(s,1H),7.78(s,1H),7.36(s,1H),6.76(s,1H),6.11(s,1H),5.72-5.68(m,2H),3.89-3.84(m,2H),3.31-3.25(m,2H),3.02-2.99(m,2H),1.94-1.86(m,1H),1.68-1.64(m,2H),1.41(s,9H),1.25-1.15(m,2H)。
Example 24:3- (5-isopropylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (compound 35).
The first step: synthesis of 7-bromo-2-iodo-N-isopropylthieno [3,2-b ] pyridin-5-amine (23 a).
2d (450 mg), p-toluenesulfonic anhydride (1650 mg) were added to benzotrifluoride (5 mL) and chloroform (5 mL), and isopropylamine (523.06 mg) was then added dropwise, and the reaction was stirred at 25℃for 2 hours. After spin-drying the system, flash column chromatography (eluent system A) gave 23a (450 mg).
MS(ESI):m/z 396.6[M+H] + 。
And a second step of: synthesis of 7-bromo-N-isopropyl-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-5-amine (23 b).
Potassium carbonate (313.26 mg), pd (dppf) Cl were added sequentially at room temperature 2 ·CH 2 Cl 2 (82.92 mg) was added to a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-5-boronic acid pinacol ester (409.80 mg) and 23a (450 mg) in 1, 4-dioxane (9 mL)/water (1.5 mL), followed by stirring at 70℃for 4 hours. The reaction was quenched with water, extracted with EA, and the organic layer was dried and concentrated, followed by flash column chromatography (eluent system A) to give 23b (400 mg).
MS(ESI):m/z 420.8[M+H] + 。
And a third step of: synthesis of 3- (5- (isopropylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (23 c).
23b (100 mg), 3-amino-2, 2-dimethyl-1-propanol (73.45 mg), potassium tert-butoxide (79.89 mg), pd (OAc) 2 (5.33 mg), BINAP (29.56 mg) was added to toluene (3 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. Flash column chromatography (eluent system A) of the spin-dried reaction solvent gave 23c (45 mg).
MS(ESI):m/z 444.2[M+H] + 。
Fourth step: synthesis of 3- (5- (isopropylamino) -2- (1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (Compound 35).
23c (45 mg) and p-toluenesulfonic acid (19.22 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solvent was concentrated to dryness under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 35 (28 mg).
MS(ESI):m/z 360.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.93(s,1H),7.80(s,1H),7.39(s,1H),6.74(s,1H),5.88-5.76(m,2H),5.69(s,1H),4.84(t,J=5.2Hz,1H),4.08-3.95(m,1H),3.27(d,J=5.2Hz,2H),3.05(d,J=5.8Hz,2H),1.13(d,J=6.4Hz,6H),0.90(s,6H)。
Example 25:3- (2- (1H-pyrazol-5-yl) -5- (pyrrolidin-1-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (compound 55).
The first step: synthesis of 7-bromo-2-iodo-5- (pyrrolidin-1-yl) thieno [3,2-b ] pyridine (25 a).
Trifluoromethanesulfonic anhydride (1190 mg) was added to a solution of 2d (500 mg) in methylene chloride (10 mL) at 0deg.C, followed by slow dropwise addition of tetrahydropyrrole (699.26 mg), and the reaction was stirred at 25deg.C for 2 hours. After water quenching and spin-drying of the system, flash column chromatography (eluent system a) afforded compound 25a (240 mg).
MS(ESI):m/z 408.6[M+H] + 。
And a second step of: synthesis of 7-bromo-5- (pyrrolidin-1-yl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridine (25 b).
Potassium carbonate (162.16 mg), pd (dppf) Cl were added sequentially at room temperature 2 ·CH 2 Cl 2 (42.93 mg) was added to a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-5-boronic acid pinacol ester (212.14 mg) and 25a (240 mg) of 1, 4-dioxane (6 mL) in water (1 mL), followed by stirring at 70℃for 4 hours. The reaction was quenched with water, extracted with EA, and the organic layer was dried and concentrated, followed by flash column chromatography (eluent system A) to give compound 25b (100 mg).
MS(ESI):m/z 432.8[M+H] + 。
And a third step of: synthesis of 2, 2-dimethyl-3- (5- (pyrrolidin-1-yl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (25 c).
25b (100 mg), 3-amino-2, 2-dimethyl-1-propanol (71.41 mg), potassium tert-butoxide (77.68 mg), pd (OAc) 2 (5.18mg)、BINAP (28.74 mg) was added to toluene (3 mL), N 2 Heating to 120 ℃ under protection for reaction for 2 hours. The spin-dried reaction solvent was subjected to flash column chromatography (eluent system a) to give compound 25c (50 mg).
MS(ESI):m/z 456.2[M+H] + 。
Fourth step: synthesis of 3- (2- (1H-pyrazol-5-yl) -5- (pyrrolidin-1-yl) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (compound 55).
25c (48 mg) and p-toluenesulfonic acid (19.96 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. Concentrated under reduced pressure, purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 55 (25 mg).
MS(ESI):m/z 372.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.95(s,1H),7.81(s,1H),7.43(s,1H),6.75(s,1H),5.96(t,J=5.6Hz,1H),5.68(s,1H),4.84(t,J=5.2Hz,1H),3.39(t,J=6.2Hz,4H),3.26(d,J=5.1Hz,2H),3.14(d,J=5.9Hz,2H),1.92(t,J=6.3Hz,4H),0.90(s,6H)。
Example 26:3- (2- (1H-pyrazol-5-yl) -5- (2, 4-trimethylpent-2-ylamino) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (compound 75).
The first step: synthesis of 7-bromo-2-iodo-N- (2, 4-trimethylpent-2-yl) thieno [3,2-b ] pyridin-5-amine (26 a).
2d (200 mg), p-toluenesulfonic anhydride (733.51 mg) were added to benzotrifluoride (5 mL) and chloroform (5 mL), followed by dropwise addition of 2, 4-trimethyl-2-pentylamine (508.28 mg), and the reaction was stirred at 25℃for 2 hours. After the system was spin-dried, thin layer chromatography (eluent system B) gave compound 26a (232 mg).
The compound had no MS response.
And a second step of: synthesis of 7-bromo-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -N- (2, 4-trimethylpent-2-yl) thieno [3,2-b ] pyridin-5-amine (26 b).
26a (280 mg), 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-5-boronic acid pinacol ester (250.05 mg), pdCl 2 (dppf)·CH 2 Cl 2 (48.90 mg), potassium carbonate (206.76 mg), 1, 4-dioxane (12 mL) and water (4 mL), N 2 After protection, the reaction was stirred at 70℃for 4 hours. After extraction with ethyl acetate and spin-drying of the extract, compound 26B (160 mg) was obtained by thin layer chromatography (eluent system B).
MS(ESI):m/z 490.8[M+H] + 。
And a third step of: synthesis of 2, 2-dimethyl-3- (2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -5- (2, 4-trimethylpent-2-ylamino) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (26 c).
26b (160 mg), 3-amino-2, 2-dimethyl-1-propanol (100.75 mg), pd (OAc) 2 (7.31 mg), BINAP (40.54 mg), potassium tert-butoxide (91.32 mg) were added to toluene (7 mL), N 2 Protection, heating to 120 ℃ and reacting for 5 hours. The system was filtered, and the filtrate was concentrated and subjected to thin layer chromatography (eluent system B) to give compound 26c (85 mg).
MS(ESI):m/z 514.3[M+H] + 。
Fourth step: synthesis of 3- (2- (1H-pyrazol-5-yl) -5- (2, 4-trimethylpent-2-ylamino) thieno [3,2-b ] pyridin-7-ylamino) -2, 2-dimethyl-1-propanol (Compound 75).
26c (82 mg) was added to methanol (6 mL), then p-toluenesulfonic acid (41.23 mg) was added, the reaction was allowed to react at 25℃for 2 hours, the reaction system was spin-dried, purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 75 (30 mg).
MS(ESI):m/z 430.8[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ12.91(s,1H),7.79(s,1H),7.35(s,1H),6.79(d,J=2.1Hz,1H),5.73(s,1H),5.64(t,J=5.6Hz,1H),5.62(s,1H),4.82(t,J=5.2Hz,1H),3.28(d,J=5.3Hz,2H),3.02(d,J=5.8Hz,2H),1.93(s,2H),1.44(s,6H),0.93(s,9H),0.90(s,6H)。
Example 27:3- (5- (tert-butylamino) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) thieno [3,2-b ] pyridin-7-ylamino) -1-propanol (compound 76).
A solution of compound 2f (50 mg), compound 2g (11.22 mg) and cesium carbonate (97.07 mg) in dimethyl sulfoxide (2 mL) was placed in a microwave tube, and the temperature was raised to 120℃for reaction for 5 hours. Quenching reaction with water, and extracting with EA. The organic layer was dried and concentrated and purified by preparative TLC (eluent system a) to give compound 76 (30 mg).
MS(ESI):m/z 430.2[M+H] + 。
1 H-NMR(DMSO-d 6 ,400MHz):δ7.58(s,1H),7.23(s,1H),6.58(s,1H),6.11-6.10(m,1H),5.84(s,1H),5.53-5.50(m,1H),4.54-4.51(m,1H),4.00-3.97(m,1H),3.65(m,1H),3.49(m,2H),3.20-3.17(m,2H),2.43-2.32(m,2H),1.981-1.566(m,7H),1.41(s,9H)。
[ Activity test ]
Experimental example 1: agonism of the compounds of the invention on IL-1 beta expression in THP-1 cells after PMA-induced differentiation.
The present experimental example uses HTRF (homogeneous time resolved fluorescence) assay to test the effect of the compounds of the present invention on IL-1β levels of the NLRP3 downstream cytokines to assess the agonism of the compounds on the hllrp 3 inflammatory body or hllrp 3 inflammatory body pathway at the cellular level.
Reagent: RPMI 1640 (Hyclone); heat-inactivated FBS (fetal bovine serum) (Gibco); PMA (tetradecanoyl phorbol acetate) (bi yun day).
And (3) cells: THP-1 (Nanjing Corp.).
The kit comprises: IL-1. Beta. Detection kit (CISBIO).
The experimental steps are as follows:
1) THP-1 cells in logarithmic growth phase were grown at 5X 10 5 Density of individual/well inoculated in T75 flask, placed at 37℃in 5% CO 2 After 24 hours of culture in a cell incubator, THP-1 suspension cells were induced to become adherent macrophages with 1. Mu.M PMA; the medium was RPMI 1640 containing 10% heat-inactivated FBS and 0.05mM beta-mercaptoethanol;
2) After 24 hours of cell induction culture, adherent cells were trypsinized, centrifuged at 1000rpm for 5min, the supernatant removed, and the cell density resuspended to 2X 10 using RPMI 1640 medium containing 2% heat-inactivated FBS 6 mu.L/well of cell resuspension was plated in 96-well plates at 1X 10 cells per well 5 A plurality of;
3) Taking a proper amount of a DMSO solution of a 10mM compound to be tested, and preparing the DMSO solution into a 2X test concentration by using an RPMI 1640 culture medium containing 2% heat-inactivated FBS; adding 50 μl/well of the dilution into 96-well plate cells, mixing thoroughly, and placing the plate at 37deg.C with 5% CO 2 Is cultured in a cell culture box for 6 hours; collecting the supernatant, and measuring the level of IL-1 beta according to the instructions of the IL-1 beta detection kit;
4)EC 50 the results are shown in Table 1, fitted by the GraphPad software log (agonist) vs. response-Variable slope four-parameter method.
Experimental example 2: THP1 cells (THP 1- def NLRP3 cells) is described.
The test example adopts HTRF detection method to test the compound of the invention on THP1- def The effect of IL-1β levels in NLRP3 cells to assess the specificity of the compound for hllrp 3 inflammatory bodies or hllrp 3 inflammatory body pathway agonism.
Reagent: the same as in experimental example 1.
And (3) cells: THP1- aef NLRP3(InvivoGen)。
The kit comprises: the same as in experimental example 1.
The experimental steps are as follows:
1) THP1- def NLRP3 cells at 5X 10 5 Density of individual/well inoculated in T75 flask, placed at 37℃in 5% CO 2 Is cultured for 24 hours in an incubatorAfter that, THP 1-was induced with 1. Mu.M PMA def NLRP3 suspension cells become adherent macrophages; the medium was RPMI 1640 containing 10% heat-inactivated FBS and 0.05mM beta-mercaptoethanol;
2) After cell induction for 24 hours, adherent cells were trypsinized, centrifuged at 1000rpm for 5min, and the supernatant was removed and the cell density was resuspended to 2X 10 using RPMI 1640 medium containing 2% heat-inactivated FBS 6 individual/mL; spreading 50 μl/well of cell resuspension into 96-well plate with cell number of 1×10 per well 5 A plurality of;
3) An appropriate amount of 10mM DMSO solution of the test compound was prepared at a 2 Xtest concentration in RPMI 1640 medium containing 2% heat-inactivated FBS. Adding 50 μl/well of the dilution into 96-well plate cells, mixing thoroughly, and placing the plate at 37deg.C with 5% CO 2 Is cultured in a cell culture box for 6 hours; collecting the supernatant, and measuring the level of IL-1 beta according to the instructions of the IL-1 beta detection kit;
4)EC 50 the results are shown in Table 1, fitted by the GraphPad software log (agonist) vs. response-Variable slope four-parameter method.
Experimental example 3: agonism of hTLR7 by the compounds of the invention.
This experimental example tests the activation of TLR7 signaling pathway by compounds of the invention by detecting luciferase in HEK-hTLR7-NF- κb-reporter cells to assess the specificity of the compounds for agonism of the NLRP3 pathway.
Reagent: DMEM (High glucose); FBS (fetal bovine serum) (Gibco).
And (3) cells: HEK-hTLR7-NF- κB-Luciferase gene cell (humanized TLR7NF- κB-Luciferase reporter gene cell) (Nanjac Bai).
The kit comprises: bright-Glo TM Luciferase detection kit (Promega).
The experimental steps are as follows:
1) HEK-hTLR7-NF- κB-Luciferase gene cells in logarithmic growth phase were digested with pancreatin and resuspended to 2X 10 with medium 6 The concentration of each mL was added to 50. Mu.L/well of cell resuspension in 96-well plates, the number of cells per well being 1X 10 6 A plurality of; taking an appropriate amount of 10Preparing DMSO solution of the compound to be tested into 2 Xtest concentration with culture medium, adding 50 μl/well to 96-well plate cells, placing 96-well plate at 37deg.C and 5% CO 2 Is cultured in an incubator for 16 hours; the medium was DMEM containing 10% fbs;
2) After the cell incubation has ended, 100. Mu.L/well Bright-Glo is added T M Luciferase detection reagent, incubated for 5min at room temperature, and enzyme-labeled instrument for reading relative Luciferase activity units (Relative Luciferase Unit, RLU);
3) Stimulation of hTLR7 by Compounds EC 50 The results are shown in Table 1, fitted by the GraphPad software log (agonist) vs. response-Variable slope four-parameter method.
Experimental example 4: agonism of hTLR8 by the compounds of the invention.
This experimental example tests the activation of TLR8 signaling pathway by compounds of the invention by detecting the secretion of alkaline phosphatase in HEK-Blue cell lines to assess the specificity of the compounds for agonism of the NLRP3 pathway.
Reagent: DMEM (High glucose); FBS (Gibco); QUANTI-Blue (InvivoGen/rep-qb 2).
And (3) cells: HEK-Blue TM hTLR8 cells (human TLR8 cells) (invitogen).
The experimental steps are as follows:
1) HEK-BlueTMhTLR8 cells in logarithmic growth phase were digested with pancreatin and resuspended to 2X 10 with medium 6 The concentration of individual/mL was added to 50. Mu.L/well of cell suspension in 96-well plates; preparing a proper amount of a DMSO solution of a compound to be tested in 10mM, preparing a 2 Xtest concentration by using a culture medium, and adding 50 mu L/hole into cells of a 96-well plate; the plates were placed at 37℃in 5% CO 2 Is cultured in an incubator for 16 hours; the medium was DMEM containing 10% fbs.
2) After the cell incubation, 10. Mu.L of the cell culture supernatant was transferred to a 96-well plate, 90. Mu.L/well of QUANTI-Blue detection solution was added, and incubated at 37℃for 3 hours, with an ELISA reader OD 620 Reading;
3) Stimulation of hTLR8 by Compounds EC 50 The junctions were fitted by GraphPad software log (agonist) vs. response-Variable slope four-parameter methodThe results are shown in Table 1.
TABLE 1
The results show that the compounds of the invention represented by the compounds listed in Table 1 have remarkable agonism on IL-1β expression in THP-1 cells after PMA induced differentiation, but have remarkable agonism on THP-1 def IL-1. Beta. Expression in NLRP3 cells had no agonism even at the highest compound test concentration (30. Mu.M). All compounds tested had no activating effect on hTLR7 and hTLR8 at 100 μm. In conclusion, the compounds of the present invention represented by the compounds listed in table 1 have remarkable specific agonistic activity against hllrp 3 and/or its signaling pathway.
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.
Claims (22)
1. A compound having the structure of formula V or a pharmaceutically acceptable form thereof,
wherein,
R 1 is a 5-6 membered heteroaryl optionally substituted with one or more substituents, each independently selected from C 1-3 Alkyl and 4-7 membered heterocyclyl;
R 4 is NR (NR) 41a R 41b ;R 41a And R is 41b Each independently selected from hydrogen and C 1-6 Alkyl, or R 41a And R is 41b Together with the N atom to which it is attached form a 4-7 membered heterocyclic group, wherein said C 1-6 Alkyl optionally substituted with one or more C 1-4 Alkyl is substituted, and R 41a And R is 41b Are not hydrogen at the same time;
-N(R 33 )-(L 2 ) p -(L 3 ) q -R 3 selected from:
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts.
2. A compound according to claim 1,
wherein,
-N(R 33 )-(L 2 ) p -(L 3 ) q -R 3 selected from:
3. a compound according to claim 1,
wherein,
R 1 is a 5-6 membered nitrogen containing heteroaryl optionally substituted with one or more substituents, each independently selected from C 1-3 Alkyl and 4-7 membered heterocyclyl.
4. A compound according to claim 1,
wherein,
R 1 selected from pyrazolyl or pyridinyl, optionally substituted with one or more substituents, each independently selected from C 1-3 Alkyl and 4-7 membered heterocyclyl.
5. A compound according to claim 1,
Wherein,
R 1 selected from pyrazolyl or pyridinyl, optionally substituted with one or more substituents, each independently selected from methyl and tetrahydro-2H-pyran-2-yl.
6. A compound according to claim 1,
wherein,
R 1 selected from pyrazolyl, 1, 3-dimethyl-1H-pyrazolyl, methylpyridinyl, and 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolyl.
7. A compound according to claim 1,
wherein,
R 1 selected from the group consisting of 1H-pyrazol-5-yl, 1, 3-dimethyl-1H-pyrazol-5-yl, 2-methylpyridin-6-yl, and 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-2-yl.
8. A compound according to claim 1,
wherein,
R 1 selected from the group consisting of 1H-pyrazol-5-yl and 2-methylpyridin-6-yl.
9. A compound according to claim 1,
wherein,
R 4 is-NR 41a R 41b Wherein R is 41a And R is 41b Each independently selected from hydrogen and C 1-4 Alkyl, and R 41a And R is 41b Not both hydrogen, or R 41a And R is 41b Together with the N atom to which it is attached form a 4-6 membered heterocyclic group, wherein said C 1-4 Alkyl optionally substituted with one or more C 1-4 Alkyl substitution.
10. A compound according to claim 1,
wherein,
R 4 is-NR 41a R 41b Wherein R is 41a And R is 41b Each independently selected from hydrogen, methyl, ethyl, isopropyl and tert-butyl, and R 41a And R is 41b Not both hydrogen, or R 41a And R is 41b Together with the N atom to which it is attached, form pyrrolidin-1-yl, wherein the methyl, ethyl, isopropyl and tert-butyl groups are each optionally substituted with one or more methyl or tert-butyl groups.
11. A compound according to claim 1,
wherein,
R 4 selected from-N (H) -C (CH) 3 ) 3 、-N(H)-CH 3 、-N(H)-C 2 H 5 -N (H) -isopropyl, -N (CH) 3 ) 2 、-N(C 2 H 5 ) 2 、-N(H)-C(CH 3 ) 2 -CH 2 -C(CH 3 ) 3 And pyrrolidin-1-yl.
12. A compound according to claim 1,
wherein,
R 4 selected from-N (H) -C (CH) 3 ) 3 。
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
14. a process for the preparation of a compound of formula V according to claim 1, comprising the steps of:
step 1: the compound IV-1 is subjected to halogenation reaction to generate a compound IV-2;
x represents a halogen atom selected from chlorine and bromine;
step 2: the compound IV-2 is subjected to iodination reaction to generate a compound IV-3;
step 3: the compound IV-3 is subjected to oxidation reaction to generate a compound IV-4;
step 4: compounds IV-4 and R 4 H reaction to give compound IV-5, wherein R 4 Is connected with thienopyridine through a nitrogen atom;
step 5: the compound IV-5 is subjected to a coupling reaction to generate a compound IV-6;
step 6: the compound IV-6 is subjected to substitution or coupling reaction to generate a compound V;
Wherein R is 1 、R 3 、R 4 、R 33 、L 2 、L 3 P and q are as defined in claim 1.
15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier.
16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 15, for use as an NLRP3 modulator.
17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 15, for use as an NLRP3 agonist.
18. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable form thereof or a pharmaceutical composition according to claim 15 in the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by NLRP 3.
19. The use of claim 18, wherein the disease mediated at least in part by NLRP3 is selected from cancer.
20. The use according to claim 19, wherein the disease is selected from leukemia, lymphoma, myeloma, breast cancer, ovarian cancer, cervical cancer, prostate cancer, bladder cancer, colorectal cancer, gastric cancer, esophageal cancer, oral cancer, pancreatic cancer, liver cancer, lung cancer, kidney cancer, skin cancer, bone cancer, brain cancer and melanoma.
21. The use according to claim 19, wherein the disease is selected from colon cancer, rectal cancer, glioma.
22. A pharmaceutical combination composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable form thereof or a pharmaceutical composition according to claim 15, and at least one other syntropy NLRP3 modulator.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910932795 | 2019-09-29 | ||
CN2019109327952 | 2019-09-29 | ||
PCT/CN2020/106080 WO2021057256A1 (en) | 2019-09-29 | 2020-07-31 | Heterocyclic nitrogen compound, pharmaceutical composition containing same, preparation method therefor and use thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114269753A CN114269753A (en) | 2022-04-01 |
CN114269753B true CN114269753B (en) | 2024-03-05 |
Family
ID=75165544
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080055686.8A Active CN114269753B (en) | 2019-09-29 | 2020-07-31 | Nitrogen-containing bicyclic compound, pharmaceutical composition containing same, preparation method and application thereof |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN114269753B (en) |
WO (1) | WO2021057256A1 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005080377A1 (en) * | 2004-02-20 | 2005-09-01 | Kirin Beer Kabushiki Kaisha | COMPOUND HAVING TGF-β INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME |
CN104936963A (en) * | 2012-11-20 | 2015-09-23 | Ktb肿瘤研究有限责任公司 | Thioether derivatives as protein kinase inhibitors |
CN105492446A (en) * | 2013-07-30 | 2016-04-13 | 爱尔兰詹森科学公司 | Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections |
CN113195469A (en) * | 2019-02-19 | 2021-07-30 | 四川科伦博泰生物医药股份有限公司 | Nitrogen-containing heterocyclic compound, preparation method and application thereof |
CN114555565A (en) * | 2019-12-13 | 2022-05-27 | 四川科伦博泰生物医药股份有限公司 | Nitrogen-containing heterocyclic compound, preparation method and application thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA005889B1 (en) * | 1997-11-11 | 2005-06-30 | Пфайзер Продактс Инк. | Thienopyrimidine and thienopyridine derivatives useful as anticancer agents |
UA77303C2 (en) * | 2002-06-14 | 2006-11-15 | Pfizer | Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use |
CL2003002287A1 (en) * | 2002-11-25 | 2005-01-14 | Wyeth Corp | COMPOUNDS DERIVED FROM TIENO [3,2-b] -PIRIDINA-6-CARBONITRILOS AND TIENEO [2,3-b] -PIRIDINA-5-CARBONITRILS, PHARMACEUTICAL COMPOSITION, PROCEDURE OF PREPARATION AND INTERMEDIARY COMPOUNDS, AND THEIR USE IN THE TREATMENT OF CANCER, APOPLEJIA, OSTEOPOROSIS |
GB0412467D0 (en) * | 2004-06-04 | 2004-07-07 | Astrazeneca Ab | Chemical compounds |
US11274100B2 (en) * | 2017-06-21 | 2022-03-15 | Daiichi Sankyo Company, Limited | EP300/CREBBP inhibitor |
-
2020
- 2020-07-31 WO PCT/CN2020/106080 patent/WO2021057256A1/en active Application Filing
- 2020-07-31 CN CN202080055686.8A patent/CN114269753B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005080377A1 (en) * | 2004-02-20 | 2005-09-01 | Kirin Beer Kabushiki Kaisha | COMPOUND HAVING TGF-β INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME |
EP1724268A1 (en) * | 2004-02-20 | 2006-11-22 | Kirin Beer Kabushiki Kaisha | Compound having tgf-beta inhibitory activity and pharmaceutical composition containing same |
CN104936963A (en) * | 2012-11-20 | 2015-09-23 | Ktb肿瘤研究有限责任公司 | Thioether derivatives as protein kinase inhibitors |
CN105492446A (en) * | 2013-07-30 | 2016-04-13 | 爱尔兰詹森科学公司 | Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections |
CN113195469A (en) * | 2019-02-19 | 2021-07-30 | 四川科伦博泰生物医药股份有限公司 | Nitrogen-containing heterocyclic compound, preparation method and application thereof |
CN114555565A (en) * | 2019-12-13 | 2022-05-27 | 四川科伦博泰生物医药股份有限公司 | Nitrogen-containing heterocyclic compound, preparation method and application thereof |
Non-Patent Citations (3)
Title |
---|
2285561-66-0;STN registry;《STN registry》;1 * |
Structure-Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines;Gonzalez Cabrera, Diego等;《Journal of Medicinal Chemistry》;第58卷(第18期);7572-7579 * |
Synthesis of novel 5-amino-thiazolo[4,5-d]pyrimidines as E. coli and S.aureus SecA inhibitors;Jang, Mi-Yeon等;《Bioorganic & Medicinal Chemistry》;第19卷(第1期);702-714 * |
Also Published As
Publication number | Publication date |
---|---|
WO2021057256A1 (en) | 2021-04-01 |
CN114269753A (en) | 2022-04-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110156786B (en) | Pyrimido-cyclic compounds, process for their preparation and their use | |
CN113637005A (en) | KRAS inhibitors for cancer treatment | |
WO2021127429A1 (en) | Sos1 inhibitors | |
CN113286794B (en) | KRAS mutein inhibitors | |
EP1490371B1 (en) | Thiophene-based tricyclic compounds and pharmaceutical compositions comprising same | |
JP2022523981A (en) | Condensation tricyclic compound useful as an anticancer agent | |
CN110573501A (en) | Rho-related protein kinase inhibitor, pharmaceutical composition containing same, and preparation method and application thereof | |
CN110582491A (en) | Rho-related protein kinase inhibitor, pharmaceutical composition containing same, and preparation method and application thereof | |
WO2014113191A1 (en) | Hedgehog pathway signaling inhibitors and therapeutic applications thereof | |
JP2019500389A (en) | Nitrogen-containing fused heterocyclic compounds, production methods, intermediates, compositions and uses | |
CN111936484A (en) | Chromenopyridine derivatives as inhibitors of phosphatidylinositol phosphokinase | |
US20220056043A1 (en) | Nitrogen-containing fused cyclic compound, preparation method therefor and use thereof | |
JP2022523477A (en) | A pharmaceutical composition for preventing or treating a pyrrolopyrimidine derivative and a protein kinase-related disease containing the derivative as an active ingredient. | |
CN117062816A (en) | Tricyclic-amide-bicyclic PRMT5 inhibitors | |
CN110655520A (en) | Pyrimido-cyclic compounds, process for their preparation and their use | |
WO2005011609A2 (en) | Triazolopurine-based tricyclic compounds and pharmaceutical compositions comprising same | |
CN112654622B (en) | Ring-fused compound, preparation method and application thereof | |
CN110407854B (en) | Novel tetracyclic compounds | |
CA3145344A1 (en) | Pyrazolopyrimidine compound, preparation method for same and applications thereof | |
CN114269753B (en) | Nitrogen-containing bicyclic compound, pharmaceutical composition containing same, preparation method and application thereof | |
CN114555565B (en) | Nitrogen-containing heterocyclic compound, preparation method and application thereof | |
CN115380036A (en) | SSTR5 antagonists | |
JP2022554385A (en) | WDR5 inhibitors and modulators | |
CN111902401B (en) | Receptor inhibitors, pharmaceutical compositions comprising the same and uses thereof | |
CN114096533B (en) | Tri-ring compound, pharmaceutical composition containing same, 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 |