CN112654605B - 桥杂环基取代的嘧啶类化合物及其制备方法和医药用途 - Google Patents
桥杂环基取代的嘧啶类化合物及其制备方法和医药用途 Download PDFInfo
- Publication number
- CN112654605B CN112654605B CN202080004748.2A CN202080004748A CN112654605B CN 112654605 B CN112654605 B CN 112654605B CN 202080004748 A CN202080004748 A CN 202080004748A CN 112654605 B CN112654605 B CN 112654605B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- cancer
- pyrazol
- acetonitrile
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 190
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 69
- -1 pyrimidine compound Chemical class 0.000 title description 124
- 150000001875 compounds Chemical class 0.000 claims abstract description 197
- 238000000034 method Methods 0.000 claims abstract description 192
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 230000000694 effects Effects 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 8
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 claims abstract 4
- 239000000203 mixture Substances 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 13
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 claims description 12
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 8
- 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 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 206010025135 lupus erythematosus Diseases 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 5
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 5
- 206010046851 Uveitis Diseases 0.000 claims description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010005949 Bone cancer Diseases 0.000 claims description 4
- 208000018084 Bone neoplasm Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000013452 Fallopian tube neoplasm Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 206010038038 rectal cancer Diseases 0.000 claims description 4
- 201000001275 rectum cancer Diseases 0.000 claims description 4
- 201000000849 skin cancer Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 3
- 229940123371 Tyrosine kinase 2 inhibitor Drugs 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 5
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 12
- 108010010057 TYK2 Kinase Proteins 0.000 abstract description 5
- 102000015774 TYK2 Kinase Human genes 0.000 abstract description 5
- 150000003230 pyrimidines Chemical class 0.000 abstract description 3
- 229940043355 kinase inhibitor Drugs 0.000 abstract 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 546
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 183
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 124
- 239000012071 phase Substances 0.000 description 121
- 238000005481 NMR spectroscopy Methods 0.000 description 105
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 238000004262 preparative liquid chromatography Methods 0.000 description 96
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 94
- 238000000746 purification Methods 0.000 description 88
- 238000011049 filling Methods 0.000 description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
- 125000000753 cycloalkyl group Chemical group 0.000 description 62
- 239000000243 solution Substances 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 53
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 47
- 235000019253 formic acid Nutrition 0.000 description 47
- 230000015572 biosynthetic process Effects 0.000 description 44
- 125000001072 heteroaryl group Chemical group 0.000 description 44
- 238000003786 synthesis reaction Methods 0.000 description 44
- 230000002829 reductive effect Effects 0.000 description 42
- KMLMOVWSQPHQME-REOHCLBHSA-N (1s)-2,2-difluorocyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1CC1(F)F KMLMOVWSQPHQME-REOHCLBHSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 30
- 125000003545 alkoxy group Chemical group 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- 125000003342 alkenyl group Chemical group 0.000 description 21
- 125000000304 alkynyl group Chemical group 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- LBGSWBJURUFGLR-UHFFFAOYSA-N 1-methylpyrazol-4-amine Chemical compound CN1C=C(N)C=N1 LBGSWBJURUFGLR-UHFFFAOYSA-N 0.000 description 20
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000651 prodrug Substances 0.000 description 20
- 229940002612 prodrug Drugs 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000007788 liquid Substances 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 16
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 16
- 230000014759 maintenance of location Effects 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 125000006413 ring segment Chemical group 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 12
- DFNYGALUNNFWKJ-UHFFFAOYSA-N aminoacetonitrile Chemical compound NCC#N DFNYGALUNNFWKJ-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- IQHFNSQRXUWHNN-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C=O Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C=O IQHFNSQRXUWHNN-UHFFFAOYSA-N 0.000 description 11
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 11
- 125000003367 polycyclic group Chemical group 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- 108010024121 Janus Kinases Proteins 0.000 description 10
- 102000015617 Janus Kinases Human genes 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 238000012546 transfer Methods 0.000 description 10
- DQXNTSXKIUZJJS-UHFFFAOYSA-N 2,4-dichloro-5-methylpyrimidine Chemical compound CC1=CN=C(Cl)N=C1Cl DQXNTSXKIUZJJS-UHFFFAOYSA-N 0.000 description 9
- KIYWNSABYZWMPU-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NCC#N Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NCC#N KIYWNSABYZWMPU-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 108091000080 Phosphotransferase Proteins 0.000 description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
- 125000004043 oxo group Chemical group O=* 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 102000020233 phosphotransferase Human genes 0.000 description 9
- 125000003003 spiro group Chemical group 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 description 8
- 125000005366 cycloalkylthio group Chemical group 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- OGCQAPFFVXUDSW-UHFFFAOYSA-N CN1N=CC(NC2=NC=CC(C3=CC(CC4)NC4C3)=N2)=C1.OC(C(F)(F)F)=O Chemical compound CN1N=CC(NC2=NC=CC(C3=CC(CC4)NC4C3)=N2)=C1.OC(C(F)(F)F)=O OGCQAPFFVXUDSW-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- GTKFXWNAGQFYDM-UHFFFAOYSA-N CC(C#N)C(=O)N1C2CCC1C=C(C2)C3=NC(=NC=C3)NC4=CN(N=C4)C Chemical compound CC(C#N)C(=O)N1C2CCC1C=C(C2)C3=NC(=NC=C3)NC4=CN(N=C4)C GTKFXWNAGQFYDM-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VBHXOVWWJRTZGW-UHFFFAOYSA-N N#CCNS(=O)(=O)N1C2CCC1C=C(C2)C1=CC=NC(=N1)NC=1C=NN(C=1)C Chemical compound N#CCNS(=O)(=O)N1C2CCC1C=C(C2)C1=CC=NC(=N1)NC=1C=NN(C=1)C VBHXOVWWJRTZGW-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 150000007942 carboxylates Chemical class 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 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 5
- RKORKXLEGJOTTK-UHFFFAOYSA-N 1-(oxetan-3-yl)pyrazol-4-amine Chemical compound C1=C(N)C=NN1C1COC1 RKORKXLEGJOTTK-UHFFFAOYSA-N 0.000 description 5
- UJMIBUXTYDMTRC-UHFFFAOYSA-N 1-tert-butyl-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid Chemical compound CC(C)(C)C(CCC1C2)(C=C2C2=NC(NC3=CN(C)N=C3)=NC=C2)N1C(O)=O UJMIBUXTYDMTRC-UHFFFAOYSA-N 0.000 description 5
- SBIVBNSOTWNDSJ-UHFFFAOYSA-N CCCS(=O)(=O)N1CC(C1)N1C2CCC1C=C(C2)C1=CC=NC(=N1)NC=1C=NN(C=1)C Chemical compound CCCS(=O)(=O)N1CC(C1)N1C2CCC1C=C(C2)C1=CC=NC(=N1)NC=1C=NN(C=1)C SBIVBNSOTWNDSJ-UHFFFAOYSA-N 0.000 description 5
- PWUBONDMIMDOQY-UHFFFAOYSA-N acetonitrile;hydrochloride Chemical compound Cl.CC#N PWUBONDMIMDOQY-UHFFFAOYSA-N 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- LMBZZTJQNYGICT-JEDNCBNOSA-N (3r)-pyrrolidine-3-carbonitrile;hydrochloride Chemical compound Cl.N#C[C@@H]1CCNC1 LMBZZTJQNYGICT-JEDNCBNOSA-N 0.000 description 4
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 4
- XORHNJQEWQGXCN-UHFFFAOYSA-N 4-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C=1C=NNC=1 XORHNJQEWQGXCN-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- XUHZSILBRIBQBZ-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=C(C(=N2)C3=CC4CCC(C3)N4C(=O)NCC#N)F Chemical compound CN1C=C(C=N1)NC2=NC=C(C(=N2)C3=CC4CCC(C3)N4C(=O)NCC#N)F XUHZSILBRIBQBZ-UHFFFAOYSA-N 0.000 description 4
- KMANYIJZQUDSSS-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C2=CC=C(C=C2)C(F)(F)F Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C2=CC=C(C=C2)C(F)(F)F KMANYIJZQUDSSS-UHFFFAOYSA-N 0.000 description 4
- SNJIKCZZNRTYQV-NNGSBXSVSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)N2C[C@@H](CC2)C#N Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)N2C[C@@H](CC2)C#N SNJIKCZZNRTYQV-NNGSBXSVSA-N 0.000 description 4
- AQROFEMUZVWVMT-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(CC#C)=O Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(CC#C)=O AQROFEMUZVWVMT-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- YWWQBMDEEXUDHE-UHFFFAOYSA-N ClC1=NC=CC(=N1)C1=CC2N(C(C1)CC2)C(=O)OC(C)(C)C Chemical compound ClC1=NC=CC(=N1)C1=CC2N(C(C1)CC2)C(=O)OC(C)(C)C YWWQBMDEEXUDHE-UHFFFAOYSA-N 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 101001077604 Homo sapiens Insulin receptor substrate 1 Proteins 0.000 description 4
- 101000617830 Homo sapiens Sterol O-acyltransferase 1 Proteins 0.000 description 4
- 102100025087 Insulin receptor substrate 1 Human genes 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 102100021993 Sterol O-acyltransferase 1 Human genes 0.000 description 4
- 101000697584 Streptomyces lavendulae Streptothricin acetyltransferase Proteins 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000004530 micro-emulsion Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- WJLKJRCGDXKJDQ-UHFFFAOYSA-N 1-(4-aminopyrazol-1-yl)-2-methylpropan-2-ol Chemical compound CC(C)(O)CN1C=C(N)C=N1 WJLKJRCGDXKJDQ-UHFFFAOYSA-N 0.000 description 3
- VCURCUIEDUUUEA-UHFFFAOYSA-N 1-(difluoromethyl)-4-nitropyrazole Chemical compound [O-][N+](=O)C=1C=NN(C(F)F)C=1 VCURCUIEDUUUEA-UHFFFAOYSA-N 0.000 description 3
- JYZVNUKJBUJJIK-UHFFFAOYSA-N 1-(difluoromethyl)pyrazol-4-amine Chemical compound NC=1C=NN(C(F)F)C=1 JYZVNUKJBUJJIK-UHFFFAOYSA-N 0.000 description 3
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 description 3
- RBCYXFQWCHFXEN-UHFFFAOYSA-N 2-(3,3-difluorocyclobutyl)-1-[3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-8-azabicyclo[3.2.1]oct-2-en-8-yl]propan-1-one Chemical compound CC(C(C1)CC1(F)F)C(N(C(CC1)C2)C1C=C2C1=NC(NC2=CN(C)N=C2)=NC=C1)=O RBCYXFQWCHFXEN-UHFFFAOYSA-N 0.000 description 3
- TYJRXMZXDBSURR-UHFFFAOYSA-N 2-phenylcyclopropane-1-carbaldehyde Chemical compound O=CC1CC1C1=CC=CC=C1 TYJRXMZXDBSURR-UHFFFAOYSA-N 0.000 description 3
- CATVJEVOFGUNHO-UHFFFAOYSA-N 4-nitro-1-(oxetan-3-yl)pyrazole Chemical compound C1=C([N+](=O)[O-])C=NN1C1COC1 CATVJEVOFGUNHO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- HTWSKBRLTFYEHX-UHFFFAOYSA-N C(#N)CNS(=O)(=O)N1C(OCC1)=O Chemical compound C(#N)CNS(=O)(=O)N1C(OCC1)=O HTWSKBRLTFYEHX-UHFFFAOYSA-N 0.000 description 3
- YDYJAMAGJRCQNW-JCYILVPMSA-N C1CC1N2C=C(C=N2)NC3=NC=CC(=N3)C4=CC5CCC(C4)N5C(=O)[C@@H]6CC6(F)F Chemical compound C1CC1N2C=C(C=N2)NC3=NC=CC(=N3)C4=CC5CCC(C4)N5C(=O)[C@@H]6CC6(F)F YDYJAMAGJRCQNW-JCYILVPMSA-N 0.000 description 3
- NIUJXAPDUVVHKT-UHFFFAOYSA-N CC(C)(CN1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C=O)=N2)=C1)O Chemical compound CC(C)(CN1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C=O)=N2)=C1)O NIUJXAPDUVVHKT-UHFFFAOYSA-N 0.000 description 3
- VABIBKAWRLHPNO-UHFFFAOYSA-N CC(C)N1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C=O)=N2)=C1 Chemical compound CC(C)N1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C=O)=N2)=C1 VABIBKAWRLHPNO-UHFFFAOYSA-N 0.000 description 3
- ISYOQRUPCGCVPT-UHFFFAOYSA-N CC1(CC1(F)F)C(=O)N2C3CCC2C=C(C3)C4=NC(=NC=C4)NC5=CN(N=C5)C Chemical compound CC1(CC1(F)F)C(=O)N2C3CCC2C=C(C3)C4=NC(=NC=C4)NC5=CN(N=C5)C ISYOQRUPCGCVPT-UHFFFAOYSA-N 0.000 description 3
- OPROWDVRSRVEOE-UHFFFAOYSA-N CC1=CN=C(NC2=CN(C)N=C2)N=C1C(CC1CC2)=CC2N1C=O Chemical compound CC1=CN=C(NC2=CN(C)N=C2)N=C1C(CC1CC2)=CC2N1C=O OPROWDVRSRVEOE-UHFFFAOYSA-N 0.000 description 3
- NLQSJSQFJAKFDN-UHFFFAOYSA-N CCN1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C=O)=N2)=C1 Chemical compound CCN1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C=O)=N2)=C1 NLQSJSQFJAKFDN-UHFFFAOYSA-N 0.000 description 3
- CMTVZFGWGHJHMT-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C(C5CC5)(F)F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C(C5CC5)(F)F CMTVZFGWGHJHMT-UHFFFAOYSA-N 0.000 description 3
- RNCBXKUPGPYBOP-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C56CC(C5)(C6)F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C56CC(C5)(C6)F RNCBXKUPGPYBOP-UHFFFAOYSA-N 0.000 description 3
- ZZDPLNIRJDRMCY-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C56CC(C5)C6 Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C56CC(C5)C6 ZZDPLNIRJDRMCY-UHFFFAOYSA-N 0.000 description 3
- IAAQVWQRRPRODQ-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CC(C5)CO Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CC(C5)CO IAAQVWQRRPRODQ-UHFFFAOYSA-N 0.000 description 3
- LXOTXUUWWXABPN-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CC(C5)OC Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CC(C5)OC LXOTXUUWWXABPN-UHFFFAOYSA-N 0.000 description 3
- QQUKFERVZILTBP-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CC5(F)Cl Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CC5(F)Cl QQUKFERVZILTBP-UHFFFAOYSA-N 0.000 description 3
- ISSYANIZZYOSCZ-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CC5F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CC5F ISSYANIZZYOSCZ-UHFFFAOYSA-N 0.000 description 3
- XLULLYMMUDRULN-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CCC(C5)(F)F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CCC(C5)(F)F XLULLYMMUDRULN-UHFFFAOYSA-N 0.000 description 3
- QADXZKXXMIGCRL-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CCOC5 Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)C5CCOC5 QADXZKXXMIGCRL-UHFFFAOYSA-N 0.000 description 3
- SZQCKRYRLGLLBC-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)CC(F)F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)CC(F)F SZQCKRYRLGLLBC-UHFFFAOYSA-N 0.000 description 3
- VYEMPFXRRKZHIN-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NC5(CC5)C#N Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NC5(CC5)C#N VYEMPFXRRKZHIN-UHFFFAOYSA-N 0.000 description 3
- ZWGWFOAMNHRXLA-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NC5(CC5)C(F)(F)F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NC5(CC5)C(F)(F)F ZWGWFOAMNHRXLA-UHFFFAOYSA-N 0.000 description 3
- KFDOFPJWTQNLNB-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NC5CC5(F)F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NC5CC5(F)F KFDOFPJWTQNLNB-UHFFFAOYSA-N 0.000 description 3
- IMEOXSUCHVPVHI-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NC5COC5 Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NC5COC5 IMEOXSUCHVPVHI-UHFFFAOYSA-N 0.000 description 3
- CURMPFOABKHXAF-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NCC(F)F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NCC(F)F CURMPFOABKHXAF-UHFFFAOYSA-N 0.000 description 3
- UABCJLPURTTYOF-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NCCOC(F)(F)F Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)NCCOC(F)(F)F UABCJLPURTTYOF-UHFFFAOYSA-N 0.000 description 3
- CIGBLMNRYSKQQP-YJNKEBTESA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)[C@@H]5C[C@H]5C#N Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C(=O)[C@@H]5C[C@H]5C#N CIGBLMNRYSKQQP-YJNKEBTESA-N 0.000 description 3
- RPHNEHSGUOCCFT-UHFFFAOYSA-N CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C5CNC5.Cl Chemical compound CN1C=C(C=N1)NC2=NC=CC(=N2)C3=CC4CCC(C3)N4C5CNC5.Cl RPHNEHSGUOCCFT-UHFFFAOYSA-N 0.000 description 3
- JPKNMWJWXAQNTI-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C2(CC2)C(F)(F)F Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C2(CC2)C(F)(F)F JPKNMWJWXAQNTI-UHFFFAOYSA-N 0.000 description 3
- MTCNJZBNSNPRKF-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C2(COC2)C Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C2(COC2)C MTCNJZBNSNPRKF-UHFFFAOYSA-N 0.000 description 3
- HYLKBDQDZQKLHK-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C21CC(C2)(C1)C(F)(F)F Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C21CC(C2)(C1)C(F)(F)F HYLKBDQDZQKLHK-UHFFFAOYSA-N 0.000 description 3
- ZHTOFFASOMARDK-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C2=NC=C(C=C2)C(F)(F)F Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)C2=NC=C(C=C2)C(F)(F)F ZHTOFFASOMARDK-UHFFFAOYSA-N 0.000 description 3
- SPCQWMYLXYMEBK-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)N2CC(C2)C#N Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)N2CC(C2)C#N SPCQWMYLXYMEBK-UHFFFAOYSA-N 0.000 description 3
- QTTRWIVSRXRDSY-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)N2CC(CC2)C(F)(F)F Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(=O)N2CC(CC2)C(F)(F)F QTTRWIVSRXRDSY-UHFFFAOYSA-N 0.000 description 3
- DYFBCCSHIKAJFM-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(CC#N)=O Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(CC#N)=O DYFBCCSHIKAJFM-UHFFFAOYSA-N 0.000 description 3
- IJJITAMGEVQIPW-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2N(C(C1)CC2)CC1(C)COC1 Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2N(C(C1)CC2)CC1(C)COC1 IJJITAMGEVQIPW-UHFFFAOYSA-N 0.000 description 3
- IKPWKKCIAJAURI-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2NC(C1)CC2 Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2NC(C1)CC2 IKPWKKCIAJAURI-UHFFFAOYSA-N 0.000 description 3
- XZBRLFQMFOLMGW-UHFFFAOYSA-N CN1N=CC(NC(N=C2C(CC3CC4)=CC4N3C=O)=NC=C2F)=C1 Chemical compound CN1N=CC(NC(N=C2C(CC3CC4)=CC4N3C=O)=NC=C2F)=C1 XZBRLFQMFOLMGW-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- QRAMUUQTMMDEOV-RUXDESIVSA-N ClC=1C(=NC(=NC1)NC=1C=NN(C1)C)C1=CC2CCC(C1)N2C(=O)[C@H]2C(C2)(F)F Chemical compound ClC=1C(=NC(=NC1)NC=1C=NN(C1)C)C1=CC2CCC(C1)N2C(=O)[C@H]2C(C2)(F)F QRAMUUQTMMDEOV-RUXDESIVSA-N 0.000 description 3
- VTZMMTKMWUFISF-UHFFFAOYSA-N FC1(CN(CC1)C(=O)N1C2C=C(CC1CC2)C2=NC(=NC=C2)NC=2C=NN(C2)C)F Chemical compound FC1(CN(CC1)C(=O)N1C2C=C(CC1CC2)C2=NC(=NC=C2)NC=2C=NN(C2)C)F VTZMMTKMWUFISF-UHFFFAOYSA-N 0.000 description 3
- 241000232901 Nephroma Species 0.000 description 3
- HFHWFPCVFUOYSR-JCYILVPMSA-N O=C(C1CC1)NN1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C([C@H](C3)C3(F)F)=O)=N2)=C1 Chemical compound O=C(C1CC1)NN1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C([C@H](C3)C3(F)F)=O)=N2)=C1 HFHWFPCVFUOYSR-JCYILVPMSA-N 0.000 description 3
- PWSALDBHBYVSNS-UHFFFAOYSA-N O=CN(C(CC1)C2)C1C=C2C1=NC(NC2=CN(C3COC3)N=C2)=NC=C1 Chemical compound O=CN(C(CC1)C2)C1C=C2C1=NC(NC2=CN(C3COC3)N=C2)=NC=C1 PWSALDBHBYVSNS-UHFFFAOYSA-N 0.000 description 3
- YDRXQJFYMXQCTC-UHFFFAOYSA-N OCCN1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C=O)=N2)=C1 Chemical compound OCCN1N=CC(NC2=NC=CC(C(CC3CC4)=CC4N3C=O)=N2)=C1 YDRXQJFYMXQCTC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 3
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 3
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- PVXOUGHWLCBJOW-UHFFFAOYSA-N azetidine-1-carboxamide Chemical compound NC(=O)N1CCC1 PVXOUGHWLCBJOW-UHFFFAOYSA-N 0.000 description 3
- AOUMEYPKBXRHIU-UHFFFAOYSA-N bicyclo[1.1.1]pentane-3-carbonitrile Chemical compound C1C2CC1(C#N)C2 AOUMEYPKBXRHIU-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- GFBLFDSCAKHHGX-UHFFFAOYSA-N cyclobutanecarbonitrile Chemical compound N#CC1CCC1 GFBLFDSCAKHHGX-UHFFFAOYSA-N 0.000 description 3
- AUQDITHEDVOTCU-UHFFFAOYSA-N cyclopropyl cyanide Chemical compound N#CC1CC1 AUQDITHEDVOTCU-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- XDEFHGLUBFLYGV-UHFFFAOYSA-N ethyl 2-(4-nitropyrazol-1-yl)acetate Chemical compound CCOC(=O)CN1C=C([N+]([O-])=O)C=N1 XDEFHGLUBFLYGV-UHFFFAOYSA-N 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 210000001595 mastoid Anatomy 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 208000025351 nephroma Diseases 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- CXLGNJCMPWUZKM-UHFFFAOYSA-N oxane-4-carbaldehyde Chemical compound O=CC1CCOCC1 CXLGNJCMPWUZKM-UHFFFAOYSA-N 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- GSXCEVHRIVLFJV-UHFFFAOYSA-N thiophene-3-carbonitrile Chemical compound N#CC=1C=CSC=1 GSXCEVHRIVLFJV-UHFFFAOYSA-N 0.000 description 3
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- 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 2
- AKFKERAVXIGUNB-UHFFFAOYSA-N 1,3-dimethyl-4-nitropyrazole Chemical compound CC1=NN(C)C=C1[N+]([O-])=O AKFKERAVXIGUNB-UHFFFAOYSA-N 0.000 description 2
- AXLKRXWNAFFPDB-UHFFFAOYSA-N 1,3-dimethylpyrazol-4-amine Chemical compound CC1=NN(C)C=C1N AXLKRXWNAFFPDB-UHFFFAOYSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- KMSWFVSXBMWVIT-UHFFFAOYSA-N 1-cyclopropylpyrazol-4-amine Chemical compound C1=C(N)C=NN1C1CC1 KMSWFVSXBMWVIT-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- GELKGHVAFRCJNA-UHFFFAOYSA-N 2,2-Dimethyloxirane Chemical compound CC1(C)CO1 GELKGHVAFRCJNA-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 2
- MAVOONNUTMUHHG-UHFFFAOYSA-N 2-(4-aminopyrazol-1-yl)acetamide Chemical compound NC(=O)CN1C=C(N)C=N1 MAVOONNUTMUHHG-UHFFFAOYSA-N 0.000 description 2
- AXQLNAAVMSWBEQ-UHFFFAOYSA-N 2-(4-aminopyrazol-1-yl)ethanol Chemical compound NC=1C=NN(CCO)C=1 AXQLNAAVMSWBEQ-UHFFFAOYSA-N 0.000 description 2
- MVTANXJTPWHBTC-UHFFFAOYSA-N 2-(4-nitropyrazol-1-yl)acetamide Chemical compound NC(=O)CN1C=C([N+]([O-])=O)C=N1 MVTANXJTPWHBTC-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 description 2
- GVVVJOVWEIZBJR-UHFFFAOYSA-N 2-methyl-1-(4-nitropyrazol-1-yl)propan-2-ol Chemical compound CC(C)(O)CN1C=C([N+]([O-])=O)C=N1 GVVVJOVWEIZBJR-UHFFFAOYSA-N 0.000 description 2
- QZJUBFJRKQTWAD-UHFFFAOYSA-N 4-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-N-(1-methylpyrazol-4-yl)pyrimidin-2-amine hydrochloride Chemical compound Cl.C12C=C(CC(CC1)N2)C2=NC(=NC=C2)NC=2C=NN(C2)C QZJUBFJRKQTWAD-UHFFFAOYSA-N 0.000 description 2
- HHGWNOSKFDRZHS-UHFFFAOYSA-N 5-chloro-1-methylpyrazol-4-amine Chemical compound CN1N=CC(N)=C1Cl HHGWNOSKFDRZHS-UHFFFAOYSA-N 0.000 description 2
- 238000003727 ADP Glo Kinase Assay Methods 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- ZQHKTTCMFIJDRY-UHFFFAOYSA-N CC(C)(C)OC(=O)N1C2CCC1C=C(C2)C3=NC(=NC=C3S(=O)(=O)C)Cl Chemical compound CC(C)(C)OC(=O)N1C2CCC1C=C(C2)C3=NC(=NC=C3S(=O)(=O)C)Cl ZQHKTTCMFIJDRY-UHFFFAOYSA-N 0.000 description 2
- VDQLXHNFWADLRA-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(C(=O)O)=O Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(C(=O)O)=O VDQLXHNFWADLRA-UHFFFAOYSA-N 0.000 description 2
- KPCZXRZDJBYLNI-UHFFFAOYSA-N CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(C(=O)OC)=O Chemical compound CN1N=CC(=C1)NC1=NC=CC(=N1)C1=CC2CCC(C1)N2C(C(=O)OC)=O KPCZXRZDJBYLNI-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102000042838 JAK family Human genes 0.000 description 2
- 108091082332 JAK family Proteins 0.000 description 2
- 108010000837 Janus Kinase 1 Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- AQCROWCJOFXVCW-UHFFFAOYSA-N NC1=CN(NC(C2CC2)=O)N=C1 Chemical compound NC1=CN(NC(C2CC2)=O)N=C1 AQCROWCJOFXVCW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000001712 STAT5 Transcription Factor Human genes 0.000 description 2
- 108010029477 STAT5 Transcription Factor Proteins 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000008512 biological response Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940125890 compound Ia Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical group [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 238000003209 gene knockout Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229960001008 heparin sodium Drugs 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000004068 intracellular signaling Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000012053 oil suspension Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- RLJWTAURUFQFJP-UHFFFAOYSA-N propan-2-ol;titanium Chemical compound [Ti].CC(C)O.CC(C)O.CC(C)O.CC(C)O RLJWTAURUFQFJP-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- OPDHRWAOWFEPAW-UHFFFAOYSA-N tert-butyl n-(1-methylpyrazol-4-yl)carbamate Chemical compound CN1C=C(NC(=O)OC(C)(C)C)C=N1 OPDHRWAOWFEPAW-UHFFFAOYSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N tetraisopropyl titanate Substances CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000003260 vortexing Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- PCEIEQLJYDMRFZ-UHFFFAOYSA-N (1-cyanocyclopropyl)azanium;chloride Chemical compound Cl.N#CC1(N)CC1 PCEIEQLJYDMRFZ-UHFFFAOYSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- 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 1
- MFCBCXRMDAOFOT-IUYQGCFVSA-N (1r,2r)-2-cyanocyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C#N MFCBCXRMDAOFOT-IUYQGCFVSA-N 0.000 description 1
- 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 1
- 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 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- 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 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- BSGIKRCNMBTGEB-UHFFFAOYSA-N (5-bromo-1-methylpyrrolo[2,3-c]pyridin-2-yl)-[6-[(dimethylamino)methyl]-4-methyl-3,4-dihydro-1h-isoquinolin-2-yl]methanone Chemical compound BrC1=NC=C2N(C)C(C(=O)N3CC(C4=CC(CN(C)C)=CC=C4C3)C)=CC2=C1 BSGIKRCNMBTGEB-UHFFFAOYSA-N 0.000 description 1
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- VICOOSNNZUPVHM-IGPZRPDBSA-M (e,3r,5s)-7-[2-(4-fluorophenyl)-4-(3-phenylpentan-3-yl)phenyl]-3,5-dihydroxyhept-6-enoate Chemical compound C=1C=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=CC=1C(CC)(CC)C1=CC=CC=C1 VICOOSNNZUPVHM-IGPZRPDBSA-M 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- JKSYHPUINDBWRF-UHFFFAOYSA-N 1,5-dimethylpyrazol-4-amine Chemical compound CC1=C(N)C=NN1C JKSYHPUINDBWRF-UHFFFAOYSA-N 0.000 description 1
- SKCBKBCACWDALV-UHFFFAOYSA-N 1-(trifluoromethyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(C(F)(F)F)CC1 SKCBKBCACWDALV-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- 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 1
- 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 1
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- KSJJMSKNZVXAND-UHFFFAOYSA-N 1-cyanocyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(C#N)CC1 KSJJMSKNZVXAND-UHFFFAOYSA-N 0.000 description 1
- HENLKZLWIDJRSC-UHFFFAOYSA-N 1-ethylpyrazol-4-amine Chemical group CCN1C=C(N)C=N1 HENLKZLWIDJRSC-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- OEXNVHXUPNHOPP-UHFFFAOYSA-N 1-propan-2-ylpyrazol-4-amine Chemical group CC(C)N1C=C(N)C=N1 OEXNVHXUPNHOPP-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- AXINVSXSGNSVLV-UHFFFAOYSA-N 1h-pyrazol-4-amine Chemical compound NC=1C=NNC=1 AXINVSXSGNSVLV-UHFFFAOYSA-N 0.000 description 1
- HLFLYOQLHYYNLT-UHFFFAOYSA-N 2,2-difluoro-1-methylcyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(C)CC1(F)F HLFLYOQLHYYNLT-UHFFFAOYSA-N 0.000 description 1
- WSSNWLHFBOKGGL-UHFFFAOYSA-N 2,2-difluorocyclopropan-1-amine;hydrochloride Chemical compound Cl.NC1CC1(F)F WSSNWLHFBOKGGL-UHFFFAOYSA-N 0.000 description 1
- YSVKPVHTHFECBE-UHFFFAOYSA-N 2,2-difluoroethanamine;hydrochloride Chemical compound Cl.NCC(F)F YSVKPVHTHFECBE-UHFFFAOYSA-N 0.000 description 1
- BFNMOMYTTGHNGJ-UHFFFAOYSA-N 2,2-dimethylcyclopropane-1-carboxylic acid Chemical compound CC1(C)CC1C(O)=O BFNMOMYTTGHNGJ-UHFFFAOYSA-N 0.000 description 1
- PQLHCTKAQZYUMI-UHFFFAOYSA-N 2,4-dichloro-5-methylsulfanylpyrimidine Chemical compound CSC1=CN=C(Cl)N=C1Cl PQLHCTKAQZYUMI-UHFFFAOYSA-N 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- WLOWIPYSYJEWHB-UHFFFAOYSA-N 2-(3,3-difluorocyclobutyl)acetic acid Chemical compound OC(=O)CC1CC(F)(F)C1 WLOWIPYSYJEWHB-UHFFFAOYSA-N 0.000 description 1
- PKYWPFQIIQKHCB-UHFFFAOYSA-N 2-(trifluoromethoxy)ethanamine;hydrochloride Chemical compound Cl.NCCOC(F)(F)F PKYWPFQIIQKHCB-UHFFFAOYSA-N 0.000 description 1
- GSNLYQDUCHEFFQ-UHFFFAOYSA-N 2-(trifluoromethyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)C1CC1C(F)(F)F GSNLYQDUCHEFFQ-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- FOAOSDYEDASXTN-UHFFFAOYSA-N 2-chloro-2-fluorocyclopropane-1-carboxylic acid Chemical compound OC(=O)C1CC1(F)Cl FOAOSDYEDASXTN-UHFFFAOYSA-N 0.000 description 1
- IZDJJYRXECMSLX-UHFFFAOYSA-N 2-chloro-5-methylpyridine-3-carbaldehyde Chemical compound CC1=CN=C(Cl)C(C=O)=C1 IZDJJYRXECMSLX-UHFFFAOYSA-N 0.000 description 1
- PAMQVKKXWCRZMF-UHFFFAOYSA-N 2-chloro-N-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-4-amine Chemical compound CN1N=CC(NC2=NC(Cl)=NC=C2C(F)(F)F)=C1 PAMQVKKXWCRZMF-UHFFFAOYSA-N 0.000 description 1
- IGBHPXFFSBIMKR-UHFFFAOYSA-N 2-cyanocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1CCC1C#N IGBHPXFFSBIMKR-UHFFFAOYSA-N 0.000 description 1
- JDEFPFLTCXIVDH-UHFFFAOYSA-N 2-cyanopropanoic acid Chemical compound N#CC(C)C(O)=O JDEFPFLTCXIVDH-UHFFFAOYSA-N 0.000 description 1
- ACYULLZJZXDWRB-UHFFFAOYSA-N 2-cyclopropyl-2,2-difluoroacetic acid Chemical compound OC(=O)C(F)(F)C1CC1 ACYULLZJZXDWRB-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- HZQKMZGKYVDMCT-UHFFFAOYSA-N 2-fluorocyclopropane-1-carboxylic acid Chemical compound OC(=O)C1CC1F HZQKMZGKYVDMCT-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- AHDDRJBFJBDEPW-UHFFFAOYSA-N 2-phenylcyclopropane-1-carboxylic acid Chemical compound OC(=O)C1CC1C1=CC=CC=C1 AHDDRJBFJBDEPW-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- IGOPOYHPIKTQSS-UHFFFAOYSA-N 3,3,3-trifluoropropan-1-amine;hydrochloride Chemical compound [Cl-].[NH3+]CCC(F)(F)F IGOPOYHPIKTQSS-UHFFFAOYSA-N 0.000 description 1
- KSNKQSPJFRQSEI-UHFFFAOYSA-N 3,3,3-trifluoropropanoic acid Chemical compound OC(=O)CC(F)(F)F KSNKQSPJFRQSEI-UHFFFAOYSA-N 0.000 description 1
- DXLZFZGHXIZHFB-UHFFFAOYSA-N 3,3-difluorocyclopentane-1-carboxylic acid Chemical compound OC(=O)C1CCC(F)(F)C1 DXLZFZGHXIZHFB-UHFFFAOYSA-N 0.000 description 1
- SHJWFIDAWODQSR-UHFFFAOYSA-N 3,3-difluoropropanoic acid Chemical compound OC(=O)CC(F)F SHJWFIDAWODQSR-UHFFFAOYSA-N 0.000 description 1
- YYVPZQADFREIFR-UHFFFAOYSA-N 3,3-difluoropyrrolidine;hydrochloride Chemical compound [Cl-].FC1(F)CC[NH2+]C1 YYVPZQADFREIFR-UHFFFAOYSA-N 0.000 description 1
- IJDSDHSDNKDDER-UHFFFAOYSA-N 3-(hydroxymethyl)cyclobutane-1-carboxylic acid Chemical compound OCC1CC(C(O)=O)C1 IJDSDHSDNKDDER-UHFFFAOYSA-N 0.000 description 1
- CGISBZCYXGUFNK-UHFFFAOYSA-N 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid Chemical compound C1C2(C(F)(F)F)CC1(C(=O)O)C2 CGISBZCYXGUFNK-UHFFFAOYSA-N 0.000 description 1
- NIAIUSFJVYYGNP-UHFFFAOYSA-N 3-(trifluoromethyl)pyrrolidine;hydrochloride Chemical compound Cl.FC(F)(F)C1CCNC1 NIAIUSFJVYYGNP-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-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
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- MFBJJYLOKZSNPI-UHFFFAOYSA-N 3-cyanobicyclo[1.1.1]pentane-1-carboxylic acid Chemical compound C1C2(C#N)CC1(C(=O)O)C2 MFBJJYLOKZSNPI-UHFFFAOYSA-N 0.000 description 1
- CQOUAQUBJPKQON-UHFFFAOYSA-N 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid Chemical compound C1C2(F)CC1(C(=O)O)C2 CQOUAQUBJPKQON-UHFFFAOYSA-N 0.000 description 1
- KBEIFKMKVCDETC-UHFFFAOYSA-N 3-iodooxetane Chemical compound IC1COC1 KBEIFKMKVCDETC-UHFFFAOYSA-N 0.000 description 1
- PRADZEMZRCCINO-UHFFFAOYSA-N 3-methoxycyclobutane-1-carboxylic acid Chemical compound COC1CC(C(O)=O)C1 PRADZEMZRCCINO-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DUQGFIKXKISULR-UHFFFAOYSA-N 3-methyloxetane-3-carbaldehyde Chemical compound O=CC1(C)COC1 DUQGFIKXKISULR-UHFFFAOYSA-N 0.000 description 1
- PMPZEEUNGQSAIQ-UHFFFAOYSA-N 3-methyloxetane-3-carboxylic acid Chemical compound OC(=O)C1(C)COC1 PMPZEEUNGQSAIQ-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- PACQLVFDTLRNQU-UHFFFAOYSA-N 4-(8-azabicyclo[3.2.1]oct-2-en-8-yl)-N-(1-methylpyrazol-4-yl)pyrimidin-2-amine Chemical compound C12C=CCC(CC1)N2C2=NC(=NC=C2)NC=2C=NN(C2)C PACQLVFDTLRNQU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ITSSPVBIKSPBLS-UHFFFAOYSA-N 4-chloro-n-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound C1=NN(C)C=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 ITSSPVBIKSPBLS-UHFFFAOYSA-N 0.000 description 1
- RCLMLYLFDJEUJY-UHFFFAOYSA-N 4-cyanooxane-4-carboxylic acid Chemical compound OC(=O)C1(C#N)CCOCC1 RCLMLYLFDJEUJY-UHFFFAOYSA-N 0.000 description 1
- ISGHIGMGRPSNGM-UHFFFAOYSA-N 4-cyanothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC(C#N)=CS1 ISGHIGMGRPSNGM-UHFFFAOYSA-N 0.000 description 1
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- SWKPKONEIZGROQ-UHFFFAOYSA-N 4-trifluoromethylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1 SWKPKONEIZGROQ-UHFFFAOYSA-N 0.000 description 1
- NJHGVAYLDHROPT-UHFFFAOYSA-N 5-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=N1 NJHGVAYLDHROPT-UHFFFAOYSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- KPLHMXMUFYNADB-UHFFFAOYSA-N 6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-(1-methylpyrazol-4-yl)pyrimidine-2,4-diamine Chemical compound CN1N=CC(C2=C(N)N=C(N)N=C2C2=CC(CC3)NC3C2)=C1 KPLHMXMUFYNADB-UHFFFAOYSA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTIGYCOXALLCIB-UHFFFAOYSA-N BrCC(=O)OCC.CN(C=O)C Chemical compound BrCC(=O)OCC.CN(C=O)C BTIGYCOXALLCIB-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- MLGCDSJFWJZBFT-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1C2C=C(CC1CC2)C2=NC(=NC=C2C(F)(F)F)NC=2C=NN(C2)C Chemical compound C(C)(C)(C)OC(=O)N1C2C=C(CC1CC2)C2=NC(=NC=C2C(F)(F)F)NC=2C=NN(C2)C MLGCDSJFWJZBFT-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- CGSJQOIZMOMCGF-UHFFFAOYSA-N C12C=C(CC(CC1)N2)C2=NC(=NC=C2C(F)(F)F)NC=2C=NN(C2)C Chemical compound C12C=C(CC(CC1)N2)C2=NC(=NC=C2C(F)(F)F)NC=2C=NN(C2)C CGSJQOIZMOMCGF-UHFFFAOYSA-N 0.000 description 1
- LRPZSTGOODSVNV-UHFFFAOYSA-N CC(C)(C)OC(=O)N1C2CCC1C=C(C2)C3=NC(=NC=C3SC)Cl Chemical compound CC(C)(C)OC(=O)N1C2CCC1C=C(C2)C3=NC(=NC=C3SC)Cl LRPZSTGOODSVNV-UHFFFAOYSA-N 0.000 description 1
- XHSXYHXWCFWSGR-UHFFFAOYSA-N CC(CN(C(CC1)C2)C1C=C2C1=NC(NC2=CN(C)N=C2)=NC=C1)(CN1)C1=O Chemical compound CC(CN(C(CC1)C2)C1C=C2C1=NC(NC2=CN(C)N=C2)=NC=C1)(CN1)C1=O XHSXYHXWCFWSGR-UHFFFAOYSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101000651232 Dictyostelium discoideum Dual specificity protein kinase splB Proteins 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010091824 Focal Adhesion Kinase 1 Proteins 0.000 description 1
- 102100037813 Focal adhesion kinase 1 Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000883515 Homo sapiens Chitinase-3-like protein 1 Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 108010019437 Janus Kinase 2 Proteins 0.000 description 1
- 108010019421 Janus Kinase 3 Proteins 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102100032352 Leukemia inhibitory factor Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 108010044012 STAT1 Transcription Factor Proteins 0.000 description 1
- 102000006381 STAT1 Transcription Factor Human genes 0.000 description 1
- 108010081691 STAT2 Transcription Factor Proteins 0.000 description 1
- 102000004265 STAT2 Transcription Factor Human genes 0.000 description 1
- 108010019992 STAT4 Transcription Factor Proteins 0.000 description 1
- 102000005886 STAT4 Transcription Factor Human genes 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000111306 Torreya nucifera Species 0.000 description 1
- 235000006732 Torreya nucifera Nutrition 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046799 Uterine leiomyosarcoma Diseases 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- 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 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- MBOJMCCWZHTXSJ-UHFFFAOYSA-N [1-(trifluoromethyl)cyclopropyl]azanium;chloride Chemical compound Cl.FC(F)(F)C1(N)CC1 MBOJMCCWZHTXSJ-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- FYJKEHKQUPSJDH-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;potassium Chemical compound [K].C[Si](C)(C)N[Si](C)(C)C FYJKEHKQUPSJDH-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 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 1
- MJZQSPDYIKSJCN-UHFFFAOYSA-N azetidine-3-carbonitrile;hydrochloride Chemical compound Cl.N#CC1CNC1 MJZQSPDYIKSJCN-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- ORCXPYPDHLVQFP-UHFFFAOYSA-N bicyclo[1.1.1]pentane-3-carboxylic acid Chemical compound C1C2CC1(C(=O)O)C2 ORCXPYPDHLVQFP-UHFFFAOYSA-N 0.000 description 1
- 150000001602 bicycloalkyls Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 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
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 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 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 230000005745 host immune response Effects 0.000 description 1
- 102000054350 human CHI3L1 Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- ZTUJDPKOHPKRMO-UHFFFAOYSA-N hydron;2,2,2-trifluoroethanamine;chloride Chemical compound Cl.NCC(F)(F)F ZTUJDPKOHPKRMO-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 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 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- ZBQCPWMIGVSOGB-UHFFFAOYSA-N non-7-enoic acid Chemical class CC=CCCCCCC(O)=O ZBQCPWMIGVSOGB-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AVPKHOTUOHDTLW-UHFFFAOYSA-N oxane-4-carboxylic acid Chemical compound OC(=O)C1CCOCC1 AVPKHOTUOHDTLW-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- ZGNYUQSBJCCWGF-UHFFFAOYSA-N oxetan-3-amine;hydrochloride Chemical compound Cl.NC1COC1 ZGNYUQSBJCCWGF-UHFFFAOYSA-N 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- BOTREHHXSQGWTR-UHFFFAOYSA-N oxolane-3-carboxylic acid Chemical compound OC(=O)C1CCOC1 BOTREHHXSQGWTR-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- OWTCGJRBQMOICX-UHFFFAOYSA-M phenacyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1C(=O)C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 OWTCGJRBQMOICX-UHFFFAOYSA-M 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000009832 plasma treatment Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005316 response function Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 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
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- BESFCRTTXQYNBW-UHFFFAOYSA-N tert-butyl 3-(cyanomethylidene)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=CC#N)C1 BESFCRTTXQYNBW-UHFFFAOYSA-N 0.000 description 1
- CJDKVEWDWXIBSM-UHFFFAOYSA-N tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate Chemical compound C1C(OS(=O)(=O)C(F)(F)F)=CC2CCC1N2C(=O)OC(C)(C)C CJDKVEWDWXIBSM-UHFFFAOYSA-N 0.000 description 1
- MENILFUADYEXNU-UHFFFAOYSA-N tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1C(=O)CC2CCC1N2C(=O)OC(C)(C)C MENILFUADYEXNU-UHFFFAOYSA-N 0.000 description 1
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- 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
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Transplantation (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
桥杂环基取代的嘧啶类化合物及其制备方法和医药用途。特别地,涉及通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物,及其作为JAK1和TYK2激酶抑制剂的用途,和用于治疗与JAK1和TYK2激酶活性相关的疾病,例如炎症、自身免疫性病症、癌症等中的用途。其中通式(I)中的各取代基的定义与说明书中的定义相同。
Description
技术领域
本发明属于医药技术领域,具体涉及一种桥杂环基取代的嘧啶类化合物、其制备方法及含有其的药物组合物,以及其用于调节Janus激酶1(JAK1)和酪氨酸蛋白质激酶2(TYK2)活性并且用于治疗和/或预防与JAK1和TYK2活性相关的疾病的用途。
背景技术
胞内信号传递过程是细胞对外界刺激产生反应,并最终引发特异性生物学效应的有效方式。细胞因子能够通过多种信号转导通路进行胞内信号传递,从而参与调控造血功能和免疫相关的许多重要的生物学功能。蛋白酪氨酸激酶中的Janus激酶(JAK)家族和转录激活子(STAT)在细胞因子信号转导过程中扮演重要角色(J.Immunol.2015,194,21)。
Janus激酶(JAK)家族在涉及免疫应答的细胞增殖和功能的细胞因子依赖性调解中起着一定的作用。目前,有四种已知的哺乳动物JAK家族成员:JAK1(亦称Janus激酶-1)、JAK2(亦称Janus激酶-2)、JAK3(亦称Janus激酶,白细胞,JAKL1,L-JAK和Janus激酶-3)、Tyk2(亦称蛋白质-酪氨酸激酶2)。JAK1、JAK2和Tyk2广泛存在于各种组织和细胞中,而JAk3仅存在于骨髓和淋巴系统中(J.Med.Chem.2014,57,5023)。
Tyk2是第一个被发现的JAK激酶,在调控IL-12和细菌脂多糖(LPS)的生物学应答反应中起着重要作用,也参与IL-6、IL-10和IL-12介导的信号转导通路。靶向Tyk2可成为治疗IL-12、IL-23、或I型IFN介导的疾病的新策略,所述疾病包括但不限于类风湿性关节炎、多发性硬化症、狼疮、银屑病、银屑病性关节炎、炎症性肠炎、葡萄膜炎、结节病、红斑狼疮和癌症。
JAK1在调控多种细胞因子受体家族的生物学应答功能中起着重要的作用。JAK1基因敲除小鼠具有早期的出生后致死因子显型,神经系统也受到损害,导致幼鼠出现先天缺陷。研究表明JAK1基因敲除小鼠会出现胸腺细胞和B细胞的分泌缺陷,JAK1基因敲除的组织对LIF、IL-6、IL-10的反应明显减弱。临床试验表明JAK1抑制剂在治疗类风湿性关节炎、溃疡性结肠炎、克罗恩病、红斑狼疮、斑秃、特应性皮炎等多种炎症和自身免疫性疾病方面都表现出很好的疗效。
细胞因子与受体结合后,受体形成二聚体,与受体偶联的JAK相互靠近并进行酪氨酸残基磷酸化而活化。进而催化受体本身的酪氨酸残基磷酸化,形成“停泊位点”。信号转导和转录激活子(Signal Transducer and Activator of Transcription,STAT)是一组能与靶基因调控与DNA结合的胞质蛋白。STAT家族包括STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b和SyAT6。STAT通过SH2结构域识别“停泊位点”并被JAK激酶对其C端酪氨酸残基进行磷酸化从而被激活。激活的STAT因子转入细胞核内,在调节先天性和获得性宿主免疫反应中起着重要的作用。
JAK/STAT信号转导通路的激活促进各种疾病的发生,包括但不限于,许多异常免疫应答,如过敏、哮喘、类风湿性关节炎、肌萎缩性脊髓侧索硬化症和多发性硬化症等。其还与癌症,例如白血病(急性髓性白血病和急性淋巴细胞白血病)、实体瘤(子宫平滑肌肉瘤、前列腺癌)等相关(Curr.Opin.Rheumatol.2014,26,237)。
鉴于JAK1和TYK2在炎症信号通路中扮演的重要角色,能同时抑制这两种激酶的药物有进一步提升药效的潜力,给患者带来更大的获益。
发明内容
本发明人经过潜心研究,设计合成了一系列桥杂环基取代的嘧啶类化合物,并对其进行了JAK1和TYK2活性的筛选,研究结果显示该类化合物具有突出的JAK1和TYK2抑制活性,并且可以被开发为治疗与JAK1和TYK2活性相关的疾病的药物。
因此,本发明的目的在于一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,
其中:
R1选自环烷基、杂环基、芳基和杂芳基,其中所述环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被一个或多个R4取代;
每个R4各自独立地选自卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)Ra、-O(O)CRa、-C(O)ORa、-C(O)NRaRb、NRaRb、-NHC(O)Ra、-S(O)nRa、-S(O)nNRaRb和-NHS(O)nRa,其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代;
R2选自氢、卤素、氨基、氰基、羟基、巯基、羧基、烷基、烷氧基和环烷基,其中所述烷基、烷氧基和环烷基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代;
L选自单键、-CR5R6-、-C(O)-、-C(S)-、-N(Ra)-、-S(O)n-、-O-、-S-、-C(O)N(Ra)-、-C(O)-C(O)-N(Ra)-和-S(O)nN(Ra)-;
R5和R6各自独立地选自氢、卤素、羟基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代;
或者R5和R6及其连接的原子一起形成环烷基或杂环基,其中所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代;
R3选自烷基、环烷基、杂环基、芳基和杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被一个或多个R7取代;
每个R7各自独立地选自卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、ORa、-C(O)Ra、-O(O)CRa、-C(O)ORa、-C(O)NRaRb、NRaRb、-NHC(O)Ra、-S(O)nRa、-S(O)nNRaRb和-NHS(O)nRa,其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
Ra和Rb各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代;
或者Ra和Rb与他们连接的氮原子一起形成含氮杂环基,其中所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代;且
n为0、1或2。
在本发明的一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐:
其中,R2、R3、R4和L如通式(I)化合物中所定义;且
m为0、1、2或3。
在本发明的一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,
其中,
R3选自烷基、环烷基和杂环基,优选烷基和环烷基,其中所述烷基、环烷基和杂环基各自独立地任选进一步被一个或多个R7取代;
且R7如权利要求1所定义,优选选自卤素、氰基、芳基、环烷基和烷基,其中所述环烷基和烷基各自独立地任选被一个或多个卤素取代。
在本发明的另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,
其中,
L选自单键、-CR5R6-、-C(O)-、-S(O)n-、-O-、-S-、-C(O)N(Ra)-、-C(O)-C(O)-N(Ra)-和-S(O)nN(Ra)-,优选-S(O)n-、-C(O)-、-C(O)N(Ra)-和-S(O)nN(Ra)-,更优选-C(O)-和-C(O)N(Ra)-。
其中,R5、R6、Ra和n如通式(I)化合物中所定义。
在本发明的一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,
其中,
R2选自氢、卤素、氰基、羟基、羧基、烷基和环烷基,优选氢、卤素、氰基和烷基,更优选氢和卤素。
在本发明的另一个优选的实施方案中,根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,
其中,
R1选自环烷基、杂环基、芳基和杂芳基,优选芳基和杂芳基,更优选杂芳基,其中所述环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被一个或多个R4取代;且
R4如通式(I)化合物中所定义,优选为烷基。
本发明典型的化合物包括但不限于:
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐。
本发明进一步提供一种制备根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐的方法,其包括以下步骤:
步骤1:将化合物Ia在碱性条件下与N-苯基双(三氟甲烷磺酰)亚胺反应得到化合物Ib,其中提供碱性条件的试剂优选为六甲基二硅基胺基钾;
步骤2:将化合物Ib在碱性条件和催化剂存在下与联硼酸频那醇酯(Ic)反应得到化合物Id,其中,提供碱性条件的试剂优选为醋酸钾,催化剂优选为Pd(dppf)Cl2-CH2Cl2;
步骤3:将化合物Id在碱性条件和催化剂存在下与化合物Ie反应得到化合物If,其中,提供碱性条件的试剂优选为碳酸钾,催化剂优选为Pd(dppf)Cl2;
步骤4:将化合物If与化合物Ig在酸性条件下反应得到化合物Ih,其中,提供酸性条件的试剂优选为对甲苯磺酸;
步骤5:将化合物Ih在酸性条件下发生脱保护反应得到化合物Ii,其中,提供酸性条件的试剂优选为三氟乙酸;
步骤6:将化合物Ii在碱性条件下,与R3-L-X(X=Cl、Br、I、OPh或)反应得到通式(I)化合物,其中,提供碱性条件的试剂优选为三乙胺;或者由化合物Ii与R3-L-OH在碱性条件和催化剂存在下反应得到得到通式(I)化合物,其中提供碱性条件的试剂优选为DIPEA,催化剂优选为HATU,
其中,R1、R2、R3和L如通式(I)化合物中所定义。
本发明另外提供一种药物组合物,其含有治疗有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐,以及药学上可接受的载体。
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐,或者含有其的药物组合物,在制备JAK1和TYK2抑制剂中的用途。
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,或者含有其的药物组合物,在制备预防和/或治疗与JAK1和TYK2活性相关的疾病的药物中的用途,其中所述疾病选自炎症、自身免疫性疾病和癌症,所述炎症优选选自类风湿性关节炎、银屑病性关节炎、炎症性肠炎、葡萄膜炎、银屑病和特应性皮炎,所述自身免疫性疾病优选选自多发性硬化症和狼疮;所述癌症优选选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,或者含有其的药物组合物,其用作药物。
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,或者含有其的药物组合物,其用作JAK1和TYK2抑制剂。
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,或者含有其的药物组合物,其预防和/或治疗与JAK1和TYK2活性相关的疾病,其中所述疾病选自炎症、自身免疫性疾病和癌症,所述炎症优选选自类风湿性关节炎、银屑病性关节炎、炎症性肠炎、葡萄膜炎、银屑病和特应性皮炎,所述自身免疫性疾病优选选自多发性硬化症和狼疮;所述癌症优选选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明进一步涉及一种抑制JAK1和TYK2的方法,其包括将本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,或者含有其的药物组合物,与JAK1和TYK2接触。
本发明进一步涉及一种预防和/或治疗与JAK1和TYK2活性相关的疾病的方法,其包括向需要其的受试者施用治疗有效量的本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药或其可药用盐,或者含有其的药物组合物,其中所述疾病选自炎症、自身免疫性疾病和癌症,所述炎症优选选自类风湿性关节炎、银屑病性关节炎、炎症性肠炎、葡萄膜炎、银屑病和特应性皮炎,所述自身免疫性疾病优选选自多发性硬化症和狼疮;所述癌症优选选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
按照本发明所属领域的常规方法,本发明通式(I)所示的化合物可以与酸生成药学上可接受的酸式加成盐。所述酸包括无机酸和有机酸,特别优选盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
按照本发明所属领域的常规方法,本发明通式(I)所示的化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱,可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等,可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。
此外,本发明还包括本发明通式(I)所示的化合物的前药。本发明所述的前药是通式(I)所示的化合物的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
含活性成分的药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物,此类组合物可含有一种或多种选自以下的成分:甜味剂、矫味剂、着色剂和防腐剂,以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸;粘合剂,例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收,因而在较长时间内提供缓释作用的已知技术将其包衣。例如,可使用水溶性味道掩蔽物质,例如羟丙基甲基纤维素或羟丙基纤维素,或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊,或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂,例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶;分散剂或湿润剂,可以是天然产生的磷脂例如卵磷脂,或烯化氧与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol),或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物,例如聚环氧乙烷山梨醇单油酸酯,或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物,例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂,例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油,或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂,以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水,适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油,或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂,例如大豆卵磷脂,和由脂肪酸和己糖醇酐衍生的酯或偏酯,例如山梨坦单油酸酯,和所述偏酯和环氧乙烷的缩合产物,例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射,将注射液或微乳注入患者的血流中。或者,最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度,可使用连续静脉内递药装置。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液,例如在1,3-丁二醇中制备的溶液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。为此目的,可使用包括合成甘油单或二酯在内的任何调和固定油。此外,脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体,因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员熟知,药物的给药剂量依赖于多种因素,包括但并非限定于以下因素:所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外,最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明可以含有通式(I)所示的化合物,及其药学上可接受的盐、水合物或溶剂化物作为活性成分,与药学上可接受的载体或赋型剂混合制备成组合物,并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应等。本发明化合物可作为唯一的活性成分,也可以与其它治疗与JAK1和TYK2活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。
发明的详细说明
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基,例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括:
术语“稠环烷基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括:
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。桥环烷基的非限制性实例包括:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;最优选包含3至8个环原子,其中1~3个是杂原子;最优选包含5至7个环原子,其中1~2或1~3个是杂原子。单环杂环基的非限制性实例包括氧杂环丁基、氮杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等,优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括:
术语“稠杂环基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括:
术语“桥杂环基”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。桥杂环基的非限制性实例包括:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:
杂环基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:
芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,含1至3个杂原子;更优选为5元或6元,含1至2个杂原子;优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等,优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基;更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:
杂芳基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基,其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基,其中烷氧基如上所定义。
术语“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代基”指=O。
术语“羧基”指-C(O)OH。
术语“巯基”指-SH。
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基),其中烷基和环烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物,其中R为烷基、环烷基、杂环基、芳基、杂芳基。
术语“磺酸基”指-S(O)2OH。
术语“磺酸酯基”指-S(O)2O(烷基)或-S(O)2O(环烷基),其中烷基和环烷基如上所定义。
术语“磺酰基”指-S(O)2R基团的化合物,其中R为烷基、环烷基、杂环基、芳基、杂芳基。
术语“氨基酰基”指-C(O)-NRR’,其中R、R’各自独立地为氢、烷基、环烷基、杂环基、芳基、杂芳基。
术语“氨基磺酰基”或“磺酰氨基”指-S(O)2-NRR’,其中R、R’各自独立地为氢、烷基、环烷基、杂环基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案。
本发明通式(I)所示的化合物或其盐可通过如下方案制备:
步骤1:将化合物Ia在碱性条件下与N-苯基双(三氟甲烷磺酰)亚胺反应得到化合物Ib,其中提供碱性条件的试剂优选为六甲基二硅基胺基钾;
步骤2:将化合物Ib在碱性条件和催化剂存在下与联硼酸频那醇酯(Ic)反应得到化合物Id,其中,提供碱性条件的试剂优选为醋酸钾,催化剂优选为Pd(dppf)Cl2-CH2Cl2;
步骤3:将化合物Id在碱性条件和催化剂存在下与化合物Ie反应得到化合物If,其中,提供碱性条件的试剂优选为碳酸钾,催化剂优选为Pd(dppf)Cl2;
步骤4:将化合物If与化合物Ig在酸性条件下反应得到化合物Ih,其中,提供酸性条件的试剂优选为对甲苯磺酸;
步骤5:将化合物Ih在酸性条件下发生脱保护反应得到化合物Ii,其中,提供酸性条件的试剂优选为三氟乙酸;
步骤6:将化合物Ii在碱性条件下,与R3-L-X(X=Cl、Br、I、OPh或)反应得到通式(I)化合物,其中,提供碱性条件的试剂优选为三乙胺;或者由化合物Ii与R3-L-OH在碱性条件和催化剂存在下反应得到得到通式(I)化合物,其中提供碱性条件的试剂优选为DIPEA,催化剂优选为HATU,
其中,R1、R2、R3和L如通式(I)化合物中所定义。
具体实施方式
以下结合实施例进一步描述本发明,但这些实施例并非限制着本发明的范围。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10-6(ppm)的单位给出。NMR的测定是用Brukerdps300型核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用1100Series LC/MSD Trap(ESI)质谱仪(生产商:Agilent)。
实施例中无特殊说明,制备液相使用lc3000高效液相色谱仪以及lc6000高效液相色谱仪(生产商:创新通恒)。色谱柱为DaisogelC18 10μm 60A(20mm×250mm)。流动相:乙腈,水(0.05甲酸%)。
HPLC的测定使用岛津LC-20AD高压液相色谱仪(Agilent TC-C18 250×4.6mm 5μm色谱柱)和岛津LC-2010AHT高压液相色谱仪(Phenomenex C18 250×4.6mm5μm色谱柱)。
薄层层析硅胶板使用青岛海洋化工GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用青岛海洋硅胶100~200目、200~300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自网化商城、北京耦合、Sigma、百灵威、易世明、上海书亚、伊诺凯、南京药石、安耐吉化学等公司。
实施例中无特殊说明,反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
微波反应使用CEM Discover SP型微波反应器。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温,为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂的体系有:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:石油醚和乙酸乙酯体系,D:丙酮,溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括:A:二氯甲烷和甲醇体系,B:石油醚、乙酸乙酯和二氯甲烷体系,C:石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例
实施例1:((S)-2,2-二氟环丙基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(1)的制备
步骤1:3-(((三氟甲基)磺酰基)氧基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯的合成(1b)
于-78℃,氮气氛围下将六甲基二硅基胺基钾(10.7mL,10.7mmol)加入3-氧代-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(2.00g,8.88mmol)的无水四氢呋喃(30mL)混合液中,-78℃搅拌0.5小时。滴加N-苯基双(三氟甲烷磺酰)亚胺(3.82g,10.7mmol)的无水四氢呋喃溶液(20mL)中,滴加完毕后于-78℃搅拌2小时。加入饱和氯化铵水溶液(20mL)淬灭,用乙酸乙酯(30mL*3)萃取,有机相用氢氧化钾溶液(1mol/L)和饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残留液经快速(flash)柱色谱法(流动相:石油醚/乙酸乙酯,10/1至2/1)纯化,得到3.10g淡黄色油状液体标题化合物。收率:97.8%。
步骤2:叔丁基3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酸的合成(1d)
于室温氮气氛围下,将Pd(dppf)Cl2二氯甲烷络合物(423mg,0.518mmol)加入3-(((三氟甲基)磺酰基)氧基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯(3.70g,10.4mmol),醋酸钾(3.05g,31.1mmol)和联硼酸频那醇酯(2.90g,11.4mmol)的二氧六环(50mL)溶液中,于80℃搅拌过夜。旋干溶剂,加入水(40mL)中,用乙酸乙酯(50mL*3)萃取,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残留液经快速柱色谱法(流动相:石油醚/乙酸乙酯=10/1至2/1)纯化,得到1.20g黄色油状液体标题化合物。收率:34.6%。
步骤3:3-(2-氯嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯的合成(1f)
于室温氮气氛围下,将Pd(dppf)Cl2(262mg,0.358mmol)加入叔丁基3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酸(1.20g,3.58mmol),碳酸钾(1.24g,8.95mmol)和2,4-二氯嘧啶(534mg,3.58mmol)的二氧六环(40mL)和水(10mL)的混合溶液中,于80℃搅拌过夜。旋干溶剂,加入水(40mL)中,用乙酸乙酯(50mL*3)萃取,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残留液经快速柱色谱法(流动相:石油醚/乙酸乙酯=10/1至1/1)纯化,得到830mg黄色油状液体标题化合物。收率:72.1%。
步骤4:叔丁基3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸的合成(1b)
于室温,将对甲苯磺酸(37.3mg,0.217mmol)加入3-(2-氯嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯(700mg,2.17mmol),和1-甲基-1H-吡唑-4-胺(211mg,2.17mmol)的二氧六环(10mL)溶液中,于90℃搅拌过夜。旋干溶剂,加入水(40mL)中,用乙酸乙酯(50mL*3)萃取,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残留液经快速柱色谱法(流动相:石油醚/乙酸乙酯=10/1至1/1)得到600mg棕色油状液体标题化合物。收率:72.4%。
步骤5:4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺三氟乙酸盐的合成(1i)
于室温,用三氟乙酸(2mL)加入叔丁基3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸(200mg,0.524mmol)的二氯甲烷(6mL)溶液中,搅拌30分钟,低温浓缩,得到157mg白色固体粗品标题化合物。
步骤6:((S)-2,2-二氟环丙基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮的合成(1)
于室温,将2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(224mg,0.590mmol)加入(S)-2,2-二氟环丙烷-1-羧酸(60mg,0.492mmol)的N,N-二甲基甲酰胺(10mL)溶液中,于室温搅拌30分钟。加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺三氟乙酸盐(157mg,0.414mmol)和N,N-二异丙基乙胺(190mg,1.48mmol),于室温搅拌过夜。加入水(50mL)中,用乙酸乙酯(30mL×3)萃取,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残留物经制备液相色谱法纯化,得95.0mg黄色固体标题化合物,收率:59.4%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-50%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 387[M+H]+;
1H NMR(300MHz,CD3OD):δppm 8.28(m,1H),7.89(s,1H),7.55(s,1H),7.12-7.22(m,1H),6.81-6.83(m,1H),4.94-5.05(m,1H),4.75-4.77(m,1H),3.86-3.88(m,3H),2.98-3.10(m,2H),2.52-2.69(m,1H),2.16-2.41(m,2H),2.00-2.12(m,2H),1.75-1.79(m,2H)。
实施例1-a和1-b:化合物1-a和1-b的制备
化合物1-a和1-b由化合物1通过超临界液体色谱法(SFC)分离得到。
SFC分离条件:
色谱柱型号:AS-H 4.6mm x 250mm,5μm,流动相:MeOH(0.2%NH3·H2O)/CO2=35∶65,流速:40g/min。
1-a:保留时间:2.87min;
LC-MS:m/z 387[M+H]+
1H NMR(400MHz,DMSO):δppm9.36(s,1H),8.35-8.29(m,1H),7.83(s,1H),7.49(s,1H),7.18-7.06(m,1H),6.84-6.80(m,1H),4.85-4.79(m,2H),3.81(s,3H),3.18-3.05(m,1H),2.88-2.81(m,1H),2.51-2.49(m,1H),2.39-2.29(m,1H),2.10-1.66(m,5H)。
1-b:保留时间:3.79min。
LC-MS:m/z 387[M+H]+
1H NMR(400MHz,DMSO):δppm9.36(s,1H),8.34(d,J=5.2Hz,1H),7.82(d,J=6Hz,1H),7.51(s,1H),7.19-7.15(m,1H),6.83-6.82(m,1H),4.90-4.71(m,2H),3.81(s,3H),3.21-3.16(m,1H),3.06-2.90(m,1H),2.51-2.27(m,1H),2.11-2.09(m,1H),1.98-1.67(m,5H)。
实施例2:N-(氰基甲基)-3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(2)的制备
步骤1:(氰基甲基)氨基甲酸苯酯的合成(2c)
于0℃,将苯基氯甲酸酯(844mg,5.38mmol)加入2-氨基乙腈(500mg,5.38mmol)的四氢呋喃(6mL)和饱和碳酸氢钠水溶液(2mL)的混合液中,于0℃搅拌30min。加水(20mL),用乙酸乙酯(30mL*3)萃取,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残留液用快速柱色谱法(流动相:石油醚/乙酸乙酯,100/1至10/1)纯化,得到800mg白色固体标题化合物。收率:84.6%。
步骤2:N-(氰基甲基)-3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺的合成(2)
于室温,将三乙胺(102mg,1.01mmol)加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺三氟乙酸盐(200mg,0.504)和苯基(氰基甲基)氨基甲酸酯(106mg,0.605mmol)的四氢呋喃(5mL)溶液中,于60℃搅拌过夜,减压浓缩,残留物经制备液相色谱法纯化,得11.0mg黄色固体标题化合物,收率:5.99%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-50%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 365[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm9.32(s,1H),8.33-8.31(m,1H),7.81(s,1H),7.51(s,1H),7.40-7.31(m,1H),7.26-7.15(m,1H),6.82-6.80(m,1H),4.57-4.48(m,2H),4.04-4.02(m,2H),3.80(s,3H),2.97-2.92(m,1H),2.33-2.28(m,1H),2.20-2.10(m,1H),2.05-1.85(m,2H),1.68-1.64(m,1H)。
实施例3:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(3)的制备
步骤1:苯基(2,2,2-三氟乙基)氨基甲酸酯的合成(3b)
于0℃,将苯基氯甲酸酯(476mg,3.03mmol)加入2,2,2-三氟乙胺(300mg,3.03mmol)的四氢呋喃(6mL)和饱和碳酸氢钠水溶液(2mL)的混合液中,于0℃搅拌30min。加水(20mL),用乙酸乙酯(30mL*3)萃取,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,快速柱色谱法(流动相:PE/EA=100∶1-10∶1)得到593mg白色固体。收率:89.3%。
LC-MS:m/z=220[M+H]
步骤2:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺的合成(3)
于室温,将三乙胺(102mg,1.01mmol)加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺三氟乙酸盐(200mg,0.504mmol)和苯基(2,2,2-三氟乙基)氨基甲酸酯(133mg,0.605mmol)的四氢呋喃(5mL)溶液中,于60℃搅拌过夜,减压浓缩,残留物经制备液相色谱法纯化得15mg白色固体粉末。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-80%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 408[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm 9.36(s,1H),8.36(d,J=3Hz,1H),7.84(s,1H),7.55(s,1H),7.32-7.29(m,1H),7.24(s,1H),6.84(d,J=3Hz,1H),4.64(s,1H),4.56(s,1H),3.90-3.76(m,5H),2.98(d,J=12Hz,1H),2.33(d,J=12Hz,1H),2.20-2.18(m,1H),2.02-1.96(m,2H),1.72-1.67(m,1H)。
实施例3-a和3-b:化合物3-a和3-b的制备
化合物3-a和3-b由化合物3通过SFC分离得到。
SFC分离条件:
色谱柱型号:(R,R)whelk-0121.1mm x 250mm,5μm,流动相:MeOH(0.2%NH3·H2O)/CO2=35∶65,流速:40g/min。
3-a:保留时间:5.19min;
LC-MS:m/z 408[M+H]+
1H NMR(400MHz,CDCl3):δppm 8.29(d,J=5.2Hz,1H),7.73(s,1H),7.54(s,1H),7.14-7.12(m,2H),6.66(d,J=5.2Hz,1H),5.04-5.01(m,1H),4.55-4.48(m,2H),3.94-3.92(m,1H),3.88(s,3H),3.85-3.81(m,1H),3.12-3.07(m,1H),2.38-2.28(m,2H),2.02-1.86(m,2H),1.75-1.72(m,1H)。
3-b:保留时间:7.42min。
LC-MS:m/z 408[M+H]+
1H NMR(400MHz,CDCl3):δppm 8.30(d,J=5.2Hz,1H),7.74(s,1H),7.54(s,1H),7.14(s,1H),6.87(s,1H),6.67(d,J=5.2Hz,1H),4.85-4.82(m,1H),4.55-4.47(m,2H),3.98-3.94(m,1H),3.90(s,3H),3.86-3.82(m,1H),3.13-3.09(m,1H),2.40-2.29(m,2H),2.37-2.01(m,2H),1.79-1.67(m,1H)。
实施例4:N-(氰基甲基)-3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-磺酰胺(4)的制备
步骤1:N-(氰基甲基)-2-氧代恶唑烷-3-磺酰胺的合成(4d)
在0℃,将2-溴乙醇(1.25g,10.0mmol)的二氯甲烷(2mL)溶液滴加入氯磺酰异氰酸酯(1.42g,10mmol)的二氯甲烷(50mL)溶液中,于0℃反应1.5小时,滴加入2-氨基乙腈盐酸盐(925mg,10.0mmol)和三乙胺(5.10g,50.0mmol)的二氯甲烷(40mL)溶液,滴毕后自然恢复室温反应30分钟,加入盐酸水溶液(40mL,1M),分相,有机相用饱和盐水洗涤,干燥,减压浓缩,得到棕色油状液体600mg,不经纯化,直接用于下一步。
步骤2:N-(氰基甲基)-3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-磺酰胺的合成(4)
将N-(氰基甲基)-2-氧代噁唑烷-3-磺酰胺(400mg,1.95mmol)、4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺三氟乙酸盐(616mg,1.63mmol)和三乙胺(660mg,6.52mmol)加入乙腈(15mL)中,于65℃反应过夜,反应液降温至室温,浓缩,残留物经制备液相色谱法纯化,得到25.0mg白色固体标题产物,收率:3.83%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈15-55%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 401[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm9.34(s,1H),8.33(d,J=5.1Hz,1H),8.26(s,1H),7.83(s,1H),7.50(s,1H),7.16(d,J=5.1Hz,1H),6.82(d,J=5.1Hz,1H),4.42-4.40(m,2H),4.06(s,2H),3.80(s,3H),3.06-3.04(m,1H),2.51-2.43(m,1H),2.27-2.07(m,2H),2.01-1.1.94(m,1H),1.73-1.68(m,1H)。
实施例5:4,4,4-三氟-1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)丁-1-酮(5)的制备
于室温,将2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(345mg,0.907mmol)加入4,4,4-三氟丁酸(129mg,0.907mmol)的N,N-二甲基甲酰胺(5mL)溶液中,于室温搅拌30分钟。加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺三氟乙酸盐(300mg,0.756mmol)和N,N-二异丙基乙胺(293mg,2.27mmol),于室温搅拌过夜。加入水(50mL)中,用乙酸乙酯(30mL*3)萃取,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残留物经制备液相色谱法纯化,得35.0mg淡黄色固体标题化合物,收率:11.4%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈40-90%;波长:210nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 407[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm 9.34(s,1H),8.34(d,J=5.4Hz,1H),7.83(d,J=4.8Hz,1H),7.51(s,1H),7.21(s,1H),6.82-6.81(m,1H),4.91-4.63(m,2H),3.81(s,3H),2.95-2.72(m,1H),2.69-2.62(m,3H),2.41-2.27(m,2H),2.23-2.09(m,1H),2.02-1.92(m,1H),1.88-1.74(m,2H)。
实施例6:N-(1-甲基-1H-吡唑-4-基)-4-(8-((3,3,3-三氟丙基)磺酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)嘧啶-2-胺(6)的制备
于室温,将3,3,3-三氟丙烷-1-磺酰氯(119mg,0.604mmol)加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺三氟乙酸盐(200mg,0.526mmol)的二氯甲烷(10mL)溶液中,于室温搅拌过夜,减压浓缩残留物经制备液相色谱法纯化,得53.0mg黄色固体标题化合物,收率:12.0%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈20-60%;波长:254nm;流速:45mL/min;流动相:乙腈,水(0.05甲酸%)。
LC-MS:m/z 443[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm 9.41(s,1H),8.35(d,J=6Hz,1H),7.83(s,1H),7.51(s,1H),7.23-7.17(m,1H),6.85(d,J=6Hz,1H),4.57-4.50(m,3H),3.81(s,3H),3.49-3.43(m,2H),3.02-2.96(m,1H),2.71-2.62(m,2H),2.19-2.17(m,1H),2.02-1.98(m,2H),1.71-1.67(m,1H)。
实施例7:(R)-1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羰基)吡咯烷-3-腈(7)的制备
于0℃,氮气保护下,将三光气(90mg,0.302mmol)加入(R)-吡咯烷-3-甲腈盐酸盐(100mg,0.754mmol)和吡啶(238mg,3.02mmol)的二氯甲烷(10mL)溶液中,搅拌2小时。于室温,加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺盐酸盐(240mg,0.754mmol)和三乙胺(535mg,5.28mmol)于室温搅拌过夜。减压浓缩,残留物经制备液相色谱法纯化,得化合物83.0mg黄色固体标题化合物,收率:27.2%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-50%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 405[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm 9.30(s,1H),8.32(d,J=6Hz,1H),7.81(s,1H),7.50(s,1H),7.19-7.17(m,1H),6.79(d,J=6Hz,1H),4.49-4.42(m,1H),4.39-4.33(m,1H),3.79(s,3H),3.69-3.60(m,1H),3.57-3.51(m,1H),3.49-3.41(m,2H),3.38-3.36(m,1H),3.01-2.95(m,1H),2.39-2.32(m,1H),2.23-2.06(m,3H),1.97-1.85(m,2H),1.67-1.60(m,1H)。
实施例8:(3,3-二氟吡咯烷-1-基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(8)的制备
与实施例7的制备方法相同,除了用3,3-二氟吡咯烷盐酸盐替代(R)-吡咯烷-3-甲腈盐酸盐,制得标题化合物8。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈20-60%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 416[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm 9.30(s,1H),8.32(d,J=6Hz,1H),7.81(s,1H),7.50(s,1H),7.19-7.17(m,1H),6.79(d,J=6Hz,1H),4.48-4.42(m,1H),4.37-4.36(m,1H),3.79(s,3H),3.73-3.69(m,1H),3.60-3.53(m,3H),3.00-2.96(m,1H),2.42-2.28(m,3H),2.08-2.06(m,1H),1.93-1.91(m,2H),1.67-1.60(m,1H)。
实施例9:(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(3-(三氟甲基)吡咯烷-1-基)甲酮(9)的制备
与实施例7的制备方法相同,除了用3-(三氟甲基)吡咯烷盐酸盐替代(R)-吡咯烷-3-甲腈盐酸盐,制得标题化合物9。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈15-65%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 448[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm 9.30(s,1H),8.31(d,J=6Hz,1H),7.81(s,1H),7.50(s,1H),7.22-7.16(m,1H),6.79(d,J=6Hz,1H),4.44-4.36(m,2H),3.79(s,3H),3.65-3.39(m,4H),3.24-3.14(m,1H),3.02-2.89(m,1H),2.37-2.32(m,1H),2.13-2.06(m,2H),1.93-1.91(m,3H),1.66-1.60(m,1H)。
实施例10:1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羰基)氮杂环丁烷-3-腈(10)的制备
与实施例7的制备方法相同,除了用氮杂环丁烷-3-腈盐酸盐替代(R)-吡咯烷-3-甲腈盐酸盐,制得标题化合物10。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22-27min,乙腈10-50-70%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 391[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm9.31(s,1H),8.31(d,J=6Hz,1H),7.81(s,1H),7.50(s,1H),7.18-7.17(m,1H),6.78(d,J=6Hz,1H),4.45-4.39(m,1H),4.33-4.27(m,1H),4.24-4.16(m,2H),4.10-4.04(m,2H),3.79(s,3H),3.76-3.70(m,1H),2.97-2.92(m,1H),2.35-2.29(m,1H),2.11-2.06(m,1H),1.96-1.85(m,2H),1.67-1.60(m,1H)。
实施例11:N-(氰基甲基)-3-(5-氟-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(11)的制备
与实施例1和2的制备方法相同,除了用2,4-二氯-5-氟嘧啶替代2,4-二氯嘧啶(1e),制得标题化合物11。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 383[M+H]+;
1H NMR(300MHz,DMSO-d6):δppm9.40(s,1H),8.38(s,1H),7.75(s,1H),7.49(s,1H),7.40-7.36(m,1H),7.10-7.09(m,1H),4.59-4.57(m,1H),4.49-4.46(m,1H),4.05(d,J=6.0Hz,2H),3.80(s,3H),3.02-2.96(m,1H),2.42-2.33(m,1H),2.17-2.09(m,1H),2.02-1.93(m,2H),1.76-1.68(m,1H)。
实施例12:3-(5-氟-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(12)的制备
与实施例1和3的制备方法相同,除了用2,4-二氯-5-氟嘧啶替代2,4-二氯嘧啶(1e),制得标题化合物12。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈15-15-55%;波长:254nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 426[M+H]
1H NMR(300MHz,DMSO-d6):δppm 9.39(s,1H),8.38(d,J=4.1Hz,1H),7.75(s,1H),7.49(s,1H),7.29(t,J=6.2Hz,1H),7.09(d,J=5.0Hz,1H),4.68-4.60(m,1H),4.57-4.49(m,1H),3.92-3.71(m,5H),3.10-2.97(m,1H),2.35-2.31(m,1H),2.24-2.08(m,1H),2.02-1.87(m,2H),1.78-1.63(m,1H)。
实施例12-a和12-b:化合物12-a和12-b的制备
化合物12-a和12-b由化合物12通过SFC分离得到。
SFC分离条件:
色谱柱型号:AS-H 4.6mm x 250mm,5μm,流动相:MeOH(0.2%NH3·H2O)/CO2=35∶65,流速:40g/min。
12-a:保留时间:2.97min;
LC-MS:m/z 426[M+H]
1H NMR(400MHz,DMSO-d6):δppm 9.40(s,1H),8.38(d,J=4.4Hz,1H),7.75(s,1H),7.50(s,1H),7.28(t,J=8.4Hz,1H),7.10-7.09(m,1H),4.63-4.52(m,2H),3.83-3.80(m,2H),3.77(s,3H),3.04-3.00(m,1H),2.35-2.31(m,1H),2.24-2.08(m,1H),2.02-1.87(m,2H),1.78-1.63(m,1H)。
12-b:保留时间:5.25min。
LC-MS:m/z 426[M+H]
1H NMR(400MHz,DMSO-d6):δppm9.40(s,1H),8.38(d,J=4.4Hz,1H),7.75(s,1H),7.50(s,1H),7.28(t,J=8.4Hz,1H),7.10-7.09(m,1H),4.62-4.53(m,2H),3.83-3.80(m,2H),3.77(s,3H),3.04-3.00(m,1H),2.35-2.31(m,1H),2.17-2.14(m,1H),2.02-1.87(m,2H),1.74-1.67(m,1H)。
实施例13:(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(3-甲基氧杂环丁-3-基)甲酮(13)的制备
与实施例1的制备方法相同,除了用3-甲基氧杂环丁烷-3-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物13。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈10-10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 381[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.34(s,1H),8.34(d,J=5.2Hz,1H),7.81(s,1H),7.50(s,1H),7.16(s,1H),6.81(d,J=5.2Hz,1H),5.00-4.65(m,3H),4.41-4.25(m,2H),3.96-3.85(m,1H),3.80(s,3H),2.92-2.89(m,1H),2.42-2.40(m,1H),2.24-1.85(m,3H),1.70-1.64(m,1H),1.53(s,1H),1.48(s,2H)。
实施例14:N-(2,2-二氟环丙基)-3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(14)的制备
与实施例2的制备方法相同,除了用2,2-二氟环丙烷-1-胺盐酸盐替代2-氨基乙腈(2a),制得标题化合物14。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-70%;波长:254nm;流速:45mL/min;流动相:乙腈,水0.05%甲酸水溶液。
LC-MS:m/z=402[M+H]
1H NMR(300MHz,DMSO-d6):δppm 9.31(s,1H),8.33(d,J=5.3Hz,1H),7.81(s,1H),7.52(s,1H),8.33(d,J=4.1Hz,1H),6.99(s,1H),6.82(d,J=5.2Hz,1H),4.57-4.48(m,2H),3.80(s,3H),3.14-3.11(m,1H),2.98-2.92(m,1H),2.51-2.49(m,1H),2.32-2.42(m,1H),2.13-2.07(m,2H),1.79-1.76(m,1H),1.67-1.62(m,1H),1.47-1.44(m,1H)。
实施例15:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(氧杂环丁-3-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(15)的制备
与实施例2的制备方法相同,除了用氧杂环丁烷-3-胺盐酸盐替代2-氨基乙腈(2a),制得标题化合物15。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈10-10-40%;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 382[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.31(s,1H),8.32(d,J=5.2Hz,1H),7.81(s,1H),7.52(s,1H),7.31-7.11(m,2H),6.80(d,J=5.2Hz,1H),4.76-4.56(m,4H),4.55-4.47(m,1H),4.46-4.39(m,2H),3.81(s,3H),3.03-2.89(m,1H),2.35-2.22(m,1H),2.20-2.04(m,1H),1.99-1.86(m,2H),1.72-1.56(m,1H)。
实施例16:(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(4-(三氟甲基)苯基)甲酮(16)的制备
与实施例1的制备方法相同,除了用4-(三氟甲基)苯甲酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物16。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈40%等度;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 455[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.35(s,1H),8.35(d,J=5.1Hz,1H),7.83(s,3H),7.76-7.73(m,1H),7.66-7.63(m,1H),7.50(s,1H),7.28-7.13(m,1H),6.84(d,J=5.4Hz1H),5.05-4.93(m,1H),4.38-4.24(m,1H),3.80(s,3H),3.16-3.10(m,1H),2.87-2.82(m,1H),2.21-2.03(m,3H),1.73(m,1H)。
实施例17:(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(5-(三氟甲基)吡啶-2-基)甲酮(17)的制备
与实施例1的制备方法相同,除了用5-(三氟甲基)吡啶甲酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物17。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈40%等度;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 456[M+H]
1H NMR(300MHz,DMSO-d6):δppm 9.34(s,1H),9.05(s,1H),8.39-8.35(m,2H),7.96-7.89(m,1H),7.83(s,1H),7.50(s,1H),7.28-7.14(m,1H),6.84-6.82(m,1H),5.11-4.73(m,2H),3.80(s,3H),3.13-3.03(m,1H),2.57-2.47(m,1H),2.21-2.03(m,3H),1.77(m,1H)。
实施例18:5-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰基)噻吩-3-甲腈(18)的制备
与实施例1的制备方法相同,除了用4-氰基噻吩-2-甲酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物18。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈35%等度;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 418[M+H]
1H NMR(300MHz,DMSO-d6):δppm 9.34(s,1H),8.74(s,1H),8.36(d,J=5.1Hz,1H),8.03(s,1H),7.84(s,1H),7.50(s,1H),7.28-7.24(m,1H),6.84(d,J=5.1Hz1H),5.04-5.01(m,1H),4.90-4.85(m,1H),3.81(s,3H),3.11-3.06(m,1H),2.57-2.51(m,1H),2.24-2.05(m,3H),1.77-1.73(m,1H)。
实施例19:3-(5-甲基-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(19)的制备
与实施例1和2的制备方法相同,除了用2,2,2-三氟乙胺盐酸盐替代2-氨基乙腈(2a)和用2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶(1e),制得标题化合物19。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-17min,乙腈5-5-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 422[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.20(s,1H),8.21(s,1H),7.76(s,1H),7.45(s,1H),7.28(t,J=6.2Hz,1H),6.31(d,J=4.5Hz,1H),4.59-4.43(m,2H),3.92-3.80(m,2H),3.78(s,3H),3.00-2.84(m,1H),2.26-2.15(m,2H),2.09(s,3H),2.03-1.89(m,2H),1.79-1.66(m,1H)。
实施例19-a和19-b:化合物19-a和19-b的制备
化合物19-a和19-b由化合物19通过手性分离得到。
手性柱分离方法:
色谱柱型号:IA 4.6mm x 250mm,5μm,流动相:IPA(0.2%NH3·H2O)/hexane=30∶70,流速:14mL/min。
19-a:保留时间:9.89min;
LC-MS:m/z 422[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.20(s,1H),8.21(s,1H),7.76(s,1H),7.44(s,1H),7.27(t,J=12.4Hz,1H),6.30(d,J=4.4Hz,1H),4.59-4.50(m,1H),4.49-4.42(m,1H),3.85-3.80(m,2H),3.77(s,3H),2.99-2.84(m,1H),2.22-2.15(m,2H),2.10(s,3H),1.95-1.80(m,2H),1.75-1.70(m,1H)。
19-b:保留时间:17.84min。
LC-MS:m/z 422[M+H]
1H NMR(400MHz,DMSO-d6):δppm9.20(s,1H),8.21(s,1H),7.76(s,1H),7.44(s,1H),7.27(t,J=12.4Hz,1H),6.30(d,J=4.8Hz,1H),4.56-4.52(m,1H),4.48-4.44(m,1H),3.84-3.80(m,2H),3.77(s,3H),2.95-2.89(m,1H),2.21-2.16(m,2H),2.10(s,3H),1.96-1.81(m,2H),1.76-1.71(m,1H)。
实施例20:3-(5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(20)的制备
与实施例1和3的制备方法相同,除了用2,4,5-三氯嘧啶替代2,4-二氯嘧啶(1e),制得标题化合物20。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈37%等度;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 442[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.65(s,1H),8.40(s,1H),7.76(s,1H),7.47(s,1H),7.27(s,1H),6.70(s,1H),5.60-4.50(m,2H),3.87-3.80(m,5H),3.05-2.99(m,1H),2.23-2.19(m,2H),2.01-1.92(m,2H),1.77-1.71(m,1H)。
实施例21:((S)-2,2-二氟环丙基)(3-(5-氟-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(21)的制备
与实施例1的制备方法相同,除了2,4-二氯-5-氟嘧啶替代2,4-二氯嘧啶(1e),制得标题化合物21。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈15-15-55%;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 405[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.51(s,1H),8.48-8.46(m,1H),7.84-7.82(m,1H),7.55-7.53(m,1H),7.20-7.12(m,1H),4.98-4.90(m,2H),3.87(s,3H),3.28-3.02(m,2H),2.70-2.51(m,1H),2.23-2.16(m,2H),2.06-1.88(m,4H)。
实施例22:((S)-2,2-二氟环丙基)(3-(5-甲基-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(22)的制备
与实施例1的制备方法相同,除了2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶(1e),制得标题化合物22。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈15-15-55%;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 401[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.23(d,J=4.2Hz,1H),8.23(d,J=3.7Hz,1H),7.77(d,J=4.8Hz,1H),7.43(d,J=7.2Hz,1H),6.44-6.27(m,1H),4.88-4.61(m,2H),3.77(s,3H),3.25-2.83(m,2H),2.47-2.21(m,2H),2.21-2.05(m,4H),2.03-1.71(m,4H)。
实施例22-a和22-b:化合物22-a和22-b的制备
化合物22-a和22-b由化合物22通过SFC分离得到。
SFC分离条件:
色谱柱型号:AS-H 4.6mm x 250mm,5μm,流动相:EtOH(0.2%NH3·H2O)/CO2=35∶65,流速:40g/min。
22-a:保留时间:2.67min;
LC-MS:m/z 401[M+H]+
1H NMR(400MHz,CDCl3):δppm8.20-8.18(m,1H),7.76-7.71(m,1H),7.46(s,1H),7.00-6.78(m,1H),6.28(d,J=5.2Hz,1H),5.01-4.98(m,1H),4.61-4.56(m,1H),3.89(s,3H),3.11-3.01(m,1H),2.59-2.51(m,2H),2.42-2.31(m,1H),2.27-2.21(m,1H),2.17-2.01(m,5H),1.96-1.84(m,1H),1.72-1.64(m,1H)。
22-b:保留时间:3.28min。
LC-MS:m/z 401[M+H]+
1H NMR(400MHz,CDCl3):δppm8.20-8.19(m,1H),7.76-7.71(m,1H),7.48(s,1H),7.00-6.84(m,1H),6.35-6.30(m,1H),5.01-4.86(m,1H),4.62-4.57(m,1H),3.89(s,3H),3.07-3.02(m,1H),2.59-2.55(m,2H),2.42-2.31(m,1H),2.27-2.21(m,1H),2.17-2.01(m,5H),1.95-1.89(m,1H),1.73-1.63(m,1H)。
实施例23:(3-(5-氯-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)((S)-2,2-二氟环丙基)甲酮(23)的制备
与实施例1的制备方法相同,除了2,4,5-三氯嘧啶替代2,4-二氯嘧啶(1e),制得标题化合物23。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈20-20-60%;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 421[M+H]
1H NMR(300MHz,DMSO-d6):δppm9.68(d,J=3.3Hz,1H),8.42(d,J=3.0Hz,1H),7.77(s,1H),7.43(s,1H),6.70(s,1H),4.86-4.69(m,2H),3.80-3.78(m,3H),3.23-2.94(m,2H),2.50-2.46(m,1H),2.40-2.29(m,1H),2.18-2.07(m,1H),2.02-1.88(m,4H)。
实施例23-a和23-b:化合物23-a和23-b的制备
化合物23-a和23-b由化合物23通过SFC分离得到。
SFC分离条件:
色谱柱型号:AS-H 4.6mm x 250mm,5μm,流动相:EtOH(0.2%NH3·H2O)/CO2=35∶65,流速:40g/min。
23-a:保留时间:3.67min;
LC-MS:m/z 421[M+H]+
1H NMR(400MHz,CDCl3):δppm8.31-8.29(m,1H),7.77-7.72(m,1H),7.51-7.45(m,1H),7.03-6.93(m,1H),6.82-6.78(m,1H),5.03-4.97(m,1H),4.63-4.57(m,1H),3.89(s,3H),3.22-3.09(m,1H),2.41-2.24(m,3H),2.18-2.15(m,3H),1.70-1.64(m,2H)。
23-b:保留时间:4.53min。
LC-MS:m/z 421[M+H]+
1H NMR(400MHz,CDCl3):δppm8.31-8.29(m,1H),7.77-7.69(m,1H),7.50-7.45(m,1H),7.00-6.86(m,1H),6.76-6.75(m,1H),5.12-4.87(m,1H),4.63-4.57(m,1H),3.89(s,3H),3.20-3.07(m,1H),2.55-2.52(m,3H),2.25-2.17(m,3H),1.71-1.62(m,2H)。
实施例24:3-(2-((1-(二氟甲基)-1H-吡唑-4-基)氨基)-5-氟嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(24)的制备
步骤1:1-(二氟甲基)-4-硝基-1H-吡唑的合成(24b)
于室温,将二氟氯乙酸钠(13.5g,88.4mmol)分批加入到4-硝基-1H-吡唑(5.00g,44.2mmol)和碳酸铯(14.4g,44.2mmol)的N,N-二甲基甲酰胺(40mL)溶液中。于120℃油浴加热搅拌30分钟。反应降温后加入乙酸乙酯(300mL)稀释,用水(200mL*3)洗涤,有机相用饱和食盐水(100mL)洗涤。用无水硫酸钠干燥,减压浓缩,残余物用硅胶柱色谱法分离纯化(流动相:PE/EA=100∶1-10∶1),得到5.7g无色油状液体标题化合物。收率:79.2%。
LC-MS:m/z 164[M+H]+
步骤2:1-(二氟甲基)-1H-吡唑-4-胺的合成(24c)
于室温,氮气氛围下,将钯炭(2.00g)加入到1-(二氟甲基)-4-硝基-1H-吡唑(5.7g,34.9mmol)的甲醇(70mL)溶液中,置换氢气三次,于室温搅拌过夜。
反应液抽滤,滤液减压浓缩,得到5.5g黄色油状液体粗品标题化合物。
LC-MS:m/z 133[M+H]+
步骤3~步骤6,与实施例1和3的制备方法相同,除了用1-(二氟甲基)-1H-吡唑-4-胺替代1-甲基-1H-吡唑-4-胺(1g),用2,4-二氯-5-氟嘧啶替代2,4-二氯嘧啶(1e),制得标题化合物24。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈10-10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 462[M+H]+
1H NMR(400MHz,DMSO-d6)δppm 9.72(s,1H),8.44(d,J=4.1Hz,1H),8.19(s,1H),7.91-7.58(m,2H),7.34-7.25(m,1H),7.13-7.06(m,1H),4.67-4.56(m,1H),4.55-4.44(m,1H),3.88-3.69(m,2H),3.05-2.93(m,1H),2.36-2.28(m,1H),2.21-2.05(m,1H),2.00-1.88(m,2H),1.72-1.67(m,1H)。
实施例25:3-(2-((1-甲基-1H-吡唑-4-基)氨基)-5-(三氟甲基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(25)的制备
步骤1:4-氯-N-(1-甲基-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-胺和2-氯-N-(1-甲基-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-4-胺的合成(25c)。
于0℃,氯化锌四氢呋喃溶液(24.7mL,24.7mmol)滴加入2,4-二氯-5-(三氟甲基)嘧啶(4.70g,21.6mmol)的二氯乙烷(50mL)和叔丁醇(50mL)溶液中,搅拌十分钟,滴加1-甲基-1H-吡唑-4-胺(2.00g,20.6mmol)和三乙胺(5.00g,49.44mmol)二氯乙烷(25mL)和叔丁醇(25mL)溶液,自然升至室温,并搅拌过夜,反应液加入水中(200mL),用二氯乙烷(100mL*3)萃取,合并有机相,干燥,减压浓缩,残留液经快速柱色谱法(流动相:石油醚/乙酸乙酯=100/1至5/1)纯化,得1.20g棕色油状标题化合物。收率:20.0%。
LC-MS:m/z 278[M+H]+
步骤2,与实施例1f的制备方法相同,除了用1-甲基-1H-吡唑-4-氨4-氯-N-(1-甲基-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-胺替代2,4-二氯嘧啶(1e),制得标题化合物25d。
步骤3,与实施例1i的制备方法相同,除了用叔丁基-3-(2-((1-甲基-1H-吡唑-4-基)氨基)-5-(三氟甲基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸盐替代叔丁基3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸(1h),制得标题化合物25e。
步骤4,与实施例3的制备方法相同,除了用4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)-5-(三氟甲基)嘧啶-2-胺替代4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺,制得标题化合物25。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈40-40-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 476[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.06(s,1H),8.54(s,1H),7.93(s,1H),7.76(s,1H),7.47(d,J=6.0Hz 1H),7.29-7.24(m,1H),4.63-4.52(m,2H),3.85-3.75(m,5H),3.01-2.95(m,1H),2.38-2.32(m,1H),2.16-1.93(m,3H),1.70-1.23(m,1H)。
实施例26:3-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(26)的制备
步骤1:1,3-二甲基-1H-吡唑-4-胺的合成(26b)。
于室温,氮气保护下,将Pd/C(100mg,10%)加入1,3-二甲基-4-硝基-1H-吡唑(1.00g,7.08mmol)的甲醇(100mL)溶液中,氢气置换三次,室温搅拌过夜。反应液垫硅藻土过滤,甲醇淋洗,滤液减压浓缩,旋干,得棕色油状液体标题化合物700mg,收率:88.9%。
合成步骤2~5与实施例1和3的制备方法相同,除了用2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶和1,3-二甲基-1H-吡唑-4-胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物26。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈10-10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 436[M+H]+
1H NMR(400MHz,CDCl3):δppm8.17(s,1H),7.74(s,1H),6.41(s,1H),6.29-6.28(m,1H),4.85-4.81(m,1H),4.50-4.43(m,2H),4.10-3.92(m,2H),3.83(s,3H),3.06-3.00(m,1H),2.38-2.31(m,2H),2.25(s,3H),2.15(s,3H),2.11-2.07(m,2H),1.92-1.87(m,1H)。
实施例26-a和26-b:化合物26-a和26-b的制备
化合物26-a和26-b由化合物26通过SFC分离得到。
SFC分离条件:
色谱柱型号:AD-H 4.6mm x 250mm,5μm,流动相:MeOH(0.2%NH3·H2O)/CO2=35∶65,流速:40g/min。
26-a:保留时间:2.21min;
LC-MS:m/z 436[M+H]+
1H NMR(400MHz,CDCl3):δppm 8.17(s,1H),7.74(s,1H),6.41(s,1H),6.29-6.28(m,1H),4.85-4.81(m,1H),4.50-4.43(m,2H),4.10-3.92(m,2H),3.83(s,3H),3.06-3.00(m,1H),2.38-2.31(m,2H),2.25(s,3H),2.15(s,3H),2.11-2.07(m,2H),1.92-1.87(m,1H)。
26-b:保留时间:2.63min。
LC-MS:m/z 436[M+H]+
1H NMR(400MHz,CDCl3):δppm8.17(s,1H),7.74(s,1H),6.40(s,1H),6.28-6.27(m,1H),4.92-4.90(m,1H),4.51-4.49(m,1H),4.48-4.44(m,1H),3.99-3.89(m,2H),3.82(s,3H),3.06-3.00(m,1H),2.36-2.29(m,2H),2.22(s,3H),2.15(s,3H),2.09-2.05(m,2H),1.92-1.85(m,1H)。
实施例27:3-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(27)的制备
与实施例1和3的制备方法相同,除了用2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶(1e)和1,5-二甲基-1H-吡唑-4-胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物27。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈20-20-60%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 436[M+H]+
1H NMR(400MHz,DMSO-d6):δppm8.43(s,1H),8.12(s,1H),7.45(s,1H),7.27-7.24(m,1H),6.28-6.27(m,1H),4.55-4.43(m,2H),3.88-3.79(m,2H),3.68(s,3H),2.87-2.83(m,1H),2.19-2.13(m,5H),2.07(s,3H),1.94-1.91(m,2H),1.72-1.65(m,1H)。
实施例28:3-(2-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(28)的制备
与实施例1和3的制备方法相同,除了用2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶(1e)和2-(4-氨基-1H-吡唑-1-基(乙烷-1-醇替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物28。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-27min,乙腈10-10-60%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 452[M+H]+
1H NMR(400MHz,DMSO-d6):δppm9.22(s,1H),8.22(s,1H),7.83(s,1H),7.47(s,1H),7.31-7.27(m,1H),6.32-6.30(m,1H),4.88-4.86(m,1H),4.55-4.45(m,2H),4.09-4.05(m,2H),3.90-3.78(m,2H),3.76-3.70(m,2H),2.93-2.87(m,1H),2.26-2.20(m,2H),2.17(s,3H),2.09-1.95(m,2H),1.78-1.68(m,1H)。
实施例29:3-(2-((1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(29)的制备
步骤1:2-甲基-1-(4-硝基-1H-吡唑-1-基)丙-2-醇的制备(29c)。
于室温,将2,2-二甲基环氧乙烷(1.91g,26.5mmol)加入4-硝基-1H-吡唑(1.00g,8.84mmol)和碳酸铯(5.76g,17.7mmol)的N,N-二甲基甲酰胺(20mL)混合液中,100℃搅拌过夜。反应液加水(100mL)用EA(30mL*3)萃取,盐水洗涤有机相,无水硫酸钠干燥,减压浓缩,残余物经快速柱色谱法(流动相:石油醚/乙酸乙酯=20/1至2/1)纯化,得黄色油状液体标题化合物1.23g,收率:75.1%。
步骤2:1-(4-氨基-1H-吡唑-1-基)-2-甲基丙烷-2-醇的合成(29d)。
与实施例26b的制备方法相同,除了2-甲基-1-(4-硝基-1H-吡唑-1-基)丙-2-醇替代1,3-二甲基-4-硝基-1H-吡唑(26a)制得标题化合物29d。
合成步骤3~5与实施例1和3的制备方法相同,除了用2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶和1-(4-氨基-1H-吡唑-1-基)-2-甲基丙烷-2-醇替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物29
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈10-10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,水。
LC-MS:m/z 480[M+H]+
1H NMR(400MHz,CDCl3):δppm8.18(s,1H),7.88(s,1H),7.54(s,1H),6.90(s,1H),6.33-6.32(m,1H),4.86-4.83(m,1H),4.47-4.43(m,2H),4.04(s,2H),3.94-3.84(m,3H),3.15-3.11(m,1H),2.38-2.30(m,2H),2.17(s,3H),2.12-2.05(m,2H),1.91-1.84(m,1H),1.19(s,6H)。
实施例29-a和29-b:化合物29-a和29-b的制备
化合物29-a和29-b由化合物29通过SFC分离得到。
SFC分离条件:
色谱柱型号:AD-H 4.6mm x 250mm,5μm,流动相:MeOH(0.2%NH3·H2O)/CO2=35∶65,流速:40g/min。
29-a:保留时间:2.39min;
LC-MS:m/z 480[M+H]+
1H NMR(400MHz,CDCl3):δppm8.18(s,1H),7.88(s,1H),7.54(s,1H),6.90(s,1H),6.33-6.32(m,1H),4.86-4.83(m,1H),4.47-4.43(m,2H),4.04(s,2H),3.94-3.84(m,3H),3.15-3.11(m,1H),2.38-2.30(m,2H),2.17(s,3H),2.12-2.05(m,2H),1.91-1.84(m,1H),1.19(s,6H)。
29-b:保留时间:3.67min。
LC-MS:m/z 480[M+H]+
1H NMR(400MHz,CDCl3):δppm8.18(s,1H),7.88(s,1H),7.54(s,1H),6.88(s,1H),6.32-6.31(m,1H),4.88-4.85(m,1H),4.47-4.43(m,2H),4.04(s,2H),3.97-3.83(m,3H),3.15-3.11(m,1H),2.36-2.28(m,2H),2.14(s,3H),2.11-2.06(m,2H),1.88-1.83(m,1H),1.19(s,6H)。
实施例30:3-(5-甲基-2-((1-(氧杂环丁-3-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(30)的制备
步骤1:4-硝基-1-(氧杂环丁-3-基)-1H-吡唑的合成(30c)
于室温,将碳酸铯(11.5g,35.4mmol)加入到4-硝基-1H-吡唑(2.00g,17.7mmol)和3-碘氧杂环丁烷(3.91g,21.2mmol)的DMF(10mL)溶液中,于100℃搅拌2小时。反应液降温,加入乙酸乙酯(200mL)稀释,加水(100mL*3)洗涤,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残余物经快速柱色谱法(流动相:石油醚/乙酸乙酯=10/1至1/1)纯化,得到2.35g黄色固体状标题化合物,收率:78.5%。
步骤2:1-(氧杂环丁-3-基)-1H-吡唑-4-胺的合成(30d)
于室温,在氮气保护下将钯炭(1.00g)加入到4-硝基-1-(氧杂环丁-3-基)-1H-吡唑(2.35g,13.9mmol)的甲醇(100mL)溶液中,氢气置换三次,于室温搅拌过夜。反应液垫硅藻土抽滤,滤液减压浓缩,得到2.1g棕色固体标题化合物粗品。
合成步骤3~5与实施例1和3的制备方法相同,除了用2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶和1-(氧杂环丁-3-基)-1H-吡唑-4-胺替代1-甲基-1H-[吡唑-4-胺(1g),制得标题化合物30
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈40%等度;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 464[M+H]
1H NMR(400MHz,DMSO-d6):δppm 9.31(s,1H),8.24(s,1H),7.96(s,1H),7.63(s,1H),7.29(t,J=6.3Hz,1H),6.32(d,J=5.1Hz,1H),5.59-5.46(m,1H),4.96-4.80(m,4H),4.58-4.43(m,2H),3.90-3.76(m,2H),3.00-2.86(m,1H),2.28-2.16(m,2H),2.10(s,3H),2.01-1.92(m,2H),1.80-1.68(m,1H)。
实施例31:3-(2-((1-环丙基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(31)的制备
与实施例1和3的制备方法相同,除了用2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶(1e)和2-(4-氨基-1H-吡唑-1-基(乙烷-1-醇替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物31。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈40%等度;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 448[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.22(s,1H),8.21(s,1H),7.82(s,1H),7.42(s,1H),7.30-7.26(m1H),6.31-6.29(m,1H),4.57-4.51(m,1H),4.48-4.44(m,1H),3.89-3.77(m,2H),3.67-3.60(m,1H),2.94-2.88(m,1H),2.22-2.16(m,2H),2.08(s,3H),1.99-1.89(m,2H),1.76-1.66(m,1H),0.99-0.87(m,4H)。
实施例32:3-(2-((5-氯-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(32)的制备
步骤1:(1-甲基-1H-吡唑-4-基)氨基甲酸叔丁酯的合成(32b)。
于室温,将三乙胺(8.32g,82.4mmol)加入1-甲基-1H-吡唑-4-胺(4.00g,41.2mmol)和二碳酸二叔丁酯(10.8g,49.4mmol)的二氯甲烷(200mL)混合液中,室温搅拌过夜。反应液加水(100mL)用二氯甲烷(100mL*3)萃取,盐水洗涤有机相,无水硫酸钠干燥,减压浓缩,残余物经快速柱色谱法(流动相:石油醚/乙酸乙酯=20/1至2/1)纯化,得黄色油状液体标题化合物7.90g,收率:97.3%。
LC-MS:m/z 198[M+H]+
步骤2:(5-氯-1-甲基-1H-吡唑-4-基)氨基甲酸叔丁酯的合成(32c)。
于室温,氮气保护下,将NCS(2.24g,16.8mmol)加入(1-甲基-1H-吡唑-4-基)氨基甲酸叔丁酯(3.00g,15.2mmol)的二氯甲烷(60mL)溶液中,30℃搅拌过夜。反应液减压浓缩,旋干,残余物经快速柱色谱法(流动相:石油醚/乙酸乙酯=20/1至2/1)纯化,得棕色固体标题化合物2.97g,收率:84.2%。
LC-MS:m/z 232[M+H]+
步骤3:5-氯-1-甲基-1H-吡唑-4-胺(32d)的合成。
于室温,氮气保护下,将HCl/二氧六环(10mL,4M)加入(5-氯-1-甲基-1H-吡唑-4-基)氨基甲酸叔丁酯(2.00g,8.62mmol)的二氯甲烷(10mL)溶液中,室温搅拌30分钟。反应液减压浓缩,旋干,用NH3/甲醇(10mL,4M)游离,旋干,残余物经快速柱色谱法(流动相:二氯甲烷/甲醇=100/1至20/1)纯化,得棕色固体标题化合物910mg,收率:80.2%。
LC-MS:m/z 132[M+H]+
合成步骤4~6与实施例1和3的制备方法相同,除了用2,4-二氯-5-甲基嘧啶替代2,4-二氯嘧啶和5-氯-1-甲基-1H-吡唑-4-胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物32
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈20-20-70%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 456[M+H]+
1H NMR(400MHz,DMSO):δppm8.59(s,1H),8.16(s,1H),7.64(s,1H),7.28-7.25(m,1H),6.31-6.30(m,1H),4.54-4.43(m,2H),3.85-3.81(m,2H),3.77(s,2H),2.87-2.83(m,1H),2.25-2.15(m,2H),2.09(s,3H),2.01-1.93(m,2H),1.72-1.65(m,1H)。
实施例33:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(1-(三氟甲基)环丙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(33)的制备
与实施例3的制备方法相同,除了1-(三氟甲基)环丙-1-胺盐酸盐替代2-氨基乙腈(2a),制得标题化合物33。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈20-20-60%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 434[M+H]+
1H NMR(300MHz,DMSO-d6)δppm 9.33(s,1H),8.32(d,J=5.2Hz,1H),7.81(s,1H),7.49(d,J=18.1Hz,2H),7.18(d,J=5.2Hz,1H),6.80(d,J=5.2Hz,1H),4.65-4.43(m,2H),3.81(s,3H),2.92(d,J=18.0Hz,1H),2.30-2.11(m,2H),2.05-1.90(m,2H),1.65-1.61(m,1H),1.26-1.07(m,2H),1.05-0.98(m,2H)。
实施例34:3-(2-((1-甲基-1H-吡唑-4-基)氨基)-5-(甲磺酰基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(34)的制备
步骤1:叔丁基-3-(2-氯-5-(甲硫基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸盐的合成(34c)。
于室温,将[1,1′-双(二苯基膦基)二茂铁]二氯化钯(754mg,1.03mmol)和碳酸钠(2.70g,25.8mmol)加入叔丁基3-(4,4,5,5-四甲基-1,3,2-二恶英-2-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸酯(3.70g,11.3mmol)和2,4-二氯-5-(甲硫基)嘧啶(2.00g,10.3mmol)的二氧六环和水混合液(60mL,v/v=5∶1)中,氮气置换三次,90℃搅拌过夜。反应液减压浓缩,加水(150mL),用EA(100mL*3)萃取,盐水洗涤有机相,无水硫酸钠干燥,减压浓缩,残余物用硅胶柱色谱法分离纯化(流动相:石油醚/乙酸乙酯=100/1至4/1),得黄色固体状标题化合物1.30g。收率:34.0%,LC-MS:m/z 368[M+H]+。
步骤2:叔丁基-3-(2-氯-5-(甲磺酰基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸酯的合成(34d)。
于室温,将间氯过氧苯甲酸(2.15g,12.5mmol)加入叔丁基-3-(2-氯-5-(甲硫基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸盐(1.15g,3.13mmol)的二氯甲烷(20mL)溶液中,加入常温下搅拌过夜。将反应体系过滤,滤液减压浓缩,用乙酸乙酯(100mL*3)萃取,盐水洗涤有机相,无水硫酸钠干燥,减压浓缩,残余物用硅胶柱色谱法分离纯化(流动相:石油醚/乙酸乙酯=100/1至2/1),得淡黄色固体状标题化合物640mg。收率:51.4%。LC-MS:m/z 400[M+H]+
合成步骤3~5与实施例1和3的制备方法相同,除了用叔丁基-3-(2-氯-5-(甲磺酰基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸酯替代3-(2-氯嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯(1f),制得标题化合物34。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈20-20-70%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 486[M+H]+
1H NMR(300MHz,DMSO-d6):δppm10.48-10.43(d,1H),8.77-8.71(d,1H),7.92-7.79(m,1H),7.55-7.52(m,1H),7.35-7.21(m,1H),6.40-6.29(m,1H),4.54-4.46(m,2H),3.85-3.81(m,5H),3.21-3.20(m,3H),3.09-2.92(m,1H),2.18-1.94(m,5H)。
实施例35:3-(5-氰基-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(35)的制备
与实施例25的制备方法相同,除了用2,4-二氯嘧啶-5-氰基替代2,4-二氯-5-(三氟甲基)嘧啶(25a),制得标题化合物35。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈10-10-60%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 433[M+H]+
1H NMR(300MHz,DMSO-d6)δppm 9.94(s,1H),8.67(s,1H),7.92(s,1H),7.75(s,1H),7.53(d,J=5.3Hz,1H),7.31-7.22(m,1H),4.69-4.58(m,1H),4.56-4.47(m,1H),3.85(s,3H),3.84-3.71(m,2H),3.04-2.91(m,1H),2.40-2.28(m,1H),2.23-2.05(m,1H),2.01-1.87(m,2H),1.75-1.54(m,1H)。
实施例36:(3-(2-((1-环丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)((S)-2,2-二氟环丙基)甲酮(36)的制备
与实施例1的制备方法相同,除了用1-环丙基-1H-吡唑-4-胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物36。
制备方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈15-15-55%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 413[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.34(s,1H),8.35-8.32(m,1H),7.87(s,1H),7.51-7.48(m,1H),7.22-7.16(m1H),6.85-6.80(m,1H),4.89-4.84(m,1H),4.77-4.70(m,1H),3.69-3.65(m,1H),3.20-3.15(m,1H),2.96-2.85(m,1H),2.63-2.57(m,1H),2.44-2.35(m,1H),2.31-2.24(m,1H),2.14-2.05(m,2H),1.94-1.85(m,2H),1.00-0.96(m,2H),0.95-0.92(m,2H)。
实施例37:((S)-2,2-二氟环丙基)(3-(2-((1-(氧杂环丁-3-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(37)的制备
与实施例1的制备方法相同,除了用1-(氧杂环丁-3-基)-1H-吡唑-4-胺(30d)替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物37。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈15-15-55%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LCMS[M+H]:429
1H NMR(300MHz,DMSO-d6):δppm9.44(s,1H),8.40-8.23(m,1H),7.98(s,1H),7.67(s,1H),7.28-7.15(m,1H),6.88-6.79(m,1H),5.59-5.47(m,1H),4.99-4.64(m,6H),3.25-3.08(m,1H),2.98-2.80(m,1H),2.71-2.55(m,1H),2.36-2.20(m,1H),2.10-1.63(m,5H)。
实施例38:2-(4-((4-(8-((S)-2,2-二氟环丙烷-1-甲酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)嘧啶-2-基)氨基)-1H-吡唑-1-基)乙酰胺(38)的制备
步骤1:2-(4-硝基-1H-吡唑-1-基)乙酸乙酯的合成(38c)。
于室温,将4-硝基-1H-吡唑(10.0g,88.0mmol)和碳酸钾(24.0g,88.0mmol)加入2-溴乙酸乙酯的N,N-二甲基甲酰胺溶剂(200mL)中,氮气置换三次,90℃搅拌过夜。向体系加水(100mL),用EA(100mL*3)萃取,盐水洗涤有机相,无水硫酸钠干燥,减压浓缩,残余物经快速柱色谱法(流动相:石油醚/乙酸乙酯=100/1至4/1)纯化,得黄色固体状标题化合物16.0g。收率:90.0%
LC-MS:m/z 200[M+H]+
步骤2:2-(4-硝基-1H-吡唑-1-基)乙酰胺的合成(38d)。
于室温,将氨水(2.4g,17.2mmol,25-28%)加入2-(4-硝基-1H-吡唑-1-基)乙酸乙酯(1.60g,8.60mmol)甲醇(10mL)溶液中,加入常温下搅拌过夜。反应液减压浓缩,得白色固体状标题化合物1.10g。收率:74.8%
LC-MS:m/z 171[M+H]+
步骤3:2-(4-氨基-1H-吡唑-1-基)乙酰胺的合成(38e)。
于室温,将钯碳(50mg)加入2-(4-硝基-1H-吡唑-1-基)乙酰胺(300mg,1.76mmol)的甲醇(10mL)溶液中,在氢气环境下搅拌过夜。将反应液过滤,滤液减压浓缩,得红色固体标题化合物240mg,收率:96.0%.
合成步骤4~6与实施例1的制备方法相同,除了用2-(4-氨基-1H-吡唑-1-基)乙酰胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物38
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈10-10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 430[M+H]+
1H NMR(300MHz,DMSO-d6):δppm10.34-10.27(m,1H),9.35(s,1H),8.14(s,1H),7.94-7.85(m,1H),7.54-7.17(m,3H),6.82-6.79(m,1H),4.89-4.67(m,4H),3.25-2.75(m,3H),2.45-1.60(m,6H)。
实施例39:1-(4-((4-(8-((S)-2,2-二氟环丙烷-1-羰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)嘧啶-2-基)氨基)-1H-吡唑-1-基)环丙烷-1-甲酰胺(39)的制备
步骤1:1-(4-硝基-1H-吡唑-1-基)环丙烷-1-羧酸乙酯的合成(39c)。
于0℃氮气保护,将氢化钠(2.15g,57.6mmol)加入2-(4-硝基-1H-吡唑-1-基)乙酸乙酯(5.00g,26.8mmol的N,N-二甲基甲酰胺溶液(150mL)中,反应10分钟。滴加1,2-二溴乙烷(6.03g,32.0mmol),滴加完毕自然升至室温,搅拌过夜。将反应液加入水(650mL)中,用EA(100mL*3)萃取,盐水洗涤有机相,无水硫酸钠干燥,减压浓缩,残余物经快速柱色谱法(流动相:石油醚/乙酸乙酯=100/1至4/1),得黄色固体状标题化合物1.2g。收率:20.0%
LC-MS:m/z 226[M+H]+
步骤2:1-(4-硝基-1H-吡唑-1-基)环丙烷-1-甲酰胺的合成(39d)。
于室温,将氨水(743mg,5.31mmol,25-28%)加入1-(4-硝基-1H-吡唑-1-基)环丙烷-1-羧酸乙酯(400mg,1.77mmol)的甲醇溶液(10mL)中,常温下搅拌过夜。反应液减压浓缩得白色固体状标题化合物300mg。收率:86.0%
LC-MS:m/z 197[M+H]+
步骤3:1-(4-氨基-1H-吡唑-1-基)环丙烷-1-甲酰胺的合成(39e)。
于室温,将钯碳(50mg)加入1-(4-硝基-1H-吡唑-1-基)环丙烷-1-甲酰胺(300mg,1.52mmol)甲醇(10mL)溶液中,在氢气环境下搅拌过夜。将反应液过滤,滤液减压浓缩,得红色固体标题化合物250mg,收率:99.1%.
LC-MS:m/z 167[M+H]+
合成步骤4~6与实施例1的制备方法相同,除了用1-(4-氨基-1H-吡唑-1-基)环丙烷-1-甲酰胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物39
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈20-20-40%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 456[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.48(s,1H),8.37-8.34(m,1H),7.90(s,1H),7.63(s,1H),7.34(s,1H),7.23-7.15(m,1H),6.89-6.83(m,1H),6.06(s,1H),4.89-4.69(m,2H),3.22-2.52(m,3H),2.50-1.65(m,6H),1.50(s,2H),1.37(s,2H)。
实施例40:((S)-2,2-二氟环丙基)(3-(2-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(40)的制备
其余与实施例1的制备方法相同,除了用2-(4-氨基-1H-吡唑-1-基)乙烷-1-醇替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物40。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈10-10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 417[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.33(s,1H),8.33(s,1H),7.88(s,1H),7.52(s,1H),7.24-7.18(m1H),6.81(s,1H),4.88-4.70(m,3H),4.09-4.05(m,2H),3.77-3.71(m,2H),3.17-3.14(m,1H),2.95-2.83(m,1H),2.62-2.58(m,1H),2.26-2.09(m,2H),1.94-1.67(m,4H)。
实施例41:((S)-2,2-二氟环丙基)(3-(2-((1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(41)的制备
其余与实施例1的制备方法相同,除了用1-(4-氨基-1H-吡唑-1-基)-2-甲基丙-2-醇替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物41。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-22min,乙腈20-20-60%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水。
LC-MS:m/z 445[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.36(s,1H),8.37-8.31(m,1H),7.92-7.86(m,1H),7.51-7.49(m1H),7.23-7.18(m1H),6.82-6.78(m,1H),4.87-4.81(m,2H),4.70-4.67(m,1H),3.95(s,2H),3.20-3.09(m,2H),2.93-2.87(m,1H),2.48-2.25(m,1H),2.08-2.02(m,1H),1.96-1.80(m,4H),1.04(s,6H)。
实施例42:3-(2-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(42)的制备
与实施例1和3的制备方法相同,除了2-(4-氨基-1H-吡唑-1-基)乙烷-1-醇替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物42。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 438[M+H]+
1H NMR(400MHz,DMSO-d6):δppm9.34(s,1H),8.32(d,J=6Hz,1H),7.87(s,1H),7.54(s,1H),7.29-7.21(m,2H),6.80(d,J=6Hz,1H),4.92-4.88(m,1H),4.61-4.52(m,2H),4.11-4.07(m,2H),3.87-2.68(m,4H),2.97-2.92(m,1H),2.33-2.27(m,1H),2.15-2.13(m,1H),1.90-1.70(m,2H),1.65-1.60(m,1H)。
实施例43:3-(2-((1-环丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(43)的制备
与实施例1和3的制备方法相同,除了1-环丙基-1H-吡唑-4-胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物43。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈30-70%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 434[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.33(s,1H),8.40-8.32(m,1H),7.87(s,1H),7.52(s,1H),7.29-7.20(m,2H),6.83-6.81(m,1H),4.63-4.51(m,2H),3.84-3.70(m,3H),2.98-2.94(m,1H),2.32-2.10(m,2H),1.90-1.70(m,2H),1.68-1.65(m,1H),1.00-0.90(m,4H)。
实施例44:N-(2,2-二氟乙基)-3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(44)的制备
与实施例2的制备方法相同,除了用2,2-二氟乙烷-1-胺盐酸盐替代2-氨基乙腈(2a),制得标题化合物44。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 390[M+H]+
1H NMR(301MHz,DMSO-d6)δppm9.33(s,1H),8.32(d,J=5.2Hz,1H),7.80(s,1H),7.51(s,1H),7.21(s,1H),7.10-7.01(m,1H),6.83-6.76(m,1H),6.15-5.68(m,1H),4.65-4.43(m,2H),3.80(s,3H),3.48-3.35(m,2H),3.01-2.88(m,1H),2.33-2.22(m,1H),2.20-2.06(m,1H),1.99-1.84(m,2H),1.73-1.57(m,1H)。
实施例45:((S)-2,2-二氟环丙基)(3-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(45)的制备
与实施例1的制备方法相同,除了1-乙基-1H-吡唑-4-胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物45。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 401[M+H]+
1H NMR(400MHz,DMSO-d6):δppm9.37(s,1H),8.36-8.32(m,1H),7.86-7.85(m,1H),7.53-7.50(m,1H),7.24-7.19(m,1H),6.85-6.80(m,1H),4.90-4.71(m,2H),4.12-4.05(m,2H),3.32-3.18(m,1H),3.07-2.62(m,1H),2.51-2.44(m,1H),2.26-2.23(m,1H),2.13-1.80(m,5H),1.38-1.23(m,3H)。
实施例46:((S)-2,2-二氟环丙基)(3-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(46)的制备
与实施例1的制备方法相同,除了1-异丙基-1H-吡唑-4-胺替代1-甲基-1H-吡唑-4-胺(1g),制得标题化合物46。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 415[M+H]+
1H NMR(400MHz,DMSO-d6):δppm9.35(s,1H),8.36-8.33(m,1H),7.89-7.87(m,1H),7.55-7.51(m,1H),7.25-7.17(m1H),6.86-6.82(m,1H),4.97-4.71(m,2H),4.48-4.41(m,1H),3.22-3.07(m,1H),2.96-2.87(m,1H),2.63-2.54(m,1H),2.41-2.27(m,1H),2.13-1.80(m,5H),1.41-1.39(m,6H)。
实施例47:(1R,2R)-2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰)环丙烷-1-甲腈(47)的制备
与实施例1的制备方法相同,除了(1R,2R)-2-氰基环丙烷-1-甲酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物47。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 376[M+H]+
1H NMR(400MHz,DMSO-d6):δppm9.37(s,1H),8.35-8.33(m,1H),7.84-7.82(m,1H),7.50(s,1H),7.26-7.18(m,1H),6.86-6.81(m,1H),5.10-4.97(m,1H),4.84-4.73(m,1H),3.80(s,3H),3.01-2.83(m,2H),2.41-2.27(m,1H),2.09-1.83(m,3H),1.79-1.68(m,1H),1.45-1.22(m,3H)。
实施例48:(2,2-二氟-1-甲基环丙基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(48)的制备
与实施例1的制备方法相同,除了2,2-二氟-1-甲基环丙烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物48。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈30-70%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 401[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.36(s,1H),8.36-8.34(m,1H),7.85-7.83(m,1H),7.50(s,1H),7.30-7.18(m1H),6.84-6.83(m,1H),4.96-4.79(m,1H),4.85-4.47(m,1H),3.80(s,3H),2.99-2.61(m,2H),2.14-2.02(m,2H),1.97-1.86(m,1H),1.80-1.70(m,2H),1.59-1.52(m,1H),1.45-1.33(m,3H)。
实施例49:(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(2-(三氟甲基)环丙)甲酮(49)的制备
与实施例1的制备方法相同,除了2-(三氟甲基)环丙烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物49。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-70%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 419[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.35(s,1H),8.35-8.33(m,1H),7.82(s,1H),7.51-7.50(m,1H),7.25-7.18(m1H),6.84-6.81(m,1H),5.06-4.73(m,2H),3.80(s3H),2.95-2.90(m,1H),2.60-2.53(m,1H),2.42-2.21(m,2H),2.12-2.06(m,2H),1.94-1.66(m,2H),1.29-1.07(m,2H)。
实施例50:(2-氯-2-氟环丙基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(50)的制备
与实施例1的制备方法相同,除了2-氯-2-氟环丙烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物50。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-70%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 403[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.36(s,1H),8.36-8.27(m,1H),7.85-7.83(m,1H),7.51(d,J=5.1Hz,1H),7.30-7.14(m,1H),6.88-6.77(m,1H),4.97-4.66(m,2H),3.81(d,J=3.6Hz,3H),3.19-2.83(m,2H),2.45-1.59(m,7H)。
实施例51:(2-氟环丙基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(51)的制备
与实施例1的制备方法相同,除了2-氟环丙烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物51。
制备方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 369[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.40-9.34(m,1H),8.4-8.28(m,1H),7.83-7.75(m,1H),7.60-7.45(m,1H),7.35-7.15(m,1H),6.87-6.75(m,1H),5.15-4.60(m,3H),3.81(s,3H),3.00-2.75(m,1H),2.32-1.43(m,7H),1.11-1.00(m,1H)。
实施例52:(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(1-(三氟甲基)环丙)甲酮(52)的制备
与实施例1的制备方法相同,除了1-(三氟甲基)环丙烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物52。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-65%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 419[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.35(s,1H),8.35(d,J=5.2Hz,1H),7.83(s,1H),7.50(s,1H),7.20(d,J=5.5Hz,1H),6.82(d,J=5.2Hz,1H),4.96-4.85(m,1H),4.83-4.71(m,1H),3.81(s,3H),3.00-2.85(m,1H),2.49-2.39(m,1H),2.20-1.80(m,3H),1.79-1.62(m,1H),1.34-1.10(m,4H)。
实施例53:1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)丁-3-炔-1-酮(53)的制备
与实施例1的制备方法相同,除了3-丁炔酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物53。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 349[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.34(s,1H),8.34(d,J=5.2Hz,1H),7.82(s,1H),7.50(d,J=6.4Hz,1H),7.21(d,J=5.3Hz,1H),6.83-6.80(m,1H),6.35-6.19(m,1H),5.37-5.19(m,2H),4.95-4.66(m,2H),3.85-3.73(m,3H),3.00-2.88(m,1H),2.28-1.59(m,5H)。
实施例54:N-(1-氰基环丙基)-3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(54)的制备
与实施例2的制备方法相同,除了用1-氨基环丙烷-1-腈盐酸盐替代2-氨基乙腈(2a),制得标题化合物54。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 391[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.33(s,1H),8.33(d,J=3.0Hz,1H),7.81(s,1H),7.63(s,1H),7.51(s,1H),7.20-7.17(m,1H),6.81(d,J=3.0Hz,1H),4.57-4.44(m,2H),3.81(s,3H),2.94-2.88(m,1H),2.33-2.27(m,1H),2.16-2.07(m,1H),1.93-1.88(m,2H),1.68-1.59(m,1H),1.41-1.37(m,2H),1.09-1.04(m,2H)。
实施例55:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-((S)-1,1,1-三氟丙烷-2-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(55)的制备
与实施例2的制备方法相同,除了用(S)-1,1,1-三氟丙烷-2-胺盐酸盐替代2-氨基乙腈(2a),制得标题化合物55。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 422[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.32(s,1H),8.33(d,J=5.2Hz,1H),7.81(s,1H),7.52(s,1H),7.20(s,1H),7.00(t,J=8.9Hz,1H),6.81(d,J=5.2Hz,1H),4.79-4.31(m,3H),3.80(s,3H),3.00-2.90(m,1H),2.32-2.12(m,2H),1.25-1.21(m,2H),1.70-1.60(m,1H),1.25-1.21(m,3H)。
实施例56:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-((R)-1,1,1-三氟丙烷-2-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(56)的制备
与实施例2的制备方法相同,除了用(R)-1,1,1-三氟丙烷-2-胺盐酸盐替代2-氨基乙腈(2a),制得标题化合物56。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 422[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.32(s,1H),8.31(d,J=3.0Hz,1H),7.81(s,1H),7.52(s,1H),7.20(s1H),7.00(t,J=9.0Hz,1H),6.82-6.80(m,1H),4.66-4.47(m,3H),3.80(s,3H),2.99-2.89(m,1H),2.32-2.26(m,1H),2.18-2.08(m,1H),1.95-1.89(m,2H),1.70-1.61(m,1H),1.25-1.22(m,3H)。
实施例57:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(3,3,3-三氟丙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(57)的制备
与实施例2的制备方法相同,除了用3,3,3-三氟丙-1-胺盐酸盐替代2-氨基乙腈(2a),制得标题化合物57。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-55%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 422[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.32(s,1H),8.32(d,J=5.2Hz,1H),7.81(s,1H),7.52(s,1H),7.21(d,J=5.2Hz,1H),6.90-6.75(m,2H),4.54-4.46(m,2H),3.81(s,3H),3.29-3.12(m,3H),2.98-2.92(m,1H),2.49-2.37(m,2H),2.30-2.06(m,1H),1.90-1.87(m,2H),1.66-1.62(m,1H)。
实施例58:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-N-(2-(三氟甲氧基)乙基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰胺(58)的制备
与实施例2的制备方法相同,除了用2-(三氟甲氧基)乙烷-1-胺盐酸盐替代2-氨基乙腈(2a),制得标题化合物58。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 438[M+H]+
1H NMR(300MHz,DMSO)δppm 10.64(s,1H),9.31(s,1H),8.37-8.24(m,1H),7.81(s,1H),7.52(s,1H),7.21-7.07(m,1H),6.94-6.76(m,1H),4.63-4.31(m,2H),3.86-3.62(m,5H),3.10-2.91(m,2H),2.40-2.07(m,3H),2.02-1.78(m,2H),1.1.72-1.54(m,1H)。
实施例59:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(2-苯基环丙基)甲酮(59)的制备
与实施例1的制备方法相同,除了2-苯基环丙烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物59。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈30-70%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 427[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.33-9.31(m,1H),8.33(dd,J=6.0Hz,3.0Hz,1H),7.82-7.78(m,1H),7.52-7.46(m,1H),7.31-7.10(m6H),6.80(dd,J=12.0Hz,3.0Hz,1H),4.97-4.75(m,2H),3.81-3.75(m,3H),3.02-2.91(m,1H),2.37-2.18(m,3H),2.12-1.86(m,3H),1.74-1.59(m,1H),1.45-1.18(m,2H)。
实施例60:2-甲基-3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-3-氧代丙腈(60)的制备
与实施例1的制备方法相同,除了2,2-二甲基环丙烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物60。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈25-65%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 379[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.34(s,1H),8.35-8.31(m,1H),7.82(s,1H),7.51(s,1H),7.32-7.16(m1H),6.84-6.80(m,1H),4.91-4.61(m,2H),3.81-3.78(m,3H),2.98-2.85(m,1H),2.41-2.26(m,1H),2.10-2.02(m,1H),1.97-1.16(m,3H),1.70-1.60(m,1H),1.19-1.12(m,3H),1.02-0.98(m,1H),0.92-0.88(m,1H),0.81(s,1H),0.73(s,1H),0.67-0.58(m,1H)。
实施例61:3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-3-氧代丙腈(61)的制备
与实施例1的制备方法相同,除了2-氰基乙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物61。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 350[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.33(s,1H),8.34(d,J=3.0Hz,1H),7.83-7.81(m,1H),7.50(s,1H),7.20-7.17(m1H),6.81(d,J=3.0Hz,1H),4.89-4.72(m,1H),4.60-4.45(m,1H),4.12-3.99(m,2H),3.81(s,3H),3.09-2.84(m,2H),2.23-2.00(m,2H),1.91-1.63(m,2H)。
实施例62:2-甲基-3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-3-氧代丙腈(62)的制备
与实施例1的制备方法相同,除了2-氰基丙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物62。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 364[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.35(s,1H),8.36-8.34(m,1H),7.85-7.81(m,1H),7.50(s,1H),7.23-7.17(m1H),6.85-6.81(m,1H),4.94-4.70(m,2H),4.39-4.27(m,1H),3.80(s,3H),3.17-2.83(m,2H),2.28-2.06(m,2H),1.93-1.66(m,2H),1.42-1.31(m,3H)。
实施例63:1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰基)环丙烷-1-甲腈(63)的制备
与实施例1的制备方法相同,除了1-氰基环丙烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物63。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 376[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.37(s,1H),8.35(d,J=3.0Hz,1H),7.84(s,1H),7.49(s,1H),7.31-7.15(m1H),6.84(d,J=6.0Hz,1H),5.10-4.69(m,2H),3.80(s,3H),3.17-2.72(m,2H),2.27-1.98(m,3H),1.82-1.70(m,1H),1.65-1.52(m,3H),1.45-1.29(m,1H)。
实施例64:4-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羰基)四氢-2H-吡喃-4-氰基(64)的制备
与实施例1的制备方法相同,除了4-氰基四氢-2H-吡喃-4-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物64。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 420[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.37(s,1H),8.35(d,J=3.0Hz,1H),7.84(s,1H),7.49(s,1H),7.26-7.20(m1H),6.85-6.79(m,1H),5.18-4.79(m,2H),4.00-3.72(m,5H),3.62-3.50(m,2H),3.05-2.88(m,1H),2.41-2.22(m,1H),2.17-1.94(m,5H),1.91-1.77(m,2H),1.74-1.56(m,1H)。
实施例65:3,3,3-三氟-1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-1-丙酮(65)的制备
与实施例1的制备方法相同,除了3,3,3-三氟丙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物65。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 393[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.33(s,1H),8.34(d,J=3.0Hz,1H),7.83-7.81(m,1H),7.51(s,1H),7.21-7.17(m1H),6.83-6.81(m,1H),4.93-4.63(m,2H),3.81(s,3H),3.73-3.49(m,2H),3.04-2.89(m,1H),2.47-2.32(m,1H),2.24-2.04(m,2H),1.96-1.84(m,1H),1.76-1.63(m,1H)。
实施例66:3,3-二氟-1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-1-丙酮(66)的制备
与实施例1的制备方法相同,除了3,3-二氟丙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物66。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 375[M+H]+
1H NMR(300MHz,DMSO-d6)δppm 9.34(s,1H),8.34(d,J=5.2Hz,1H),7.82(d,J=5.0Hz,1H),7.50(s,1H),7.20(s,1H),6.82(d,J=5.2Hz,1H),6.51-6.06(m,1H),4.91-4.61(m,2H),3.81(s,3H),3.26-3.06(m,2H),3.02-2.95(m,1H),2.49-2.34(m,1H),2.22-2.05(m,1H),2.02-1.92(m,2H),1.70-1.61(m,1H)。
实施例67:3,3,3-三氟-2-甲基-1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-1-丙酮(67)的制备
与实施例1的制备方法相同,除了3,3,3-三氟-2-甲基丙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物67。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 407[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.35(s,1H),8.35(d,J=5.2Hz,1H),7.82-7.81(m,1H),7.51(s,1H),7.19-7.17(m,1H),6.84-6.82(m,1H),4.95-4.70(m,2H),4.04-3.88(m,1H),3.81(s,3H),2.95-2.89(m,1H),2.45-2.39(m,1H),2.22-1.66(m,4H),1.30-1.16(m,3H)。
实施例68:3,3,3-三氟-2,2-二甲基-1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)丙酮(68)的制备
与实施例1的制备方法相同,除了3,3,3-三氟-2,2-二甲基丙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物68。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈30-70%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 421[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.37(s,1H),8.35(d,J=5.2Hz,1H),7.82(s,1H),7.51(s,1H),7.22(s,1H),6.82(d,J=5.2Hz,1H),5.02-4.84(m,2H),3.79(s,3H),2.99-2.94(m,1H),2.48-2.46(m,1H),2.18-1.94(m,3H),1.69-1.65(m,1H),1.46-1.42(m,6H)。
实施例69:1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-2-(2,2,2-三氟乙氧基)-1-酮(69)的制备
与实施例1的制备方法相同,除了2-(2,2,2-三氟乙氧基)乙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物69。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 423[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.34(s,1H),8.35-8.33(m,1H),7.83-7.82(m,1H),7.50(s,1H),7.21-7.17(m1H),6.82-6.80(m,1H),4.91-4.75(m,1H),4.62-4.51(m,1H),4.43-4.27(m,2H),4.22-4.08(m,2H),3.81(s,3H),3.01-2.91(m,1H),2.45-2.37(m,1H),2.26-2.10(m,1H),2.04-1.92(m,2H),1.77-1.62(m,1H)。
实施例70:(3,3-二氟环戊基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(70)的制备
与实施例1的制备方法相同,除了3,3-二氟环戊烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物70。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈30-70%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 415[M+H]+
1H NMR(300MHz,DMSO-d6)δppm 9.34(s,1H),8.34(d,J=5.3Hz,1H),7.83(s,1H),7.51(s,1H),7.21(s,1H),6.81(d,J=5.2Hz,1H),4.94-4.63(m,2H),3.81(s,3H),3.32-3.10(m,1H),2.94-2.88(m,1H),2.41-2.29(m,3H),2.20-2.07(m,5H),1.93-1.81(m,1H),1.81-1.54(m,2H)。
实施例71:(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(3-(三氟甲基)双环[1.1.1]戊-1-基)甲酮(71)的制备
与实施例1的制备方法相同,除了3-(三氟甲基)双环[1.1.1]戊烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物71。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈30-70%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 445[M+H]+
1H NMR(300MHz,DMSO-d6)δppm 9.34(s,1H),8.34(d,J=5.0Hz,1H),7.82(d,J=3.6Hz,1H),7.50(s,1H),7.22-7.17(m,1H),6.82-6.64(m,1H),4.87-4.71(m,2H),3.80(s,3H),2.99-2.78(m,1H),2.42-2.22(m,7H),2.12-1.92(m,2H),1.92-1.57(m,2H)。
实施例72:双环[1.1.1]戊-1-基(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(72)的制备
与实施例1的制备方法相同,除了双环[1.1.1]戊烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物72。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 377[M+H]+
1H NMR(300MHz,DMSO-d6)δppm 9.34(s,1H),8.33(d,J=5.2Hz,1H),7.82(d,J=4.0Hz,1H),7.50(s,1H),7.24-7.17(m,1H),6.83-6.62(m,1H),4.89-4.68(m,2H),3.80(s,3H),2.94-2.82(m,1H),2.55-2.51(m,1H),2.45-2.43(m,1H),2.38-2.19(m,1H),2.15-2.00(m,7H),1.98-1.56(m,2H)。
实施例73:3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰基)双环[1.1.1]戊烷-1-甲腈(73)的制备
与实施例1的制备方法相同,除了3-氰基双环[1.1.1]戊烷-1-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物73。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 402[M+H]+
1H NMR(300MHz,DMSO-d6)δppm 9.35(s,1H),8.34(d,J=5.2Hz,1H),7.82(d,J=5.1Hz,1H),7.50(s,1H),7.20-7.16(m,1H),6.80(t,J=5.5Hz,1H),4.82-4.70(m,2H),3.81(s,3H),2.92-2.71(m,1H),2.66-2.52(m,6H),2.40-2.20(m,1H),2.01-1.98(m,2H),1.92-1.58(m,2H)。
实施例74:(3-氟双环[1.1.1]戊-1-基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(74)的制备
与实施例1的制备方法相同,除了3-氟双环[1.1.1]戊烷-1-羧酸替代(S)-2,2-二.氟环丙烷-1-羧酸(1j),制得标题化合物74。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 395[M+H]+
1H NMR(300MHz,DMSO-d6)δppm 9.34(s,1H),8.34(d,J=5.2Hz,1H),7.82(d,J=5.3Hz,1H),7.50(s,1H),7.20-7.18(m,1H),6.84-6.76(m,1H),4.90-4.63(m,2H),3.80(s,3H),2.96-2.80(m,1H),2.49-2.38(m,6H),2.33-2.26(m,1H),2.19-1.82(m,2H),1.79-1.63(m,2H)。
实施例75:2-环丙基-2,2-二氟-1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)乙-1-酮(75)的制备
与实施例1的制备方法相同,除了2-环丙基-2,2-二.氟乙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物75。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈30-70%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 401[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.36(s,1H),8.35(d,J=5.2Hz,1H),7.82(s,1H),7.50(s,1H),7.22(s,1H),6.83(t,J=4.8Hz,1H),4.97-4.83(m,2H),3.81(s,3H),2.97-2.83(m,1H),2.62-2.56(m,1H),2.16-1.81(m,3H),1.80-1.52(m,2H),0.74-0.56(m,4H)。
实施例76:(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(四氢呋喃-3-基)甲酮(76)的制备
与实施例1的制备方法相同,除了四氢呋喃-3-羧酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物76。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 381[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.33(s,1H),8.34(d,J=5.2Hz,1H),7.83-7.81(m,1H),7.50(s,1H),7.21-7.19(m,1H),6.88-6.75(m,1H),4.92-4.62(m,2H),3.96-3.78(m,4H),3.76-3.59(m,3H),2.93-2.91(m,1H),2.37-2.35(m,1H),2.30-1.55(m,7H)。
实施例77:2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-甲酰基)环丁烷-1-甲腈(77)的制备
与实施例1的制备方法相同,除了2-氰基环丁烷-1-甲酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物77。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-50%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 390[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.34(s,1H),8.35-8.32(m,1H),7.89-7.77(m,1H),7.49(d,J=2.2Hz,1H),7.20-7.16(m,1H),6.86-6.75(m,1H),4.89-4.45(m,2H),3.90-3.75(m,4H),3.59-3.43(m,1H),2.95-2.90(m,1H),2.42-2.36(m,1H),2.25-1.64(m,8H)。
实施例78:3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)(四氢-2H-吡喃-4-基)甲酮(78)的制备
与实施例1的制备方法相同,除了四氢吡喃-4-酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物78。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈10-40%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 395[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.33(s,1H),8.33(d,J=5.2Hz,1H),7.83-7.80(m,1H),7.51(s,1H),7.24-7.20(m,1H),6.81(d,J=5.2Hz,1H),4.89-4.66(m,2H),3.86-3.80(m,5H),2.92-2.78(m,3H),2.40-2.17(m,1H),2.08-2.00(m,2H),1.92-1.34(m,7H)。
实施例79:2-(3,3-二氟环丁基)-1-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-1-丙酮(79)的制备
与实施例1的制备方法相同,除了2-(3,3-二氟环丁基)乙酸替代(S)-2,2-二氟环丙烷-1-羧酸(1j),制得标题化合物79。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈20-60%;波长:230nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 415[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.34(s,1H),8.34(d,J=5.2Hz,1H),7.83-7.81(m,1H),7.51(s,1H),7.25-7.15(m,1H),6.82-6.80(m,1H),4.88-4.52(m,2H),3.81(s,3H),2.95-2.78(m,1H),2.75-2.55(m,4H),2.41-2.14(m,4H),2.15-1.95(m,2H),1.94-1.78(m,1H),1.79-1.61(m,1H)。
实施例80:(3-甲氧基环丁基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(80)的制备
与实施例1的制备方法相同,除了3-甲氧基环丁烷-1-甲酸替代(S)-2,2-二.氟环丙烷-1-羧酸(1j),制得标题化合物80。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 395[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.33(s,1H),8.33(d,J=5.2Hz,1H),7.87-7.76(m,1H),7.57-7.41(m,1H),7.22-7.14(m,1H),6.89-6.68(m,1H),4.90-4.43(m,2H),3.88-3.68(m,4H),3.13-3.05(m,3H),2.89-2.85(m,2H),2.40-2.29(m,2H),2.25-1.58(m,7H)。
实施例81:(3-(羟甲基)环丁基)(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)甲酮(81)的制备
与实施例1的制备方法相同,除了3-(羟甲基)环丁烷-1-羧酸替代(S)-2,2-二.氟环丙烷-1-羧酸(1j),制得标题化合物81。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 395[M+H]+
1H NMR(300MHz,DMSO-d6)δppm9.34(s,1H),8.33(d,J=5.2Hz,1H),7.85-7.80(m,1H),7.50(s,1H),7.22-7.15(m,1H),6.82-6.79(m,1H),4.86-4.40(m,2H),3.81(s,3H),3.29-3.10(m,3H),3.03-2.77(m,2H),2.42-1.54(m,10H)。
实施例82:2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-2-氧代-N-(2,2,2-三氟乙基)乙酰胺(82)的制备
步骤1:甲基2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-2-氧代乙酸酯的制备(82b)。
于0℃,将2-氯-2-氧代乙酸甲酯(174mg,1.42mmol)加入4-(8-氮杂双环[3.2.1]辛-2-烯-8-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(400mg,1.42mmol)和三乙胺(286mg,2.83mmol)的二氯甲烷(15mL)溶液中,0℃搅拌2小时。反应液加甲醇(10mL)淬灭,减压浓缩,残余物用硅胶柱色谱法分离纯化(流动相:DCM/MeOH=50∶1-20∶1),得黄色油状液体标题化合物390mg,收率:74.5%。
LC-MS:m/z 369[M+H]+
步骤2:2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-2-氧乙酸的制备(82c)。
于0℃,将一水合氢氧化锂(120mg,2.85mmol)加入甲基2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-2-氧代乙酸酯(350mg,0.95mmol)的四氢呋喃(10mL)和水(5mL)溶液中,0℃搅拌1小时。反应液加稀盐酸-二氧六环溶液,调pH=7,减压浓缩,旋干,得黄色油状液体标题化合物粗品375mg。
LC-MS:m/z 355[M+H]+
步骤3:2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-2-氧代-N-(2,2,2-三氟乙基)乙酰胺的制备(82)。
于室温下,将2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-2-氧乙酸(300mg,粗品)溶于乙腈(6mL),加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(338mg,0.890mmol),室温下反应30分钟,加入2,2,2-三氟乙烷-1-胺(59mg,0.539mmol)和N,N-二异丙基乙胺(229mg,1.78mmol),室温下反应过夜。反应液用制备液相色谱法分离,得23mg浅黄色固体状标题化合物,收率:8.9%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:2-22min,乙腈20-60%;波长:254nm;流速:45ml/min;流动相:乙腈,水。
LC-MS:m/z 436[M+H]+
1H NMR(400MHz,DMSO-d6):δppm9.43-9.35(m,2H),8.35-8.34(m,1H),7.82(s,1H),7.50(s,1H),7.20(s1H),6.84-6.82(m,1H),5.13-4.92(m,1H),4.85-4.83(m,1H),4.01-3.91(m,2H),3.80(s3H),3.01-2.94(m,1H),2.58-2.53(m,1H),2.28-2.15(m,1H),2.07-2.03(m,1H),2.00-1.88(m,1H),1.80-1.69(m,1H)。
实施例83:N-(氰基甲基)-2-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-2-氧乙酰胺(83)的制备
与实施例82的制备方法相同,除了2-氨基乙腈盐酸盐替代2,2,2-三氟乙烷-1-胺(82d),制得标题化合物83。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 393[M+H]+
1H NMR(400MHz,DMSO-d6):δppm9.45-9.43(m,1H),9.35(s,1H),8.36-8.34(m,1H),7.83(s,1H),7.50(s,1H),7.22-7.20(m1H),6.84-6.82(m,1H),5.29-4.99(m,1H),4.96-4.83(m,1H),4.20(dd,J=12.0Hz,4.0Hz,2H),3.81(s,3H),3.04-2.93(m,1H),2.58-2.54(m,1H),2.32-2.14(m,1H),2.08-2.02(m,1H),2.00-1.87(m,1H),1.81-1.67(m,1H)。
实施例84:N-(1-甲基-1H-吡唑-4-基)-4-(8-(1-(丙磺酰基)氮杂环丁-3-基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)嘧啶-2-胺(84)的制备
步骤1:3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.21]辛-2-烯-8-基)氮杂环丁烷-1-羧酸叔丁酯的合成(84b)
于室温,将钛酸四异丙酯(148mg,0.521mmol)加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺盐酸盐(400mg,1.05mmol)和3-氧代氮杂环丁烷-1-羧酸叔丁酯(180mg,1.05mmol)的无水二氯甲烷(10mL)混合液中。室温搅拌30分钟后加入醋酸硼氢化钠(267mg,1.26mmol)室温搅拌过夜,加入二氯甲烷(20mL)和氢氧化钠水溶液(2M,10mL),萃取,分相,干燥,减压浓缩,残留液经快速柱色谱法(流动相:DCM/MeOH=100∶1-10∶1)得到100mg棕黄色固体。收率:21.8%。
LC-MS:m/z 438[M+H]+
步骤2:4-(8-(氮杂环丁烷-3-基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺盐酸盐的合成(84c)
于室温,将HCl二氧六环溶液(4M,10mL)加入3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)氮杂环丁烷-1-羧酸叔丁酯(100mg,0.229mmol)的二氧六环(2mL)溶液中,室温搅拌1小时。低温减压浓缩,旋干,得到70mg棕红色油状液体粗品。收率:81.8%。
LC-MS:m/z 338[M+H]+
步骤3:N-(1-甲基-1H-吡唑-4-基)-4-(8-(1-(丙基磺酰基)氮杂环丁烷-3-基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)嘧啶-2-胺的合成(84)
于0℃,将丙基磺酰氯(32.0mg,0.224mmol)加入4-(8-(氮杂环丁烷-3-基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺盐酸盐(70mg,0.187mmol)和碳酸氢钠(47.1mg,0.561mmol)的四氢呋喃和水的混合液(5mL,V/V=4/1)中,继续反应2小时。加入乙酸乙酯(10mL)和水(10mL),分相,水相用乙酸乙酯萃取两次,每次10mL,合并有机相,用饱和盐水洗涤,干燥,减压浓缩,残留物制备液相色谱纯化纯化得到棕色固体32mg,收率:32.2%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-60%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LC-MS:m/z 444[M+H]+
1H NMR(400MHz,DMSO-d6):δppm 9.31(s,1H),8.35(d,J=4.8Hz,1H),7.85(s,1H),7.54(s,1H),7.03(s,1H),6.82(d,J=4.8Hz,1H),3.96-3.94(m,1H),3.89-3.88(m,1H),3.86(s,3H),3.76-3.73(m,2H),3.57-3.51(m,3H),3.13-3.09(m,2H),2.72-2.68(m,1H),2.18-2.14(m,2H),2.02-1.97(m,1H),1.96-1.86(m,1H),1.77-1.69(m,2H),1.67-1.55(m,1H),1.02-0.99(m,3H)。
实施例85:2-(1-((S)-2,2-二氟环丙烷-1-甲酰基)-3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)氮杂环丁-3-基)乙腈(85)的制备
步骤1:叔丁基-9(氰基甲基)-3-(3-(2-((1-甲基-1氢-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)氮杂环-1-羧酸酯的合成(85b)
于室温氮气氛围下,将3-(氰基亚甲基)氮杂环丁烷-1-羧酸叔丁酯(1.72g,8.87mmol)加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-氨基-(1-甲基-1氢-吡唑-4-基)嘧啶-2-胺(500mg,1.77mmol)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(1.35g,8.87mmol)的乙腈(50mL)溶液中,50℃搅拌72小时。加入饱和食盐水(50mL),用乙酸乙酯(50mL*3)萃取,有机相用无水硫酸钠干燥,减压浓缩,残留液经快速柱色谱法(流动相:二氯甲烷/甲醇,100/1至20/1)得到450mg黄色油状液体标题化合物。收率:53%。
LCMS[M+H]:477。
步骤2:2-(3-(3-(2-((1-甲基-1氢-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)氮杂苷-3-基)乙腈盐酸盐的合成(85c)
于室温,将盐酸/1,4二氧六环(10mL,4mol/L)加入到叔丁基-9(氰基甲基)-3-(3-(2-((1-甲基-1-氢-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)氮杂环-1-羧酸酯(450mg,0.943mmol)的二氯甲烷(20mL)溶液中,室温搅拌30分钟,低温减压浓缩,得到500mg黄色固体粗品标题化合物。
LCMS[M+H]:377。
步骤3:2-(1-((S)-2,2-二氟环丙烷-1-羰基)-3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)氮杂苷-3-基)乙腈的合成(85)
于室温,将2-(7-氧化苯并三氮唑)-N,N,N′,N-四甲基脲六氟磷酸酯(276mg,0.0.728mmol)加入(S)-2,2-二氟环丙烷-1-羧酸(54.4mg,0.485mmol)的四氢呋喃(10mL)溶液中,于室温搅拌30分钟。加入2-(3-(3-(2-((1-甲基-1氢-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)氮杂苷-3-基)乙腈盐酸盐(200mg,0.485mmol)和N,N-二异丙基乙胺(187mg,1.45mmol),于室温搅拌过夜。加入水(50mL)中,用乙酸乙酯(30mL*3)萃取,有机相用饱和盐水洗涤,无水硫酸钠干燥,减压浓缩,残留物用制备液相色谱法分离,得到20mg黄色固体状标题化合物。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-2-27min,乙腈10-10-50%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LCMS[M+H]:481
1H NMR(300MHz,DMSO-d6):δppm9.32(s,1H),8.32(d,J=4.7Hz,1H),7.83(s,1H),7.50(s,1H),7.18(s,1H),6.79(s,1H),4.50-4.28(m,1H),4.20-3.85(m,4H),3.80(s,3H),3.71-3.56(m,1H),3.23(s,2H),2.70(d,J=11.0Hz,2H),2.35-2.21(m,1H),2.13-1.98(m,1H),1.96-1.73(m,4H),1.62-1.46(m,1H)。
实施例86:3-(氰基甲基)-3-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)-N-(2,2,2-三氟乙基)氮杂环丁烷-1-甲酰胺(86)的制备
与实施例3的制备方法相同,除了2-(3-(3-(2-((1-甲基-1氢-吡唑-4-基)氨基)嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-基)氮杂苷-3-基)乙腈盐酸盐(85c)替代4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(1i),制得标题化合物86。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-70%;波长:220nm;流速:45mL/min;流动相:乙腈,0.05%甲酸水溶液。
LCMS[M+H]:502。
1H NMR(300MHz,DMSO-d6):δppm9.32(s,1H),8.32(d,J=5.1Hz,1H),7.83(s,1H),7.50(s,1H),7.18(d,J=4.8Hz,1H),7.07(t,J=6.3Hz,1H),6.79(d,J=5.2Hz,1H),3.96(d,J=8.5Hz,3H),3.89-3.82(m,1H),3.80(s,3H),3.78-3.66(m,3H),3.61-3.52(m,1H),3.25-3.10(m,2H),2.75-2.59(m,1H),2.34-2.19(m,1H),2.12-1.93(m,1H),1.92-1.72(m,2H),1.60-1.50(m,1H)。
实施例87:N-(1-甲基-1H-吡唑-4-基)-4-(8-((3-甲基氧杂环丁-3-基)甲基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)嘧啶-2-胺(87)的制备
步骤1:N-(1-甲基-1H-吡唑-4-基)-4-(8-((3-甲基氧杂环丁-3-基)甲基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)嘧啶-2-胺的制备(87)。
于室温下,将氰基硼氢化钠(133mg,2.12mmol)和钛酸四异丙酯(101mg,0.354mmol)加入4-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(200mg,0.708mmol),3-甲基氧杂环丁烷-3-甲醛(71mg,0.708mmol)和醋酸(21mg,0.354mmol)的乙腈(7mL)混合液中,室温搅拌过夜。反应液减压浓缩,残留液用制备液相色谱法分离,得32mg黄色固体状标题化合物,收率:12.3%。
制备液相色谱纯化方法:柱子:30mm×250mm;填料:C18,10μm;方法:0-22min,乙腈10-40%;波长:220nm;流速:45mL/min;流动相:乙腈/水。
LC-MS:m/z 367[M+H]+
1H NMR(300MHz,DMSO-d6):δppm9.35(s,1H),8.36(d,J=3.0Hz,1H),7.82(s,1H),7.53(s,1H),7.09-7.05(m,1H),6.86(d,J=6.0Hz,1H),4.40-4.35(m,2H),4.24-4.21(m,2H),3.80(s,3H),3.10-2.73(m,4H),2.33-1.86(m,5H),1.73-1.58(m,1H),1.36(s,3H)。
生物学评价
试验例1:本发明化合物体外JAK1激酶抑制活性的测定
实验材料:JAK1激酶(Invitrogen,PV4744)、ATP(Promega,V915B)、ADP-GloKinase Assay(Promega,V9101)、IRS1(Signalchem,I40-58-1000)。
样品配制:将本发明化合物和对照品分别溶于DMSO溶剂中,配成10mM母液。最终化合物反应最高浓度为10μM,3倍稀释,10个浓度梯度,每个浓度梯度设2个复孔。
实验方法:Echo转移0.1μL的待测化合物到384反应板中(PE,6007290),1000rpm/min,离心1min。转移5μL的JAK1激酶(终浓度4nM)到384反应板中,1000rpm/min,离心1min,25℃孵育15min。转移5μL底物混合物(1mM ATP,IRS1 0.05mg/ml,激酶缓冲溶液)到384反应板中,1000rpm/min,离心1min,25℃孵育60min。转移10μLADP-Glo到384反应板中1000rpm/min,离心1min,25℃孵育40min。转移20μL检测溶液到384反应板中1000rpm/min,离心1min,25℃孵育40min。使用Envision多功能读板机读取RLU(相对发光单元,Relativeluminescence unit)信号。信号强度用于表征激酶的活性程度。
利用以下非线性拟合公式得到化合物的IC50(半数抑制浓度):
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope));
X:化合物浓度log值;
Y:发射率(Emission Ratio);
Bottom:最低值,Top:最高值,HillSlope:斜率;
本发明化合物对JAK1激酶的抑制活性见下表1。IC50值在0-100nM标记为A,100-300nM标记为B,300-1000nM标记为C,大于1000nM标记为D,NT代表未测试。
表1:本发明化合物对JAK1激酶的抑制活性
从上述试验结果可以清楚地看出,本发明化合物具有良好的体外抗JAK1激酶活性。
试验例2:本发明化合物体外Tyk2激酶抑制活性的测定
实验材料:TYK2(Invitrogen,PV4790)、ATP(Promega,V915B)、ADP-Glo KinaseAssay(Promega,V9101)、IRS1(Signalchem,I40-58-1000)。
样品制备:将本发明化合物和对照品分别溶于DMSO溶剂中,配成10mM母液。最终化合物反应最高浓度为10μM,3倍稀释,10个浓度梯度,每个浓度梯度设2个复孔。
实验方法:Echo转移0.1μL待测化合物到384反应板中(PE,6007290),1000rpm/min,离心1min。转移5μL的TYK2激酶(终浓度4nM)到384反应板中,1000rpm/min,离心1min,25℃孵育15min。转移5μL底物混合物(1mMATP,IRS1 0.05mg/ml,激酶缓冲溶液)到384反应板中,1000rpm/min,离心1min,25℃孵育60min。转移10μLADP-Glo到384反应板中1000rpm/min,离心1min,25℃孵育40min。转移20μL检测溶液到384反应板中1000rpm/min,离心1min,25℃孵育40min。使用Envision多功能读板机读取RLU(相对发光单元,Relativeluminescence unit)信号。信号强度用于表征激酶的活性程度。
利用以下非线性拟合公式得到化合物的IC50(半数抑制浓度):
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope));
X:化合物浓度log值;
Y:发射率(Emission Ratio);
Bottom:最低值,Top:最高值,HillSlope:斜率;
本发明化合物对TYK2激酶的抑制活性见下表2。IC50值在0-100nM标记为A,100-300nM标记为B,300-1000nM标记为C,大于1000nM标记为D,NT代表未测试。
表2:本发明化合物对Tyk2激酶的抑制活性
从上述试验结果可以清楚地看出,本发明化合物具有良好的体外抗Tyk2激酶活性。
试验例3:本发明化合物对于人全血STAT3信号通路的抑制
实验材料:CD3(BD,555335),pSTAT3抗体(BD,612569),IFN-2α(Biolegend,592702)
样品制备:将本发明化合物和对照品分别溶于DMSO溶剂中,配成10mM母液。最终化合物反应最高浓度为10μM,3倍稀释,10个浓度梯度,每个浓度梯度设2个复孔。
实验方法:向含有180μL经肝素钠抗凝的流式细胞管(BD,352052),加入20μL本发明化合物后,对照加20μL PBS,37℃孵育30min;加入刺激因子2μL,37℃孵育20min;加入1mL红细胞裂解液,迅速反复颠倒5-10次或者涡旋样品,37℃孵育10min;600g离心6-8min,弃上清,涡旋至悬起沉淀;加入3mL PBS洗涤细胞;600g离心6-8min,弃上清;涡旋,悬起沉淀;加入1mL破膜液,轻轻混匀,冰上孵育30min;600g离心6-8min,弃上清;涡旋,悬起沉淀;洗涤细胞,加入3mL PBS,600g离心6-8min,弃上清;涡旋,悬起沉淀;重复2次,每个染色管加入100μL PBS,加入IFN-2α刺激,并加入CD3和pSTAT3抗体(20μL),混匀,避光;室温孵育60min。洗涤细胞,加入3mL PBS,600g离心6-8min,弃上清;涡旋,悬起沉淀。沉淀悬在150μL,避光,准备流式细胞仪分析。利用以下非线性拟合公式得到化合物的IC50(半数抑制浓度):
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope));
X:化合物浓度log值;
Y:发射率(Emission Ratio);
Bottom:最低值,Top:最高值,HillSlope:斜率
本发明化合物对于IFN-2α刺激的TYK2/JAK1介导通路的抑制情况见表3。IC50值在0-100nM标记为A,100-300nM标记为B,300-1000nM标记为C,大于1000nM标记为D,NT代表未测试。
表3:本发明化合物对于人全血STAT3信号通路的抑制情况
由表3可以看出,本发明化合物对于人全血TYK2/JAK1介导的信号通路具有很好的抑制作用。
试验例4:实施例1、实施例1-b和实施例3化合物的大鼠AIA药效学研究
实验材料:完全弗氏佐剂(Chondrex,7027)
实验方法:考察本发明化合物体内药效,选8周雌性Lewis大鼠,完全弗氏佐剂造模(J.of Immunology,2010,184:5298-5307),12天后分组,实验分为7组,分别是模型组、实施例1低剂量(3mg/kg)、实施例1高剂量组(30mg/kg),实施例1-b低剂量(1mg/kg)、实施例1-b高剂量(3mg/kg)、实施例3低剂量(3mg/kg)和实施例3高剂量组(30mg/kg),模型组给予0.5%CMC-Na,其余各组给予相应剂量的化合物,口服给药7天后根据关节肿胀程度进行评分(Proc Soc Exp Bio Med 1962,111:544-547),评分结果见表4。
表4:本发明化合物大鼠AIA药效实验结果
注:其中“*”p<0.05代表显著性差异,“**”p<0.01代表极显著性差异。
由实验结果可以看出,实施例1、实施例1-b和实施例3化合物显著抑制完全弗氏佐剂诱导的关节炎症状,表明实施例1、实施例1-b和实施例3化合物对于AIA模型有很好的药效。
实验例5:实施例1、实施例1-a、实施例1-b和实施例3化合物在大鼠体内的药代研究
为考察本发明化合物口服给药后血药浓度和药代参数,针对实验例化合物开发出相应的LC/MS/MS检测方法及血浆处理方法,方法学初步验证表明血浆中内源性物质基本不影响待测物与内标的分离测定,血浆标准曲线回归方程r大于0.95,线性关系良好,满足血浆样品中待测物的检测需求。
雄性SD大鼠口服给药剂量5mg/kg,眼眶采血,血液经肝素钠抗凝,血浆用乙腈去蛋白后,样品经LC/MS/MS方法分析,SD大鼠体内药代动力学参数(非房室模型统计矩参数)见表5。其中,AUC在<1000μg/L*h标记为C,1000-2000μg/L*h标记为B,>2000μg/L*h标记为A;Cmax在<600μg/L标记为C,600-900μg/L标记为B,>900μg/L标记为A。
表5:实施例1、实施例1-a、实施例1-b和实施例3化合物SD大鼠口服给药的药代动力学参数
由表5可以看出,实施例1、实施例1-a、实施例1-b和实施例3化合物具有良好的药代参数,适合做为口服给药。
Claims (17)
1.一种通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐,
其中:
每个R4各自独立地选自卤素、C1-C6烷基、C3-C6环烷基、3至6元杂环基,其中所述C1-C6烷基任选进一步被选自卤素、羟基的一个或多个基团取代;
R2选自氢、卤素、氰基、C1-C6烷基,其中所述C1-C6烷基任选进一步被选自卤素的一个或多个基团取代;
L选自-CR5R6-、-C(O)-、-C(S)-、-S(O)n-、-C(O)N(Ra)-、-C(O)-C(O)-N(Ra)-和-S(O)nN(Ra)-;
R5和R6各自独立地选自氢、C1-C6烷基;
R3选自C1-C6烷基、C3-C6环烷基、3-6元杂环基、苯基和5至6元杂芳基,其中所述C1-C6烷基、C3-C6环烷基、3-6元杂环基、苯基和5至6元杂芳基各自独立地任选进一步被一个或多个R7取代;
每个R7各自独立地选自卤素、氰基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、C6-C10芳基、5至10元杂芳基,其中所述C1-C6烷基、C1-C6烷氧基、C3-C6环烷基各自独立地任选进一步被选自卤素、羟基的一个或多个基团取代;
Ra选自氢、C1-C6烷基;且
n为1或2。
2.根据权利要求1所述的通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐,
其中,
L选自-S(O)n-、-C(O)-、-C(O)N(Ra)-和-S(O)nN(Ra)-,
其中,Ra和n如权利要求1所定义。
3.根据权利要求1所述的通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐,
其中,R2选自氢和卤素。
4.根据权利要求1所述的通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐,
其中,R4为C1-C6烷基。
8.根据权利要求7所述的方法,其中将化合物IIi在三乙胺条件下,与R3-L-X反应得到通式(II)化合物。
9.根据权利要求7所述的方法,其中将化合物IIi与R3-L-OH在DIPEA条件和HATU存在下反应得到通式(II)化合物。
10.一种药物组合物,其含有根据权利要求1至6中任一项所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐,以及药学上可接受的载体。
11.根据权利要求1至6中任一项所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐或者根据权利要求10所述的药物组合物在制备JAK1和TYK2抑制剂中的用途。
12.根据权利要求1至6中任一项所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐或者根据权利要求10所述的药物组合物在制备治疗与JAK1和TYK2活性相关的疾病的药物中的用途。
13.根据权利要求12所述的用途,其中所述疾病选自炎症、自身免疫性疾病和癌症。
14.根据权利要求13所述的用途,其中所述炎症选自类风湿性关节炎、银屑病性关节炎、炎症性肠炎、葡萄膜炎、银屑病和特应性皮炎。
15.根据权利要求13所述的用途,其中所述自身免疫性疾病选自多发性硬化症和狼疮。
16.根据权利要求13所述的用途,其中所述癌症选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、乳突肾性瘤、白血病、淋巴瘤和骨髓瘤。
17.根据权利要求13所述的用途,其中所述癌症选自肝细胞癌、头颈部肿瘤和非小细胞肺癌。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2019107337235 | 2019-08-09 | ||
CN201910733723 | 2019-08-09 | ||
PCT/CN2020/107054 WO2021027647A1 (zh) | 2019-08-09 | 2020-08-05 | 桥杂环基取代的嘧啶类化合物及其制备方法和医药用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112654605A CN112654605A (zh) | 2021-04-13 |
CN112654605B true CN112654605B (zh) | 2022-11-22 |
Family
ID=74570903
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080004748.2A Active CN112654605B (zh) | 2019-08-09 | 2020-08-05 | 桥杂环基取代的嘧啶类化合物及其制备方法和医药用途 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20220348572A1 (zh) |
EP (1) | EP4011865A4 (zh) |
JP (1) | JP2022543690A (zh) |
KR (1) | KR20220046593A (zh) |
CN (1) | CN112654605B (zh) |
AU (1) | AU2020328707A1 (zh) |
CA (1) | CA3144420A1 (zh) |
WO (1) | WO2021027647A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2024502648A (ja) * | 2021-01-14 | 2024-01-22 | 中国医▲薬▼研究▲開▼▲発▼中心有限公司 | 架橋ヘテロシクリル置換ピリミジン化合物、その調製方法及び医学的使用 |
CA3236262A1 (en) | 2021-10-25 | 2023-05-04 | Isaac Marx | Tyk2 degraders and uses thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014500254A (ja) * | 2010-11-09 | 2014-01-09 | セルゾーム リミティッド | Tyk2阻害剤としてのピリジン化合物およびそのアザ類似体 |
AU2014316247A1 (en) * | 2013-09-03 | 2016-03-31 | Carna Biosciences, Inc. | Novel 2,6-diaminopyrimidine derivative |
NO2721710T3 (zh) * | 2014-08-21 | 2018-03-31 | ||
WO2017035366A1 (en) * | 2015-08-26 | 2017-03-02 | Incyte Corporation | Pyrrolopyrimidine derivatives as tam inhibitors |
CN110862376A (zh) * | 2019-10-24 | 2020-03-06 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
-
2020
- 2020-08-05 EP EP20851903.3A patent/EP4011865A4/en active Pending
- 2020-08-05 AU AU2020328707A patent/AU2020328707A1/en active Pending
- 2020-08-05 CN CN202080004748.2A patent/CN112654605B/zh active Active
- 2020-08-05 KR KR1020227007091A patent/KR20220046593A/ko unknown
- 2020-08-05 US US17/633,089 patent/US20220348572A1/en active Pending
- 2020-08-05 JP JP2022507868A patent/JP2022543690A/ja active Pending
- 2020-08-05 WO PCT/CN2020/107054 patent/WO2021027647A1/zh unknown
- 2020-08-05 CA CA3144420A patent/CA3144420A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
EP4011865A1 (en) | 2022-06-15 |
CN112654605A (zh) | 2021-04-13 |
KR20220046593A (ko) | 2022-04-14 |
TW202115036A (zh) | 2021-04-16 |
AU2020328707A1 (en) | 2022-02-24 |
JP2022543690A (ja) | 2022-10-13 |
EP4011865A4 (en) | 2022-11-02 |
CA3144420A1 (en) | 2021-02-18 |
WO2021027647A1 (zh) | 2021-02-18 |
US20220348572A1 (en) | 2022-11-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112778276A (zh) | 作为shp2抑制剂的化合物及其应用 | |
JP2022523274A (ja) | Jak阻害剤化合物及びその使用 | |
CN113631557B (zh) | Jak激酶抑制剂及其制备方法和在医药领域的应用 | |
TWI846229B (zh) | 布魯頓氏酪胺酸激酶之抑制劑 | |
KR101947289B1 (ko) | 신규 피롤로피리미딘 화합물 또는 그의 염, 및 이것을 함유하는 의약 조성물, 특히 nae 저해 작용에 기초하는 종양 등의 예방제 및/또는 치료제 | |
CN113166142B (zh) | 一类五元并六元杂环化合物及其作为蛋白受体激酶抑制剂的用途 | |
CA3120514A1 (en) | Cyclic ureas | |
KR20180095054A (ko) | 피롤로피리미딘 화합물에 의한 항종양 효과 증강제 | |
WO2015178955A1 (en) | Substituted ethynyl heterobicyclic compounds as tyrosine kinase inhibitors | |
EP3766882A1 (en) | Phthalazine isoxazole alkoxy derivatives, preparation method thereof, pharmaceutical composition and use thereof | |
CN106661032A (zh) | 治疗或预防糖尿病、肥胖症和炎性肠病的1,3‑取代的2‑氨基吲哚衍生物及类似物 | |
KR20230142745A (ko) | Cdk2 억제제 및 그의 사용 방법 | |
CN112654605B (zh) | 桥杂环基取代的嘧啶类化合物及其制备方法和医药用途 | |
WO2021119254A1 (en) | Antagonists of the muscarinic acetylcholine receptor m4 | |
CN111386275A (zh) | 高活性sting蛋白激动剂 | |
CN111320624A (zh) | 三唑并吡啶类和咪唑并吡啶类化合物及其制备方法和医药用途 | |
KR20230043955A (ko) | 키나아제 억제 활성을 갖는 화합물 | |
CN110072862B (zh) | 二环性含氮杂环衍生物及含有该衍生物的药物组合物 | |
CN111320633B (zh) | 吡咯/咪唑并六元杂芳环类化合物及其制备方法和医药用途 | |
CN113825757A (zh) | 取代的稠合双环类衍生物、其制备方法及其在医药上的应用 | |
CA3207392A1 (en) | Cdk inhibitor | |
WO2024002373A1 (zh) | 取代嘧啶并环类抑制剂及其制备方法和应用 | |
TWI848162B (zh) | 橋雜環基取代的嘧啶類化合物及其製備方法和醫藥用途 | |
CN113493453A (zh) | 稠合芳香环类衍生物、其制备方法及其在医药上的应用 | |
CN113423709B (zh) | 三嗪酮并咪唑类化合物及其医药用途 |
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 | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40041168 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |