CN114907377A - Condensed tetracyclic compound, preparation method and medical application thereof - Google Patents
Condensed tetracyclic compound, preparation method and medical application thereof Download PDFInfo
- Publication number
- CN114907377A CN114907377A CN202210122528.0A CN202210122528A CN114907377A CN 114907377 A CN114907377 A CN 114907377A CN 202210122528 A CN202210122528 A CN 202210122528A CN 114907377 A CN114907377 A CN 114907377A
- Authority
- CN
- China
- Prior art keywords
- cancer
- groups
- compound
- group
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 256
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 101100177670 Caenorhabditis elegans hpk-1 gene Proteins 0.000 claims abstract description 10
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims description 181
- 125000000217 alkyl group Chemical group 0.000 claims description 135
- -1 cyano, amino Chemical group 0.000 claims description 129
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 91
- 125000000623 heterocyclic group Chemical group 0.000 claims description 83
- 229910052736 halogen Inorganic materials 0.000 claims description 78
- 150000002367 halogens Chemical class 0.000 claims description 77
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 64
- 125000001072 heteroaryl group Chemical group 0.000 claims description 52
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 125000001188 haloalkyl group Chemical group 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 40
- 125000003342 alkenyl group Chemical group 0.000 claims description 39
- 125000000304 alkynyl group Chemical group 0.000 claims description 39
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 28
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 201000011510 cancer Diseases 0.000 claims description 22
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 238000007363 ring formation reaction Methods 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 125000004434 sulfur atom Chemical group 0.000 claims description 12
- 208000035475 disorder Diseases 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 206010009944 Colon cancer Diseases 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 9
- 206010025323 Lymphomas Diseases 0.000 claims description 9
- 206010039491 Sarcoma Diseases 0.000 claims description 9
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 9
- 206010046766 uterine cancer Diseases 0.000 claims description 9
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 8
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 8
- 206010029260 Neuroblastoma Diseases 0.000 claims description 8
- 206010038389 Renal cancer Diseases 0.000 claims description 8
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 8
- 206010043515 Throat cancer Diseases 0.000 claims description 8
- 208000026935 allergic disease Diseases 0.000 claims description 8
- 208000005017 glioblastoma Diseases 0.000 claims description 8
- 201000010982 kidney cancer Diseases 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 201000007270 liver cancer Diseases 0.000 claims description 8
- 208000014018 liver neoplasm Diseases 0.000 claims description 8
- 201000005202 lung cancer Diseases 0.000 claims description 8
- 208000020816 lung neoplasm Diseases 0.000 claims description 8
- 201000000849 skin cancer Diseases 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- 206010004593 Bile duct cancer Diseases 0.000 claims description 7
- 206010005003 Bladder cancer Diseases 0.000 claims description 7
- 206010005949 Bone cancer Diseases 0.000 claims description 7
- 208000018084 Bone neoplasm Diseases 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 7
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 7
- 208000035473 Communicable disease Diseases 0.000 claims description 7
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 7
- 201000001342 Fallopian tube cancer Diseases 0.000 claims description 7
- 208000013452 Fallopian tube neoplasm Diseases 0.000 claims description 7
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 7
- 208000032612 Glial tumor Diseases 0.000 claims description 7
- 206010018338 Glioma Diseases 0.000 claims description 7
- 208000031886 HIV Infections Diseases 0.000 claims description 7
- 208000037357 HIV infectious disease Diseases 0.000 claims description 7
- 206010020751 Hypersensitivity Diseases 0.000 claims description 7
- 206010024612 Lipoma Diseases 0.000 claims description 7
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 7
- 201000004404 Neurofibroma Diseases 0.000 claims description 7
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 7
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 7
- 206010040047 Sepsis Diseases 0.000 claims description 7
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 7
- 206010057644 Testis cancer Diseases 0.000 claims description 7
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 7
- 208000006593 Urologic Neoplasms Diseases 0.000 claims description 7
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 7
- 230000007815 allergy Effects 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 208000026900 bile duct neoplasm Diseases 0.000 claims description 7
- 201000010881 cervical cancer Diseases 0.000 claims description 7
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 201000004101 esophageal cancer Diseases 0.000 claims description 7
- 206010017758 gastric cancer Diseases 0.000 claims description 7
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 7
- 201000010536 head and neck cancer Diseases 0.000 claims description 7
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 7
- 208000002672 hepatitis B Diseases 0.000 claims description 7
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 208000028867 ischemia Diseases 0.000 claims description 7
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 7
- 230000003211 malignant effect Effects 0.000 claims description 7
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 7
- 230000004770 neurodegeneration Effects 0.000 claims description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
- 201000002528 pancreatic cancer Diseases 0.000 claims description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 7
- 230000001850 reproductive effect Effects 0.000 claims description 7
- 201000002314 small intestine cancer Diseases 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- 208000023516 stroke disease Diseases 0.000 claims description 7
- 201000003120 testicular cancer Diseases 0.000 claims description 7
- 201000002510 thyroid cancer Diseases 0.000 claims description 7
- 206010044412 transitional cell carcinoma Diseases 0.000 claims description 7
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 101001059991 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 1 Proteins 0.000 description 34
- 102100028199 Mitogen-activated protein kinase kinase kinase kinase 1 Human genes 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000005605 benzo group Chemical group 0.000 description 18
- 125000006413 ring segment Chemical group 0.000 description 18
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 238000004949 mass spectrometry Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000012071 phase Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 12
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000002619 bicyclic group Chemical group 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- 230000014759 maintenance of location Effects 0.000 description 12
- 125000003367 polycyclic group Chemical group 0.000 description 12
- MQJNETSYXIIIKE-UHFFFAOYSA-N 7h-thieno[2,3-b]pyridin-6-one Chemical compound N1C(=O)C=CC2=C1SC=C2 MQJNETSYXIIIKE-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 125000000000 cycloalkoxy group Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 210000001744 T-lymphocyte Anatomy 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000004296 chiral HPLC Methods 0.000 description 8
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 229910052805 deuterium Inorganic materials 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 239000001301 oxygen Chemical group 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000011593 sulfur Chemical group 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 102100034709 Lymphocyte cytosolic protein 2 Human genes 0.000 description 5
- 101710195102 Lymphocyte cytosolic protein 2 Proteins 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- 150000003457 sulfones Chemical class 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 3
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 3
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 3
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 3
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 3
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 239000004530 micro-emulsion Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 230000009822 protein phosphorylation Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- QTWJBGXXGNBBDR-UHFFFAOYSA-N tert-butyl oxazepane-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCCCON1 QTWJBGXXGNBBDR-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 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 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 2
- 102000017578 LAG3 Human genes 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 241001614181 Phera Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 206010024627 liposarcoma Diseases 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 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 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012053 oil suspension Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- AQNQGBUEVCAVML-UHFFFAOYSA-N oxazepane Chemical compound C1CCNOCC1 AQNQGBUEVCAVML-UHFFFAOYSA-N 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 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 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 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
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- XOAAAPHKZDETSB-UHFFFAOYSA-N 1,2-difluoro-4,5-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(F)C=C1[N+]([O-])=O XOAAAPHKZDETSB-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- IQUNZGOZUJITBJ-UHFFFAOYSA-N 2-amino-6-fluorobenzonitrile Chemical compound NC1=CC=CC(F)=C1C#N IQUNZGOZUJITBJ-UHFFFAOYSA-N 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- XVGHZFWFGXDIOU-UHFFFAOYSA-N 2-aminothiophene-3-carbonitrile Chemical compound NC=1SC=CC=1C#N XVGHZFWFGXDIOU-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 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 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 238000003727 ADP Glo Kinase Assay Methods 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- 206010073135 Dedifferentiated liposarcoma Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 1
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 1
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 description 1
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 1
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 1
- 101000818543 Homo sapiens Tyrosine-protein kinase ZAP-70 Proteins 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 101150030213 Lag3 gene Proteins 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 102000001291 MAP Kinase Kinase Kinase Human genes 0.000 description 1
- 108010075654 MAP Kinase Kinase Kinase 1 Proteins 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 102100033115 Mitogen-activated protein kinase kinase kinase 1 Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 description 1
- 208000005678 Rhabdomyoma Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000032383 Soft tissue cancer Diseases 0.000 description 1
- 101100215487 Sus scrofa ADRA2A gene Proteins 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 1
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 1
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 1
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 1
- 108091008091 TCR signalosome Proteins 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102100021125 Tyrosine-protein kinase ZAP-70 Human genes 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000005366 cycloalkylthio 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
- 230000002950 deficient Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000001516 effect on protein Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004468 heterocyclylthio group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 229940044680 immune agonist Drugs 0.000 description 1
- 239000012651 immune agonist Substances 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000009125 negative feedback regulation Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 210000004976 peripheral blood cell Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000003566 phosphorylation assay Methods 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 238000011865 proteolysis targeting chimera technique Methods 0.000 description 1
- 229940124823 proteolysis targeting chimeric molecule Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 108010026668 snake venom protein C activator Proteins 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 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
- 239000007901 soft capsule Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- FPQSSQQQKLJLPA-UHFFFAOYSA-N tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(CCO)C1 FPQSSQQQKLJLPA-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 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
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Neurology (AREA)
- Communicable Diseases (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Vascular Medicine (AREA)
- Psychiatry (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Biotechnology (AREA)
- Hospice & Palliative Care (AREA)
- Immunology (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present disclosure relates to fused tetracyclic compounds, methods for their preparation, and their use in medicine. Specifically, the disclosure relates to a fused tetracyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, in particular to application of the compound in preparing a medicine for inhibiting HPK 1. Wherein each group in the general formula (I) is defined in the specification.
Description
Technical Field
The disclosure belongs to the field of medicines, and relates to a condensed tetracyclic compound, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to fused tetracyclic compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the fused tetracyclic compounds in preparation of drugs for inhibiting HPK 1.
Background
Anticancer therapy has moved from chemotherapy, targeted therapy, to the years of immunotherapy. Targets for tumor immunotherapy mainly include immune checkpoints, immune agonists, tregs, macrophages, tumor microenvironment metabolites such as IDO, A2AR pathway, and the like. Hematopoietic Progenitor cell Kinase 1(Hematopoietic promoter Kinase1, abbreviated as HPK 1; also known as Mitogen-activated protein Kinase kinase Kinase kinase Kinase1 or Mitogen-activated protein Kinase kinase Kinase1, abbreviated as MAP4K1) is a negative regulator in T cells, and has a negative feedback regulation function after TCR activation, which is related to T cell exhaustion. The signal paths that are more clearly studied are: upon binding of the TCR to the MHC-peptide, LAT is phosphorylated, recruiting the GADS-SLP76 complex, resulting in phosphorylation and pathway activation of downstream PLCs. Meanwhile, ZAP70 phosphorylates the Y381 site of HPK1, which binds to the SH2 region of SLP76, thus phosphorylating the S376 site of the latter. SLP76S376 phosphorylates recruit 14-3-3, leading to ubiquitination, resulting in disassembly of the entire TCR signalosome.
HPK1 is currently considered to be a better immunotherapy target for the following 3-point reasons: (1) the HPK1 expression profile is limited to immune cells, and the safety is good; (2) HPK1 has multiple negative regulation effects at different stages of cancer-immune cycle, and inhibition of HPK1 can regulate the immunosuppressive functions of NK cells, DC cells and T cells and can also regulate B cell activation, wherein T cell activation is the most studied; (3) HPK1 kinase activity is important in suppressing anti-cancer immune responses.
Research shows that the expression of HPK1 is related to T cell exhaustion signature, including CD3E, PD1, CTLA4, TIM-3, LAG-3 and TIGIT, and the high expression of HPK1 is related to short survival time. TCGA PanCancer database analysis showed a positive correlation between HPK1 (but not other MAP4K family members) expression and PD 1.HPK1 was up-regulated in exhausted T cells, and HPK1, TIM3 and LAG3 were more highly expressed in PD1 high T cells than PD1 low T cells. In contrast, HPK1 was down-regulated in CD4+ T cells of Systemic Lupus Erythematosus (SLE) patients, and the SLEDAI score was negatively correlated with HPK1 mRNA levels. HPK1 expression was also down-regulated in peripheral blood cells of psoriatic arthritis (PsA) patients.
The HPK1 knockout mice did not have any abnormalities at rest. Once TCR was activated, mice with either HPK1 knockdown, HPK1 kinase dead knock-in, or SLP76S376A knock-in, gave similar results and activated immune responses. HPK1 deficient mice are more susceptible to Experimental Autoimmune Encephalomyelitis (EAE). HPK1 kinase activity regulates TCR signaling and cytokine secretion in vitro; inhibition of HPK1 may alleviate PGE2 and adenosine-mediated immunosuppression. The HPK1 kinase dead mouse can inhibit the growth of tumors in vivo, and the anti-tumor effect of the HPK 1-/-mouse is almost disappeared after removing CD8+ or CD4+ T cells, which indicates that the T cells mediate most of the immunosuppressive effect of HPK 1.
The data of the mice with HPK1 knockout and kinase dead knock-in indicate that HPK1 mainly acts through kinase activity, but some documents report that the scaffold also has certain functions, so that the drug development idea for inhibiting HPK1 mainly comprises kinase inhibitors and also comprises some PROTAC molecules.
Related patents which have been disclosed so far are WO2016205942A1, WO2019238067A1, WO2021013083A1 and WO2021000925A1, among others.
Disclosure of Invention
The object of the present disclosure is to provide a compound represented by the general formula (I):
wherein:
ring a is selected from aryl, heterocyclyl and heteroaryl;
T 1 is CR T1 Or a nitrogen atom;
G 3 and G 4 Are the same or different and are each independently CR 1 Or a nitrogen atom;
G 8 is CR G8 Or a nitrogen atom;
G 1 and G 2 Are the same or different and are each independently selected fromCR 2 、NR 3 Nitrogen atom, oxygen atom and sulfur atom;
G 5 and G 6 Are the same or different and are each independently selected from CR 4 R 5 、NR 6 Oxygen atom and sulfur atom;
G 7 selected from the group consisting of CR G7a R G7b 、NR G7c Oxygen atom and sulfur atom;
G 9 selected from the group consisting of CR G9a R G9b 、NR G9c Oxygen atom and sulfur atom;
r is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl; or
Two R together form oxo;
R 0 、R 3 、R 6 、R G7c and R G9c Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;
R’、R 1 、R T1 、R G8 and R 2 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 、-OR 9 Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4 、R 5 、R G7a 、R G7b 、R G9a and R G9b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a,Alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or
R 4 And R 5 、R G7a And R G7b Or R G9a And R G9b Wherein one pair together form oxo;
R 7 and R 8 Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; or
R 7 And R 8 Together with the nitrogen atom to which it is attached, form a heterocyclyl group, which heterocyclyl group is optionally substituted with one or more of halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;
R 9 selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
m is 0, 1,2,3 or 4;
q is 0, 1,2,3 or 4; and is
n is 0, 1,2,3, 4,5 or 6.
Another aspect of the present disclosure relates to a compound represented by the general formula (I-1) or (I-2):
wherein, ring A, T 1 、G 1 To G 9 、R’、R 0 R, q and n are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof,
whereinIs composed ofT 3 Is CR T3 Or a nitrogen atom, T 5 、T 6 And T 7 Are the same or different and are each independently CR 10 Or a nitrogen atom;
T 2 and T 4 Are the same or different and are each independently selected from CR 11 、NR 12 Nitrogen atom, oxygen atom and sulfur atom;
R 10 、R T3 and R 11 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 、-OR 9 Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 12 selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
R 7 、R 8 、R 9 and m is as defined in the general formula (I), (I-1) or (I-2).
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, whereinIs composed ofR 10 、R T3 And R 11 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 、-OR 9 Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 7 、R 8 、R 9 and m is as defined in the general formula (I), (I-1) or (I-2).
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of 5-6 membered heteroaryl, 5-6 membered heterocyclyl and phenyl.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R is 0 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably, R 0 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G 1 Is a nitrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G 2 Is NH.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G 7 Is CR G7a R G7b ,R G7a And R G7b As defined in general formula (I), (I-1) or (I-2); preferably, G 7 Is CH 2 。
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G 8 Is a nitrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T 2 Is CR 11 ,R 11 As defined in general formula (I), (I-1) or (I-2); preferably, R 11 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; more preferably, T 2 Is CH.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T 3 Is CR T3 ,R T3 As defined in general formula (I), (I-1) or (I-2); preferably, R T3 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; more preferably, T 3 Is CH.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T 4 Is an oxygen atom or a sulfur atom; preferably, T 4 Is a sulfur atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T 5 Is CR 10 ,R 10 As defined in general formula (I), (I-1) or (I-2); preferably, R 10 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; further preferably, T 5 Is CR 10 ,R 10 Is a hydrogen atom or a halogen; more preferably, T 5 Is CH or CF; most preferably, T 5 Is CH.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T 6 Is CR 10 ,R 10 Such as a cartoonAs defined in formula (I), (I-1) or (I-2); preferably, R 10 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; more preferably, T 6 Is CH.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T 7 Is CR 10 ,R 10 As defined in general formula (I), (I-1) or (I-2); preferably, R 10 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; more preferably, T 7 Is CH.
Another aspect of the present disclosure relates to a compound represented by formula (II) or (III):
wherein:
T 1 、G 3 、G 4 、G 5 、G 6 、G 9 r, R', q and n are as defined in formula (I).
The disclosure also relates to a compound represented by general formula (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof:
T 1 、G 3 、G 4 、G 5 、G 6 、G 9 r, R', q and n are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein G is 5 Is CR 4 R 5 Or an oxygen atom; and/or G 6 Is CR 4 R 5 Or an oxygen atom; preferably, G 5 And G 6 One of them is CR 4 R 5 And the other is an oxygen atom; r 4 And R 5 Such as general formula (I), (I-1), (I-2), (II-1), (II-2), (III)III-1) or (III-2); more preferably, G 5 And G 6 One of them is CH 2 And the other is an oxygen atom; most preferably, G 5 Is an oxygen atom, G 6 Is CH 2 。
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein G is 9 Is NR G9c ,R G9c Is a hydrogen atom or C 1-6 An alkyl group; preferably, G 9 Is NCH 3 Or NH; more preferably, G 9 Is NCH 3 。
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein G is 9 Is an oxygen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein G is 3 Is CR 1 (ii) a And/or G 4 Is CR 1 ;R 1 As defined in general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2); preferably, R 1 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; more preferably, G 3 Is CH; and/or G 4 Is CH.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein T is 1 Is CR T1 ;R T1 As defined in general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2); preferably, R T1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, amino, cyano, hydroxy, C 1-6 Hydroxyalkyl and-CH 2 -NH 2 (ii) a More preferably, T 1 Is C-NH 2 。
In some preferred embodiments of the present disclosure, the followingThe compound shown in the general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R is the same or different and is independently selected from hydrogen atom, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 A hydroxyalkyl group; or two R together form oxo; preferably, R is the same or different and each is independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; more preferably, R is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is the same or different and each is independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 A hydroxyalkyl group; preferably, R' are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; more preferably, R' is a hydrogen atom or a halogen.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; preferably, m is 0 or 1.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2; preferably, q is 0 or 1.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2; preferably, n is 0 or 1.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 Hydroxy and C 1-6 Hydroxyalkyl, m is 1 or2, R 7 And R 8 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, amino, cyano, hydroxy, C 1-6 Hydroxyalkyl and-CH 2 -NH 2 (ii) a More preferably, R 1 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; most preferably, R 1 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is T1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 Hydroxy and C 1-6 Hydroxyalkyl, m is 1 or2, R 7 And R 8 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R T1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, amino, cyano, hydroxy, C 1-6 Hydroxyalkyl and-CH 2 -NH 2 (ii) a More preferably, R T1 Is an amino group.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R G8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 Hydroxy and C 1-6 Hydroxyalkyl, m is 1 or2, R 7 And R 8 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R G8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, amino, cyano, hydroxy, C 1-6 Hydroxyalkyl and-CH 2 -NH 2 (ii) a More preferably, R G8 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 Hydroxy and C 1-6 Hydroxyalkyl, m is 1 or2, R 7 And R 8 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R 2 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atom, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably, R 3 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is 4 And R 5 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl, or R 4 And R 5 Together form an oxo group; preferably, R 4 And R 5 Are the same or different and are each independently selected from the group consisting of hydrogen atom, halogenAnd C 1-6 An alkyl group; more preferably, R 4 And R 5 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R G7a And R G7b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl, or R G7a And R G7b Together form an oxo group; preferably, R G7a And R G7b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; more preferably, R G7a And R G7b Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is G9a And R G9b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl, or R G9a And R G9b Together form an oxo group; preferably, R G9a And R G9b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is 6 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably, R 6 Is a hydrogen atom or C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R G7c Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Alkyl halidesA group; preferably, R G7c Is a hydrogen atom or C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is G9c Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably, R G9c Is a hydrogen atom or C 1-6 Alkyl, more preferably methyl.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is 7 And R 8 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R 7 And R 8 The same or different, and each independently is a hydrogen atom or a methyl group.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is 9 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from hydrogen atoms, halogens, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 Hydroxy and C 1-6 Hydroxyalkyl, m is 1 or2, R 7 And R 8 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R 10 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, amino, cyano, hydroxy, C 1-6 Hydroxyalkyl and-CH 2 -NH 2 (ii) a Further preferably, R 10 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; more preferably, R 10 Is a hydrogen atom or a halogen.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R T3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 Hydroxy and C 1-6 Hydroxyalkyl, m is 1 or2, R 7 And R 8 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R T3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, amino, cyano, hydroxy, C 1-6 Hydroxyalkyl and-CH 2 -NH 2 (ii) a More preferably, R T3 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; most preferably, R T3 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from hydrogen atoms, halogens, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 Hydroxy and C 1-6 Hydroxyalkyl, m is 1 or2, R 7 And R 8 Are the same or different and are each independently a hydrogen atom or C 1-6 An alkyl group; preferably, R 11 Selected from hydrogen atoms, halogens and C 1-6 An alkyl group; more preferably, R 11 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably, R 12 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (II), (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is selected from the group consisting of hydrogen, halogen and C 1-6 Alkyl, q is 0 or 1, T 1 Is CR T1 ,R T1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, amino, cyano, hydroxy, C 1-6 Hydroxyalkyl and-CH 2 -NH 2 ,G 3 Is CR 1 ,G 4 Is CR 1 ,R 1 Each independently selected from hydrogen, halogen and C 1-6 Alkyl radical, G 5 And G 6 In which one is CH 2 The other is an oxygen atom, G 9 Is NR G9c ,R G9c Is a hydrogen atom or C 1-6 Alkyl, R is selected from hydrogen atom, halogen and C 1-6 Alkyl, n is 0 or 1.
In some preferred embodiments of the present disclosure, the compound of formula (II), (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is a hydrogen atom or a halogen, q is 0 or 1, T 1 Is C-NH 2 ,G 3 Is CH, G 4 Is CH, G 5 Is an oxygen atom, G 6 Is CH 2 ,G 9 Is NR G9c ,R G9c Is a hydrogen atom or C 1-6 Alkyl and R are hydrogen atoms.
Table a typical compounds of the present disclosure include, but are not limited to:
another aspect of the present disclosure relates to a compound represented by the general formula (IA) or a salt thereof,
wherein: r w Is an alkyl group;
G 1 to G 9 R and n are as defined in formula (I).
Another aspect of the present disclosure relates to a compound represented by the general formula (I-1A) or (I-2A) or a salt thereof,
wherein: r w Is an alkyl group;
G 1 to G 9 R and n are as defined in formula (I).
Another aspect of the present disclosure relates to a compound of formula (IIA) or a salt thereof,
wherein: r w Is an alkyl group;
G 3 to G 6 、G 9 R and n are as defined in formula (II).
Another aspect of the present disclosure relates to a compound represented by the general formula (II-1A) or (II-2A) or a salt thereof,
wherein: r w Is an alkyl group;
G 3 to G 6 、G 9 R and n are as defined in formula (II).
Another aspect of the present disclosure relates to a compound represented by the general formula (IC) or a salt thereof,
wherein: r m Is an amino protecting group; preferably Boc;
ring A, T 1 、R’、R 0 、G 1 To G 8 R, q and n are as defined in formula (I). Another aspect of the disclosure relates to a compound of formula (IIC) or (IIIC) or a salt thereof,
wherein: r m Is an amino protecting group; preferably Boc;
T 1 、R’、G 3 to G 6 R, q and n are as defined in formula (II) or (III). Typical intermediate compounds of the present disclosure include, but are not limited to:
another aspect of the present disclosure relates to a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:
carrying out cyclization reaction on the compound of the general formula (IA) or salt thereof and the compound of the general formula (IB) or salt thereof to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;
wherein:
R w is alkyl, preferably ethyl;
T 1 is C-NH 2 ;
Ring A, R 0 、R’、q、G 1 To G 9 R and n are as defined in formula (I).
Another aspect of the present disclosure relates to a process for preparing a compound represented by the general formula (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, which comprises:
resolving the compound of the general formula (I) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (I-1) or (I-2) or the pharmaceutically acceptable salt thereof;
wherein:
ring A, T 1 、R 0 、R’、q、G 1 To G 9 R and n are as defined in general formula (I-1) or (I-2).
Another aspect of the present disclosure relates to a process for preparing a compound represented by the general formula (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, which comprises:
carrying out cyclization reaction on the compound of the general formula (I-1A) or salt thereof and the compound of the general formula (IB) or salt thereof to obtain the compound of the general formula (I-1) or pharmaceutically acceptable salt thereof; or
Carrying out cyclization reaction on the compound of the general formula (I-2A) or salt thereof and the compound of the general formula (IB) or salt thereof to obtain the compound of the general formula (I-2) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
Ring A, R 0 、R’、q、G 1 To G 9 R and n are as defined in general formula (I-1) or (I-2).
Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
carrying out cyclization reaction on the compound of the general formula (IIA) or salt thereof and the compound of the general formula (IIB) or salt thereof to obtain a compound of the general formula (II) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
G 3 、G 4 、G 5 、G 6 、G 9 R, R', q and n are as defined in formula (II).
Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1) or (II-2), or a pharmaceutically acceptable salt thereof, comprising:
resolving the compound of the general formula (II) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (II-1) or (II-2) or the pharmaceutically acceptable salt thereof;
wherein:
T 1 、G 3 、G 4 、G 5 、G 6 、G 9 r, R', q and n are as defined in formula (II-1) or (II-2).
Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1) or (II-2), or a pharmaceutically acceptable salt thereof, comprising:
a compound of a general formula (II-1A) or a salt thereof and a compound of a general formula (IIB) or a salt thereof are subjected to cyclization reaction to obtain a compound of a general formula (II-1) or a pharmaceutically acceptable salt thereof; or
The compound of the general formula (II-2A) or the salt thereof and the compound of the general formula (IIB) or the salt thereof are subjected to cyclization reaction to obtain the compound of the general formula (II-2) or the pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
G 3 、G 4 、G 5 、G 6 、G 9 R, R', q and n are as defined in formula (II-1) or (II-2).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising:
carrying out cyclization reaction on the compound of the general formula (IIA) or salt thereof and the compound of the general formula (IIIB) or salt thereof to obtain the compound of the general formula (III) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
G 3 、G 4 、G 5 、G 6 、G 9 R, R', q and n are as defined in formula (III).
Another aspect of the present disclosure relates to a process for preparing a compound represented by the general formula (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, which comprises:
resolving the compound of the general formula (III) or pharmaceutically acceptable salt thereof to obtain a compound shown in the general formula (III-1) or (III-2) or pharmaceutically acceptable salt thereof;
wherein:
T 1 、G 3 、G 4 、G 5 、G 6 、G 9 r, R', q and n are as defined in formula (III-1) or (III-2).
Another aspect of the present disclosure relates to a process for preparing a compound represented by the general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, which comprises:
carrying out cyclization reaction on the compound of the general formula (II-1A) or salt thereof and the compound of the general formula (IIIB) or salt thereof to obtain the compound of the general formula (III-1) or pharmaceutically acceptable salt thereof; or
Carrying out cyclization reaction on the compound of the general formula (II-2A) or salt thereof and the compound of the general formula (IIIB) or salt thereof to obtain the compound of the general formula (III-2) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
G 3 、G 4 、G 5 、G 6 、G 9 R, R', q and n are as defined in formula (III-1) or (III-2).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:
carrying out deprotection reaction on the compound of the general formula (IC) or salt thereof to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;
wherein:
R m is a amino groupProtecting a base; preferably Boc;
G 9 is NH;
ring A, T 1 、R’、R 0 、G 1 To G 8 R, q and n are as defined in formula (I).
Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II) or (III), or a pharmaceutically acceptable salt thereof, comprising:
carrying out deprotection reaction on the compound of the general formula (IIC) or salt thereof to obtain a compound of a general formula (II) or pharmaceutically acceptable salt thereof; or
Carrying out deprotection reaction on the compound of the general formula (IIIC) or salt thereof to obtain a compound of a general formula (III) or pharmaceutically acceptable salt thereof;
wherein:
R m is an amino protecting group; preferably Boc;
G 9 is NH;
T 1 、R’、G 3 to G 6 R, q and n are as defined in formula (II) or (III).
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The disclosure further relates to the use of compounds of general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for inhibiting HPK 1.
The present disclosure further relates to the use of a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or condition by inhibition of HPK 1; the use of a disease or condition preferably selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders; more preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, hiv infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke, and alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.
The present disclosure further relates to the use of a compound represented by general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and diseases or conditions of reproductive disorders; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.
The present disclosure further relates to a method of inhibiting HPK1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure further relates to a method of treating and/or preventing a disease or disorder, preferably a disease or disorder treated and/or prevented by inhibiting HPK1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2), and shown in table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein said disease or condition is preferably selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders; more preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, hiv infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke, and alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.
The present disclosure further relates to a method of treating and/or preventing cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes, and diseases or conditions of reproductive disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2), and shown in table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.
The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.
The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament for inhibiting HPK 1.
The present disclosure further relates to a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or disorder, preferably for use as a medicament for the treatment and/or prevention of a disease or disorder that is treated and/or prevented by inhibition of HPK 1; wherein said disease or condition is preferably selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.
The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament for the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumors, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.
Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyoma, leiomyosarcoma, dedifferentiated liposarcoma, liposarcoma polymorpha, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; the lymphoma is selected from hodgkin's disease and non-hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); the liver cancer is preferably hepatocellular carcinoma; lung cancer is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma) and Small Cell Lung Cancer (SCLC); kidney cancer selected from renal cell carcinoma, clear cell and nephroeosinophilic tumor; the leukemia is selected from Chronic Lymphocytic Leukemia (CLL), chronic myelogenous leukemia, Acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Chronic Myelogenous Leukemia (CML) and Acute Myelogenous Leukemia (AML); the skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; the throat cancer is nasopharyngeal carcinoma.
Colorectal cancer described in the present disclosure is also called colorectal cancer, preferably colon cancer or rectal cancer; preferably, the uterine cancer is endometrial cancer.
The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
As a general guide, the active compounds of the present disclosure are preferably in unit dosage form, or in a form in which the patient can self-administer the compound in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.
The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
The compounds of the present disclosure can be administered by the addition of water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Description of the terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl group"Refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group having 1 to 12 (e.g., 1,2,3, 4,5, 6,7, 8, 9,10, 11, and 12) carbon atoms 1-20 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) 1-6 Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachmentPreferably, the substituents are selected from one or more of D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.
The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably having 1 to 12 (e.g., 1,2,3, 4,5, 6,7, 8, 9,10, 11, and 12) carbon atoms (i.e., C) 1-12 Alkylene), more preferably alkylene having 1 to 6 carbon atoms (i.e., C) 1-6 Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) 2 -), 1-ethylidene (-CH (CH) 3 ) -), 1, 2-ethylene (-CH) 2 CH 2 ) -, 1-propylene (-CH (CH) 2 CH 3 ) -), 1, 2-propylene (-CH) 2 CH(CH 3 ) -), 1, 3-propylene (-CH) 2 CH 2 CH 2 -) 1, 4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like. The alkylene group may be substituted or unsubstituted and when substituted, may be substituted at any available point of attachment, the substituent preferably being selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.
The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, preferably having 2 to 12 (e.g., 2,3,4, 5,6, 7, 8, 9,10, 11, and 12) carbon atoms (i.e., C) 2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. An alkenyl group may be substituted or unsubstituted, and when substituted, the substituent groupPreferably one or more selected from the group consisting of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably 2 to 12 (e.g. 2,3,4, 5,6, 7, 8, 9,10, 11 and 12) carbon atoms (i.e. C) 2-12 Alkynyl), more preferably alkynyl having 2 to 6 carbon atoms (i.e., C) 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3,4, 5,6, 7, 8, 9,10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14 membered cycloalkyl groups), preferably 3 to 8 (e.g., 3,4, 5,6, 7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5-to 20-membered polycyclic group having a single ring with a single carbon atom in common (referred to as a spiro atom) which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified as mono-or polyspirocycloalkyl (e.g., a bispirocycloalkyl group), preferably mono-and bispirocycloalkyl, depending on the number of spiro atoms shared between rings. More preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused cycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused cycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl groups depending on the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring includes as aboveSaid cycloalkyl (including monocyclic, spiro, fused and bridged rings) is fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring(s) attached to the parent structure are cycloalkyl, non-limiting examples of which includeEtc.; preferably, it is
Cycloalkyl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 (e.g., 3,4, 5,6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3-to 20-membered heterocyclyl group) wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), but does not include a ring moiety of-O-, -O-S-, or-S-, with the remaining ring atoms being carbon. Preferably 3 to 14 (e.g., 3,4, 5,6, 7, 8, 9,10, 11, 12, 13 and 14) ring atoms (i.e., 3 to 14 membered heterocyclyl), of which 1-4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (e.g., 3,4, 5,6, 7 and 8) (i.e., 3 to 8 membered heterocyclyl) or 6 to 14 ring atoms (e.g., 6,7, 8, 9,10, 11, 12, 13 and 14), wherein 1-3 are heteroatoms (e.g., 1,2 and 3); more preferably 3 to 8 ring atoms, of which 1-3 (e.g. 1,2 and 3) are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group having one atom (referred to as the spiro atom) in common between monocyclic rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14 (e.g. 6,7, 8, 9,10, 11, 12, 13 and 14) membered (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) membered (i.e. 7 to 10 membered spiroheterocyclyl). Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group or a multi-spiro heterocyclic group (e.g., a double-spiro heterocyclic group), preferably a mono-spiro heterocyclic group and a double-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered spiroheterocyclic group. Non-limiting examples of spiro heterocyclic groups include:
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e. to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 (e.g., 6,7, 8, 9,10, 11, 12, 13 and 14) membered (i.e., 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 (e.g., 7, 8, 9 or 10) membered (i.e., 7 to 10 membered fused heterocyclyl). They may be classified into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
the term "bridged heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected and which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 (e.g. 6,7, 8, 9,10, 11, 12, 13 and 14) membered (i.e. 6 to 14 bridged heterocyclyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) membered (i.e. 7 to 10 bridged heterocyclyl). They may be classified into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups depending on the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:
The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (e.g., 1,2,3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5,6, 7, 8, 9 or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 5 or 6 membered, e.g., furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, preferably with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived by removal of one hydrogen atom from the parent ring atom, or those derived by removal of two hydrogen atoms from the parent ring atom or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".
The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.
The term "hydroxyl protecting group" refers to a derivative of a hydroxyl group that is commonly used to block or protect the hydroxyl group while the reaction is carried out on other functional groups of the compound. As an example, the hydroxyl-protecting group may preferably be triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl.
The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.
The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
The term "aryloxy" refers to aryl-O-wherein aryl is as defined above.
The term "heteroaryloxy" refers to heteroaryl-O-wherein heteroaryl is as defined above.
The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to-OH.
The term "mercapto" refers to-SH.
The term "amino" refers to the group-NH 2 。
The term "cyano" refers to — CN.
The term "nitro" means-NO 2 。
The term "oxo" or "oxo" means "═ O".
The term "carbonyl" refers to C ═ O.
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.
The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, followed by diastereoisomeric resolution by conventional methods well known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.
In the chemical structure of the compounds described in the present disclosure, a bondDenotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structureCan be thatOrOr at the same time containAndtwo configurations.
The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. An example of a keto-enol equilibrium is between A and B as shown below.
Also as when referring to imidazolyl, it is understood to include either of the following two structures or a mixture of both tautomers.
All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.
The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, respectively 2 H (deuterium, D), 3 H (tritium, T), 11 C、 13 C、 14 C、 15 N、 17 O、 18 O、 32 p、 33 p、 33 S、 34 S、 35 S、 36 S、 18 F、 36 Cl、 82 Br、 123 I、 124 I、 125 I、 129 I and 131 i, etc., preferably deuterium.
Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, where replacement by deuterium may be partial or complete, partial replacement by deuterium meaning replacement of at least one hydrogen by at least one deuterium.
"optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano 1-6 Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.
"substituted" means that one or more, preferably 1 to 6, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.
Synthesis of the compounds of the present disclosure
In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
scheme one
The invention discloses a method for preparing a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:
carrying out cyclization reaction on the compound of the general formula (IA) or salt thereof and the compound of the general formula (IB) or salt thereof under alkaline conditions to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
Ring A, R 0 、R’、q、G 1 To G 9 R and n are as defined in formula (I).
Scheme two
A process for producing a compound represented by the general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, which comprises:
chiral preparation and resolution are carried out on the compound of the general formula (I) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (I-1) or (I-2) or the pharmaceutically acceptable salt thereof;
wherein:
ring A, T 1 、R 0 、R’、q、G 1 To G 9 R and n are as defined in general formula (I-1) or (I-2).
Scheme three
A process for producing a compound represented by the general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, which comprises:
a compound of a general formula (I-1A) or a salt thereof and a compound of a general formula (IB) or a salt thereof are subjected to cyclization reaction under alkaline conditions to obtain a compound of a general formula (I-1) or a pharmaceutically acceptable salt thereof; or
Performing cyclization reaction on the compound of the general formula (I-2A) or salt thereof and the compound of the general formula (IB) or salt thereof under alkaline conditions to obtain the compound of the general formula (I-2) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
Ring A, R 0 、R’、q、G 1 To G 9 R and n are as defined in general formula (I-1) or (I-2).
Scheme four
Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
performing cyclization reaction on the compound of the general formula (IIA) or salt thereof and the compound of the general formula (IIB) or salt thereof under alkaline conditions to obtain the compound of the general formula (II) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
G 3 、G 4 、G 5 、G 6 、G 9 R, R', q and n are as defined in formula (II).
Scheme five
A process for producing a compound represented by the general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, which comprises:
chiral preparation and resolution are carried out on the compound of the general formula (II) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (II-1) or (II-2) or the pharmaceutically acceptable salt thereof;
wherein:
T 1 、G 3 、G 4 、G 5 、G 6 、G 9 r, R', q and n are as defined in formula (II-1) or (II-2).
Scheme six
A process for producing a compound represented by the general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, which comprises:
performing cyclization reaction on the compound of the general formula (II-1A) or salt thereof and the compound of the general formula (IIB) or salt thereof under alkaline conditions to obtain the compound of the general formula (II-1) or pharmaceutically acceptable salt thereof; or
Performing cyclization reaction on the compound of the general formula (II-2A) or salt thereof and the compound of the general formula (IIB) or salt thereof under alkaline conditions to obtain the compound of the general formula (II-2) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
G 3 、G 4 、G 5 、G 6 、G 9 R, R', q and n are as defined in formula (II-1) or (II-2).
Scheme seven
Another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising:
performing cyclization reaction on the compound of the general formula (IIA) or salt thereof and the compound of the general formula (IIIB) or salt thereof under alkaline condition to obtain the compound of the general formula (III) or pharmaceutically acceptable salt thereof;
wherein:
R w is alkyl, preferably ethyl;
T 1 is C-NH 2 ;
G 3 、G 4 、G 5 、G 6 、G 9 R, R', q and n are as defined in formula (III).
Scheme eight
A process for producing a compound represented by the general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, which comprises:
chiral preparation and resolution are carried out on the compound of the general formula (III) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (III-1) or (III-2) or the pharmaceutically acceptable salt thereof;
wherein:
T 1 、G 3 、G 4 、G 5 、G 6 、G 9 r, R', q and n are as defined in formula (III-1) or (III-2).
Scheme nine
A process for producing a compound represented by the general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, which comprises:
performing cyclization reaction on the compound of the general formula (II-1A) or salt thereof and the compound of the general formula (IIIB) or salt thereof under alkaline condition to obtain the compound of the general formula (III-1) or pharmaceutically acceptable salt thereof; or
Performing cyclization reaction on the compound of the general formula (II-2A) or salt thereof and the compound of the general formula (IIIB) or salt thereof under alkaline condition to obtain the compound of the general formula (III-2) or pharmaceutically acceptable salt thereof;
wherein:
R w is an alkyl group, preferably an ethyl group;
T 1 is C-NH 2 ;
G 3 、G 4 、G 5 、G 6 、G 9 R, R', q and n are as defined in formula (III-1) or (III-2).
Scheme ten
The invention discloses a method for preparing a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:
carrying out deprotection reaction on the compound of the general formula (IC) or a salt thereof under an acidic condition to obtain a compound of the general formula (I) or a pharmaceutically acceptable salt thereof;
wherein:
R m is an amino protecting group; preferably Boc;
G 9 is NH;
ring A, T 1 、R’、R 0 、G 1 To G 8 R, q and n are as defined in formula (I).
Scheme eleven
A process for preparing a compound of the general formula (II) or (III) or a pharmaceutically acceptable salt thereof, which comprises:
carrying out deprotection reaction on the compound of the general formula (IIC) or salt thereof under an acidic condition to obtain a compound of a general formula (II) or pharmaceutically acceptable salt thereof; or
Carrying out deprotection reaction on the compound of the general formula (IIIC) or salt thereof under an acidic condition to obtain a compound of a general formula (III) or pharmaceutically acceptable salt thereof;
wherein:
R m is an amino protecting group; preferably Boc;
G 9 is NH;
T 1 、R’、G 3 to G 6 R, q and n are as defined in formula (II) or (III).
The reagents in the above synthesis schemes that provide basic conditions include organic bases including, but not limited to, triethylamine, pyridine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide in tetrahydrofuran, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, lithium bis (trimethylsilyl) amide in tetrahydrofuran, or 1, 8-diazabicycloundec-7-ene, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; preferably lithium diisopropylamide or lithium diisopropylamide in tetrahydrofuran.
Reagents that provide acidic conditions in the above synthetic schemes include organic acids including, but not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me, and inorganic acids 3 SiCl and TMSOTf; the inorganic acids include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; trifluoroacetic acid is preferred.
The reaction of the above step is preferably carried out in a solvent including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane and mixtures thereof.
Detailed Description
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10 -6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using a solventDeuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
MS measurements were carried out using a FINNIGAN LCQad (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.
Chiral HPLC assay using Agilent 1260DAD HPLC.
High performance liquid preparative chromatographs were prepared using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.
Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.
CombiFlash flash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Average inhibition rate of kinase and IC 50 The values were determined with a NovoStar microplate reader (BMG, Germany).
Known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
Example 1
4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1
First step of
9, 10-dinitro-1, 2,4,4a,5, 6-hexahydro-3H-benzo [ b ] pyrazino [1,2-d ] [1,4] oxazepan-3-carboxylic acid tert-butyl ester 1c
The compound 1, 2-difluoro-4, 5-dinitrobenzene 1a (1g, 4.3mmol, obtained after finishing Shanghai), 3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester 1B (1.32g, 6.5mmol), potassium hydroxide (730mg, 13mmol) were dissolved in 30mL of dimethyl sulfoxide, reacted at 30 ℃ for 3 hours, then heated to 60 ℃ for 5 hours, 50mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and column chromatography was purified with an eluent system B to obtain the title compound 1c (1.2g, yield: 70%).
MS m/z(ESI):395.2[M-H]。
Second step of
9, 10-dinitro-2, 3,4,4a,5, 6-hexahydro-1H-benzo [ b ] pyrazino [1,2-d ] [1,4] oxazepan 1d
Compound 1c (1.2g, 3.04mmol) was dissolved in 20mL of dichloromethane, 3mL of trifluoroacetic acid was added, and after stirring for 1 hour, the reaction mixture was concentrated under reduced pressure to give the crude title product 1d (0.89g), which was subjected to the next reaction without purification.
MS m/z(ESI):295.1[M+1]。
The third step
3-methyl-9, 10-dinitro-2, 3,4,4a,5, 6-hexahydro-1H-benzo [ b ] pyrazino [1,2-d ] [1,4] oxazepan 1e
Dissolving compound 1d (890mg, 3.02mmol) in 20mL of methanol, adding 3mL of 37% aqueous formaldehyde solution and three drops of acetic acid, stirring for reaction for 1 hour, adding sodium cyanoborohydride (271.38mg, 4.53mmol), stirring for reaction for 14 hours, concentrating the reaction solution under reduced pressure, and purifying by column chromatography with eluent system a to obtain the title compound 1e (600mg, yield: 60%).
MS m/z(ESI):309.1[M+1]。
The fourth step
1g of ethyl 2- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 9H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) acetate
Dissolving compound 1e (600mg, 1.94mmol), ethyl 3-ethoxy-3-imidopropionate hydrochloride 1f (1.14g, 5.83mmol, shanghai han hong) in 50mL of absolute ethanol, adding 10% palladium-carbon catalyst (200mg), hydrogen replacing, stirring for 14 hours, heating to 70 ℃ for reaction for 2 hours, filtering the reaction solution, concentrating under reduced pressure, and purifying by column chromatography with eluent system A to obtain the title compound 1g (350mg, yield: 52.2%).
MS m/z(ESI):345.2[M+1]。
The fifth step
4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1
Compound 2-aminothiophene-3-carbonitrile was dissolved in 10mL of tetrahydrofuran for 1h (65mg, 523.50. mu. mol), 1g (120mg, 348.42. mu. mol) of compound was added to a 2M tetrahydrofuran solution of lithium diisopropylamide for reaction with stirring for 14 hours, and then concentrated under reduced pressure, followed by purification by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30. mu.150 mm, 5. mu.m; mobile phase 1: water (10mmol/L ammonium hydrogencarbonate); mobile phase 2: acetonitrile, 20-minute gradient ratio: 25% -42%, flow rate: 30mL/min) to give the title compound 1(10mg, yield: 6.79%).
MS m/z(ESI):423.2[M+1]。
1 H NMR(500MHz,DMSO-d 6 ):δ12.59(d,1H),12.08(s,1H),10.63(d,1H),7.96(s,1H),7.59(dd,1H),7.33-7.01(m,3H),4.49-4.36(m,1H),4.09-4.02(m,1H),3.18(m,1H),3.11(m,1H),3.00-2.74(m,3H),2.29(s,3H),2.08-1.95(m,2H),1.73(t,2H)。
Examples 1-1, 1-2
(R) -4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1-1
(S) -4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1-2
(R) -4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1-1
(S) -4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1-2
Compound 1(180mg, 426.54. mu. mol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IE20 x 250mm, 5. mu.m; mobile phase 1: n-hexane; mobile phase 2: ethanol (10mmol/L ammonia) flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title compounds 1-1(70mg, yield: 8.1%), 1-2(65mg, yield: 8.1%).
Single configuration compound 1-1 (shorter retention time):
MS m/z(ESI):423.2[M+1]。
chiral HPLC analysis: retention time 12.19 min, chiral purity: 98% (chromatographic column: CHIRALPAK IE 4.6.6X 150mm,5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), ethanol 80% elution, flow rate: 1.0 mL/min).
1 H NMR(500MHz,DMSO-d 6 ) Δ 12.59(d,1H),12.11(s,1H),10.63(d,1H),7.96(s,1H),7.59(dd,1H),7.33-7.01(m,3H),4.47-4.43(m,1H),4.07-4.05(m,1H),3.17(m,1H),3.12(m,1H),3.03-2.74(m,3H),2.29(s,3H),2.08-1.95(m,2H),1.73(t, 2H). Single configuration compounds 1-2 (longer retention time):
MS m/z(ESI):423.2[M+1]。
chiral HPLC analysis: retention time 15.64 min, chiral HPLC analysis: chiral purity: 95% (chromatographic column: CHIRALPAK IE 4.6.6X 150mm,5 μm; mobile phase: n-hexane, ethanol (containing 0.1% diethylamine), 80% ethanol elution, flow rate: 1.0 mL/min).
1 H NMR(500MHz,DMSO-d 6 ):δ12.60(d,1H),12.08(s,1H),10.63(d,1H),7.95(s,1H),7.58(dd,1H),7.18-7.02(m,3H),4.45-4.40(m,1H),4.07-4.03(m,1H),3.18(m,1H),3.11(m,1H),3.00-2.77(m,3H),2.29(s,3H),2.08-1.95(m,2H),1.73(t,2H)。
Example 2
4-amino-3- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) quinolin-2 (1H) -one 2
Using the synthetic route in example 1, the starting compound of the fifth step, 1h, was replaced with the compound 2-aminobenzonitrile to obtain the title compound 2(10mg, yield: 10.33%).
MS m/z(ESI):417.2[M+1]。
1 H NMR(500MHz,CD 3 OD):δ8.11(dd,1H),7.60(ddd,1H),7.39-7.34(m,1H),7.33-7.11(m,3H),4.62-4.47(m,1H),4.14(dt,1H),3.23(s,2H),3.00(s,2H),2.80(d,1H),2.52(s,1H),2.44(s,4H),2.15(s,1H),1.76(d,1H)。
Example 3
4-amino-5-fluoro-3- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) quinolin-2 (1H) -one 3
(R) -4-amino-5-fluoro-3- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) quinolin-2 (1H) -one 3-1
(S) -4-amino-5-fluoro-3- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) quinolin-2 (1H) -one 3-2
Using the synthetic route in example 1, the compound of the starting material 1h was replaced with the compound 2-amino-6-fluorobenzonitrile 3a in the fifth step to give the title compound 3(40mg, yield: 7.9%), followed by chiral preparation (separation conditions: apparatus: GILSON 281; column: CHIRALPAK IE 250X 20mm, 5 μm; mobile phase: ethanol (containing 0.1% diethylamine): 100%), and the corresponding fractions were collected and concentrated under reduced pressure to give the title compound 3-1(10mg, yield: 1.98%), 3-2(7mg, yield: 1.38%).
Single configuration compound 3-1 (shorter retention time):
MS m/z(ESI):435.2[M+1]。
chiral HPLC analysis: retention time 29.01 min, purity: 94% (column: CHIRALPAK IE 150)4.6mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), flow rates: 1.0 mL/min). 1 H NMR(500MHz,CD 3 OD):δ7.55(td,1H),7.31-7.09(m,3H),7.01(dd,1H),4.59-4.48(m,1H),4.14(dt,1H),3.32-3.23(m,3H),3.00(s,2H),2.80(d,1H),2.51(t,1H),2.44(s,3H),2.15(s,1H),1.76(d,1H)。
Single configuration compound 3-2 (longer retention time):
MS m/z(ESI):435.2[M+1]。
chiral HPLC analysis: retention time 37.89 minutes, purity: 90% (column: CHIRALPAK IE150 x 4.6mm, 5 μm; mobile phase: n-hexane, ethanol (containing 0.1% diethylamine) flow rate: 1.0 mL/min). 1 H NMR(500MHz,CD 3 OD):δ7.55(td,1H),7.32-7.10(m,3H),7.01(dd,1H),4.61-4.49(m,1H),4.14(dt,1H),3.27(s,3H),3.01(s,2H),2.81(d,1H),2.53(t,1H),2.45(s,3H),2.15(s,1H),1.76(d,1H)。
Example 4
4-amino-5- (2,3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 4
(R) -4-amino-5- (2,3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 4-1
(S) -4-amino-5- (2,3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 4-2
First step of
10- (2-ethoxy-2-oxyethyl) -1,2,4,4a,5, 6-hexahydro-3H, 9H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-3-carboxylic acid tert-butyl ester 4a
Dissolving compound 1c (600mg, 1.94mmol), compound 1f (1.14g, 5.83mmol, shanghai han hong) in absolute ethanol (50mL), adding 10% palladium-carbon catalyst (wet) (200mg), hydrogen gas displacing, stirring for 14 hours, heating to 70 deg.C for 2 hours, filtering the reaction solution, concentrating under reduced pressure, purifying by column chromatography with eluent system A to obtain the title compound 4a (350mg, yield: 52.2%).
MS m/z(ESI):431.2[M+1]。
Second step of
10- (4-amino-6-oxo-6, 7-dihydrothieno [2,3-b ] pyridin-5-yl) -1,2,4,4a,5, 6-hexahydro-3H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-3-carboxylic acid tert-butyl ester 4b
Compound 1h (65mg, 523.50. mu. mol), Compound 4a (120mg, 348.42. mu. mol) were dissolved in tetrahydrofuran (10mL), a 2.0M solution of lithium diisopropylamide in tetrahydrofuran (1.16mL) was added, the reaction was stirred for 14 hours and concentrated under reduced pressure, and column chromatography was performed to purify the title compound 4b (10mg, yield: 6.79%) using eluent system A.
MS m/z(ESI):509.2[M+1]。
The third step
(R) -4-amino-5- (2,3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 4-1
(S) -4-amino-5- (2,3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 4-2
Compound 4b (200mg, 393.2. mu. mol) was dissolved in dichloromethane (20mL), trifluoroacetic acid was added in an amount of 5mL and reacted at room temperature for 0.5 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30: 150mM, 5. mu.m; mobile phase: water (10mmol/L ammonium hydrogencarbonate) and acetonitrile, gradient ratio: acetonitrile 38% -45%, flow rate: 30mL/min) to give the title compound 4(80mg, yield: 49.5%), followed by chiral preparation (separation condition: apparatus: GILSON 281; column: CHIRALPAK IE 20: 250mM, 5. mu.m; mobile phase: n-hexane; ethanol (10mM ammonia), flow rate: 20mL/min), the corresponding fractions were collected, concentrated under reduced pressure to give the title compound 4-1(25mg, yield: 31.2%), 4-2(25mg, yield: 31.2%).
Single configuration compound 4-1 (shorter retention time):
MS m/z(ESI):409.2[M+1]。
chiral HPLC analysis: retention time 10.1 min, purity: 95% (column: CHIRALPAK IE20 × 250mm, 5 μm); mobile phase: n-hexane; ethanol (10mM ammonia), flow rate: 20 mL/min).
1 H NMR(500MHz,DMSO-d 6 ):δ12.60(d,1H),10.63(d,1H),7.96(s,1H),7.58(dd,1H),7.18-7.02(m,3H),4.45-4.40(m,1H),3.06-3.00(m,4H),2.93-2.84(m,3H),2.02-1.96(m,2H),1.76-1.72(m,1H)。
Single configuration compound 4-2 (longer retention time):
MS m/z(ESI):409.2[M+1]。
chiral HPLC analysis: retention time 15.34 minutes, purity: 95% (column: CHIRALPAK IE20 × 250mm, 5 μm); mobile phase: n-hexane; ethanol (10mM ammonia), flow rate: 20 mL/min).
1 H NMR(500MHz,DMSO-d 6 ):δ12.60-12.58(d,1H),10.64-10.60(d,1H),7.96(s,1H),7.59-7.57(dd,1H),7.18-7.01(m,3H),4.48-4.40(m,1H),3.03-3.00(m,4H),2.93-2.84(m,3H),1.98-1.96(m,2H),1.72-1.67(m,1H)。
Biological evaluation
Test example 1 detection of enzyme Activity of HPK1 (ADP-Glo method)
1. Reagent and apparatus
1) ADP-Glo Kinase Assay Kit (including ADP-Glo Reagent and Kinase Detection Reagent)
(Promega,V9101)
2)1M Tris-HCl buffer pH 7.5 (Solibao, T1140)
3)1M MgCl 2 (Invitrogen,AM9530G)
4)1M DTT(Thermofisher,P2325)
5)20mg/mL Bovine Serum Albumin(BSA)(TAKARA 2320)
6) ATP solution (10mM) (Thermofisiher PV3227)
7) Dephosphorylated MBP (Sigma,13-110) (hereinafter referred to as MBP)
8)HPK1(Signalchem,M23-11G)
9)96-well low volume white plate(Cisbio,66PL96100)
10) PHERA star microplate reader (BMG labtech)
2. Experimental methods
2.1 reagent preparation
Assay buffer 40mM Tris-HCl buffer, 7.5; 20mM MgCl 2 ;0.1mg/mL BSA;50μM
DTT;
Hpk1 enzyme solution: preparing HPK1 enzyme solution with the final concentration of 1.5 ng/. mu.L by using the assay buffer;
atp and MBP mixed substrates: respectively preparing ATP with the final concentration of 60 mu M and MBP with the final concentration of 0.6 ug/mu L by using the assay buffer, and mixing the prepared ATP and MBP in equal volume;
d. a compound: initial concentration 33.3. mu.M, 3-fold dilution, 9 concentration gradients. Assay for all concentrations of the Compound
The buffer is diluted 33.3 times for standby.
2.2 Experimental procedures
A.96 well plates were loaded with 2. mu.L of the prepared HPK1 enzyme solution per well, no enzyme in column 1, and 2. mu.L of the assay buffer.
b. Add 2. mu.L of compound to each well, no compound to column 1 and last 1, add DMSO as a control, centrifuge, mix well and shake for 2 minutes, incubate for 10 minutes at room temperature.
c. Add 2. mu.L ATP and MBP mixture substrate to each well, centrifuge, mix well and shake for 2 minutes, incubate for 60 minutes at room temperature.
d. Add 6. mu.L ADP-Glo Reagent to each well, centrifuge, mix well and shake for 2 minutes, incubate for 40 minutes at room temperature.
e. Add 12. mu.L of enzyme Detection Reagent (Kinase Detection Reagent) to each well, centrifuge, mix well and shake for 2 minutes, incubate for 40 minutes at room temperature.
f. The microplate reader reads the plate and records the RLU (relative luminescence unit) value.
graph software mapping, calculating Compound IC 50 Values, see table 1.
TABLE 1 inhibition of HPK1 enzymatic Activity IC by Compounds of the present disclosure 50 Value of
Example numbering | HPK1/IC 50 (nM) |
1 | 0.5 |
1-1 | 0.4 |
1-2 | 0.6 |
2 | 0.7 |
3-1 | 2.4 |
3-2 | 10.5 |
4 | 1.0 |
4-2 | 1.1 |
And (4) conclusion: the disclosed compound has obvious inhibition effect on the activity of HPK1 enzyme.
Test example 2 Jurkat cell SLP76 protein phosphorylation assay (HTRF method)
1. Reagent and apparatus
1) RPMI1640 medium (Gibco,61870044)
2) Total bone Serum (Gibco,10099141C) (hereinafter referred to as FBS)
3)75cm 2 Filter cap cell culture bottle (Corning,430641)
4)PBS,pH 7.4(Gibco,10010049)
5)CD3 Antibody,anti-human,pure-functional grade(Miltenyi Biotec,130-093-387)
6)Phospho-SLP-76(Ser376)cellular kit(Cisbio,63ADK076PEG)
7)HTRF 96well low volume plate(Cisbio,66PL96100)
8)96-well plate(Corning,3788)
9) Micropore plate oscillator (Leibeier)
10) PHERA star microplate reader (BMG labtech)
11) Countstar BioMed automatic cell counter (Shanghai Rui Yu biological technology)
12) Clean bench (Thermo,1300ALL)
13)CO 2 Incubator (Thermo, I160)
2. Cells and culture method
Jurkat E6-1 cells were purchased from American type culture Collection (ATCC, TIB-152) and cultured in RPMI1640 medium (10% FBS). Cell culture density was maintained at 2X 10 5 To 2X 10 6 cells/mL, 2-3 passages a week.
3. Preparation of Compounds
a. Test compounds were dissolved to 5mM in DMSO.
b. Compound starting concentration 5mM, 3-fold dilution, 10 concentration gradients.
c. All concentrations of compounds were diluted 100-fold with culture broth and ready for use.
4. Experimental procedure
Jurkat cell count, cell density adjusted to 5X 10 with fresh medium 6 /mL。
b.96 well plates, 20. mu.L of cells were seeded per well and cultured at 37 ℃ for 4 hours.
c. mu.L of compound (5. mu.L of 0.5% DMSO in columns 1 and 12) was added to each well and incubated at 37 ℃ for 1 hour.
d. The CD3 Antibody (CD3 Antibody) was diluted to 20 ng/. mu.L in culture medium, 5. mu.L was added to each well (column 1 plus 5. mu.L of culture medium as a control), and the mixture was incubated at 37 ℃ for half an hour.
e. Cells were lysed by adding 10. mu.L of lysis buffer per well and vortexed at 850rpm for half an hour at room temperature.
f. 16 μ L of cell lysate was transferred to a fresh HTRF 96 well plate, 4 μ L of antibody mix was added to each well and left overnight at room temperature.
g. The plate was read by the microplate reader and signals at 665nm and 620nm were recorded.
Graph software mapping, calculate compound IC 50 Values, see table 2.
TABLE 2 inhibition of SLP76 protein phosphorylation by Compounds of the disclosure IC 50 Value of
Example numbering | SLP76 protein phosphorylation/IC 50 (nM) |
1 | 65 |
1-1 | 31 |
1-2 | 84 |
2 | 40 |
3-1 | 92.8 |
4 | 83.4 |
4-1 | 27.5 |
4-2 | 72 |
And (4) conclusion: the compound disclosed by the invention has obvious inhibition effect on protein phosphorylation of SLP76 of Jurkat cells.
Claims (19)
1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
ring a is selected from aryl, heterocyclyl and heteroaryl;
T 1 is CR T1 Or a nitrogen atom;
G 3 and G 4 Are the same or different and are each independently CR 1 Or a nitrogen atom;
G 8 is CR G8 Or a nitrogen atom;
G 1 and G 2 Are the same or different and are each independently selected from CR 2 、NR 3 Nitrogen atom, oxygen atom and sulfur atom;
G 5 and G 6 Are the same or different and are each independently selected from CR 4 R 5 、NR 6 Oxygen atom and sulfur atom;
G 7 selected from the group consisting of CR G7a R G7b 、NR G7c Oxygen atom and sulfur atom;
G 9 selected from the group consisting of CR G9a R G9b 、NR G9c Oxygen atom and sulfur atom;
r is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl; or
Two R together form oxo;
R 0 、R 3 、R 6 、R G7c and R G9c Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
R’、R 1 、R T1 、R G8 and R 2 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 、-OR 9 Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4 、R 5 、R G7a 、R G7b 、R G9a and R G9b The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyls, alkenyls, alkynyls, alkoxys, cycloalkyls, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or
R 4 And R 5 、R G7a And R G7b Or R G9a And R G9b Wherein a pair together form an oxo group;
R 7 and R 8 Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; or
R 7 And R 8 Together with the nitrogen atom to which it is attached, form a heterocyclyl optionally substituted with one or more of halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;
R 9 selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
m is 0, 1,2,3 or 4;
q is 0, 1,2,3 or 4; and is
n is 0, 1,2,3, 4,5 or 6.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, whereinIs composed ofT 3 Is CR T3 Or a nitrogen atom, T 5 、T 6 And T 7 Are the same or different and are each independently CR 10 Or a nitrogen atom;
T 2 and T 4 Are the same or different and are each independently selected from CR 11 、NR 12 Nitrogen atom, oxygen atom and sulfur atom;
R 10 、R T3 and R 11 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) m NR 7 R 8 、-OR 9 Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, whereinSaid alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 12 selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
R 7 、R 8 、R 9 and m is as defined in claim 1.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein G 5 Is CR 4 R 5 Or an oxygen atom; and/or G 6 Is CR 4 R 5 Or an oxygen atom; preferably, G 5 And G 6 One of them is CR 4 R 5 And the other is an oxygen atom; r 4 And R 5 As defined in claim 1.
5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein G is 9 Is NR G9c ,R G9c Is a hydrogen atom or C 1-6 An alkyl group; preferably, G 9 Is NCH 3 。
6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein G is 3 Is CR 1 (ii) a And/or G 4 Is CR 1 ;R 1 As defined in claim 1.
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein T 1 Is CR T1 ;R T1 As defined in claim 1; preferably, T 1 Is C-NH 2 。
8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is the same or different and each is independently selected from the group consisting of hydrogen, halogen and C 1-6 An alkyl group; preferably, R is a hydrogen atom.
9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R' are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, and C 1-6 An alkyl group; preferably, R' is a hydrogen atom or a halogen.
10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.
11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
15. a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises:
carrying out cyclization reaction on the compound of the general formula (IA) or salt thereof and the compound of the general formula (IB) or salt thereof to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;
wherein: r w Is an alkyl group;
T 1 is C-NH 2 ;
Ring A, R 0 、R’、q、G 1 To G 9 R and n are as defined in claim 1.
16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
17. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for inhibiting HPK 1.
18. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and diseases or conditions of reproductive disorders.
19. The use of claim 18, wherein the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, hiv infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke, and alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma; the uterine cancer is preferably endometrial cancer.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110184822X | 2021-02-10 | ||
CN202110184822 | 2021-02-10 | ||
CN2021106052508 | 2021-05-31 | ||
CN202110605250 | 2021-05-31 | ||
CN2021108590149 | 2021-07-28 | ||
CN202110859014 | 2021-07-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114907377A true CN114907377A (en) | 2022-08-16 |
Family
ID=82763330
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210122528.0A Pending CN114907377A (en) | 2021-02-10 | 2022-02-09 | Condensed tetracyclic compound, preparation method and medical application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114907377A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11897878B2 (en) | 2018-10-31 | 2024-02-13 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
US11925631B2 (en) | 2018-10-31 | 2024-03-12 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
US12037342B2 (en) | 2019-05-23 | 2024-07-16 | Gilead Sciences, Inc. | Substituted eneoxindoles and uses thereof |
-
2022
- 2022-02-09 CN CN202210122528.0A patent/CN114907377A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11897878B2 (en) | 2018-10-31 | 2024-02-13 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
US11925631B2 (en) | 2018-10-31 | 2024-03-12 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
US12037342B2 (en) | 2019-05-23 | 2024-07-16 | Gilead Sciences, Inc. | Substituted eneoxindoles and uses thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP4361157A1 (en) | Fused tetracyclic compound, preparation method therefor and application thereof in medicine | |
WO2021203768A1 (en) | Pyrimido dicyclo derivative, preparation method therefor and use thereof in medicine | |
CN114907377A (en) | Condensed tetracyclic compound, preparation method and medical application thereof | |
JP2024519188A (en) | Nitrogen-containing heterocyclic compounds, their preparation method and medical applications | |
TW202102505A (en) | A pyrroloheterocyclic derivative and preparation method and medical use thereof | |
CN117203207A (en) | Bridged ring compound, preparation method thereof and application thereof in medicine | |
CN113980032A (en) | Condensed tetracyclic derivative, preparation method and application thereof in medicine | |
CN115403595A (en) | Nitrogen-containing heterocyclic compound, preparation method and medical application thereof | |
CN116199703A (en) | Fused tetracyclic heterocyclic compound, preparation method thereof and application thereof in medicine | |
CN115385938A (en) | Benzopyrimidine compounds, preparation method thereof and application thereof in medicines | |
CN115368383A (en) | Condensed nitrogen-containing heterocyclic compound, preparation method and medical application thereof | |
WO2022017365A1 (en) | Sulfur-containing isoindoline derivative, and preparation method therefor and medical use thereof | |
CN114907349A (en) | Fused azatricyclo derivatives, preparation method and application thereof in medicines | |
CN115073472A (en) | Condensed bicyclic compound, preparation method and application thereof in medicine | |
TW202325298A (en) | A nitrogen-containing tetracyclic compound, a preparation method and medical use thereof | |
CN112996783B (en) | 2-aminopyrimidine derivatives, preparation method and application thereof in medicines | |
TW202241872A (en) | Cyclohexadiimide derivatives substituted by fused heterocyclyl, preparation method and medical use thereof | |
CN114907340A (en) | Fused azatricyclo derivatives, preparation method and application thereof in medicines | |
CN114456173B (en) | Condensed ring group substituted cyclohexanediimide derivative, preparation method and medical application thereof | |
CN116981666A (en) | Fused tetracyclic compound, preparation method thereof and application thereof in medicines | |
CN113912608B (en) | Pyrimidopyrimidinone derivatives, preparation method thereof and application thereof in medicines | |
CN113135942B (en) | Condensed pyrimidine derivative, preparation method and medical application thereof | |
CN115385937A (en) | Pyrimido-cycloalkyl compounds, preparation method and medical application thereof | |
CN114907406A (en) | Pyrimidine derivative, preparation method thereof and application thereof in medicine | |
CN116640154A (en) | Polycyclic compounds, process for their preparation and their use in medicine |
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 |