TWI529170B - 作為ｐｉｍ激酶抑制劑之三唑并吡啶化合物 - Google Patents
作為ｐｉｍ激酶抑制劑之三唑并吡啶化合物 Download PDFInfo
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- TWI529170B TWI529170B TW101106629A TW101106629A TWI529170B TW I529170 B TWI529170 B TW I529170B TW 101106629 A TW101106629 A TW 101106629A TW 101106629 A TW101106629 A TW 101106629A TW I529170 B TWI529170 B TW I529170B
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- Prior art keywords
- alkyl
- alkoxy
- formula
- compound
- methyl
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- -1 Triazolopyridine compound Chemical class 0.000 title claims description 285
- 229940122016 Pim kinase inhibitor Drugs 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims description 358
- 125000000217 alkyl group Chemical group 0.000 claims description 357
- 125000003545 alkoxy group Chemical group 0.000 claims description 246
- 150000001875 compounds Chemical class 0.000 claims description 236
- 239000000203 mixture Substances 0.000 claims description 106
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 95
- 238000006243 chemical reaction Methods 0.000 claims description 82
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 76
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 150000003839 salts Chemical class 0.000 claims description 71
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 59
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 51
- 239000012453 solvate Substances 0.000 claims description 49
- 238000011282 treatment Methods 0.000 claims description 47
- 239000002585 base Substances 0.000 claims description 45
- 229910052731 fluorine Inorganic materials 0.000 claims description 42
- 125000001153 fluoro group Chemical group F* 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 38
- 101001001642 Xenopus laevis Serine/threonine-protein kinase pim-3 Proteins 0.000 claims description 37
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 33
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 33
- 206010028980 Neoplasm Diseases 0.000 claims description 32
- 201000006417 multiple sclerosis Diseases 0.000 claims description 31
- 125000004429 atom Chemical group 0.000 claims description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims description 29
- 208000023275 Autoimmune disease Diseases 0.000 claims description 28
- 150000001412 amines Chemical class 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 25
- 101100297651 Mus musculus Pim2 gene Proteins 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 23
- 101100297652 Coturnix japonica PIM3 gene Proteins 0.000 claims description 22
- 201000011510 cancer Diseases 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
- 239000011737 fluorine Substances 0.000 claims description 17
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 208000027866 inflammatory disease Diseases 0.000 claims description 16
- 241000124008 Mammalia Species 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000005647 linker group Chemical group 0.000 claims description 13
- 206010025135 lupus erythematosus Diseases 0.000 claims description 13
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 238000005859 coupling reaction Methods 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 230000002757 inflammatory effect Effects 0.000 claims description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 10
- 125000006242 amine protecting group Chemical group 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 108091000080 Phosphotransferase Proteins 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 102000020233 phosphotransferase Human genes 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- PBVFROWIWWGIFK-UHFFFAOYSA-N fluoromethyl-(2-hydroxyethyl)-dimethylazanium Chemical compound FC[N+](C)(C)CCO PBVFROWIWWGIFK-UHFFFAOYSA-N 0.000 claims description 5
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- FIURNUKOIGKIJB-UHFFFAOYSA-N 5-methyl-1,3-dioxan-2-one Chemical compound CC1COC(=O)OC1 FIURNUKOIGKIJB-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 5
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 125000003003 spiro group Chemical group 0.000 claims 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 2
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 239000001294 propane Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 496
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 258
- 235000019439 ethyl acetate Nutrition 0.000 description 216
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 153
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 117
- 230000002829 reductive effect Effects 0.000 description 101
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 81
- 239000007787 solid Substances 0.000 description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 79
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 59
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 57
- 239000012267 brine Substances 0.000 description 56
- 239000011541 reaction mixture Substances 0.000 description 55
- 201000010099 disease Diseases 0.000 description 53
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 53
- 239000012044 organic layer Substances 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- WXFAZCYUMXZXBA-UHFFFAOYSA-N 8-methoxyquinoline-2-carbaldehyde Chemical compound C1=C(C=O)N=C2C(OC)=CC=CC2=C1 WXFAZCYUMXZXBA-UHFFFAOYSA-N 0.000 description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 238000001816 cooling Methods 0.000 description 45
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 42
- 210000004027 cell Anatomy 0.000 description 39
- 238000003818 flash chromatography Methods 0.000 description 38
- 238000010992 reflux Methods 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
- 229910052938 sodium sulfate Inorganic materials 0.000 description 33
- 235000011152 sodium sulphate Nutrition 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 27
- 239000010410 layer Substances 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- 210000001744 T-lymphocyte Anatomy 0.000 description 25
- 238000004458 analytical method Methods 0.000 description 25
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 24
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 23
- 238000001914 filtration Methods 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 239000001257 hydrogen Substances 0.000 description 19
- 238000000926 separation method Methods 0.000 description 19
- 241000699670 Mus sp. Species 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 17
- MLPVBIWIRCKMJV-UHFFFAOYSA-N 2-ethylaniline Chemical compound CCC1=CC=CC=C1N MLPVBIWIRCKMJV-UHFFFAOYSA-N 0.000 description 16
- ZPVSAUSAHRIAQM-UHFFFAOYSA-N 8-ethyl-2-methylquinoline Chemical compound C1=C(C)N=C2C(CC)=CC=CC2=C1 ZPVSAUSAHRIAQM-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 16
- 238000000746 purification Methods 0.000 description 15
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 14
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 14
- KUPHUIFUXRACHJ-UHFFFAOYSA-N 8-propan-2-yloxyquinoline-2-carbaldehyde Chemical compound C1=C(C=O)N=C2C(OC(C)C)=CC=CC2=C1 KUPHUIFUXRACHJ-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 14
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- WPYJKGWLDJECQD-UHFFFAOYSA-N quinoline-2-carbaldehyde Chemical compound C1=CC=CC2=NC(C=O)=CC=C21 WPYJKGWLDJECQD-UHFFFAOYSA-N 0.000 description 14
- 102000004127 Cytokines Human genes 0.000 description 13
- 108090000695 Cytokines Proteins 0.000 description 13
- 101000595531 Homo sapiens Serine/threonine-protein kinase pim-1 Proteins 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 206010057190 Respiratory tract infections Diseases 0.000 description 13
- 102100036077 Serine/threonine-protein kinase pim-1 Human genes 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- 230000001404 mediated effect Effects 0.000 description 13
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
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- 239000000284 extract Substances 0.000 description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 12
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 11
- 238000002965 ELISA Methods 0.000 description 11
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- 238000003556 assay Methods 0.000 description 11
- 210000003719 b-lymphocyte Anatomy 0.000 description 11
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- JSTPXQLNMGIGGW-UHFFFAOYSA-N 8-(cyclopropylmethoxy)quinoline-2-carbaldehyde Chemical compound C12=NC(C=O)=CC=C2C=CC=C1OCC1CC1 JSTPXQLNMGIGGW-UHFFFAOYSA-N 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical group COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 9
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- 238000004440 column chromatography Methods 0.000 description 9
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 9
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- SKKTUOZKZKCGTB-UHFFFAOYSA-N butyl carbamate Chemical compound CCCCOC(N)=O SKKTUOZKZKCGTB-UHFFFAOYSA-N 0.000 description 8
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- 210000002865 immune cell Anatomy 0.000 description 8
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 8
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 8
- BDLLDGUBELPPAD-UHFFFAOYSA-N 8-cyclopropylquinoline-2-carbaldehyde Chemical compound C12=NC(C=O)=CC=C2C=CC=C1C1CC1 BDLLDGUBELPPAD-UHFFFAOYSA-N 0.000 description 7
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- 239000000908 ammonium hydroxide Substances 0.000 description 7
- VALPXRNQZYGXPS-UHFFFAOYSA-N benzyl pyrrolidine-1-carboxylate Chemical compound C1CCCN1C(=O)OCC1=CC=CC=C1 VALPXRNQZYGXPS-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 230000016396 cytokine production Effects 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- UXAWXZDXVOYLII-YUMQZZPRSA-N tert-butyl (1s,4s)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1[C@@H]2N(C(=O)OC(C)(C)C)C[C@H]1NC2 UXAWXZDXVOYLII-YUMQZZPRSA-N 0.000 description 7
- 150000003512 tertiary amines Chemical class 0.000 description 7
- JCZPOYAMKJFOLA-ZXZARUISSA-N (3s,4r)-pyrrolidine-3,4-diol Chemical compound O[C@H]1CNC[C@H]1O JCZPOYAMKJFOLA-ZXZARUISSA-N 0.000 description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 6
- MLJLUBLVRXPCKT-UHFFFAOYSA-N 7-bromo-8-fluoro-2-methylquinoline Chemical compound C1=CC(Br)=C(F)C2=NC(C)=CC=C21 MLJLUBLVRXPCKT-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
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- C07—ORGANIC CHEMISTRY
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| WO2013160273A1 (en) * | 2012-04-25 | 2013-10-31 | F. Hoffmann-La Roche Ag | (3,4-dichloro-phenyl)-((s)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride and manufacturing processes |
| ES2649156T3 (es) | 2013-01-14 | 2018-01-10 | Incyte Holdings Corporation | Compuestos bicíclicos de carboxamida aromática útiles como inhibidores de quinasas Pim |
| ES2941292T3 (es) | 2013-01-15 | 2023-05-19 | Incyte Holdings Corp | Tiazolecarboxamidas y compuestos de piridinecarboxamida útiles como inhibidores de PIM quinasa |
| AR097431A1 (es) | 2013-08-23 | 2016-03-16 | Incyte Corp | Compuestos de carboxamida de furo y tienopiridina útiles como inhibidores de quinasas pim |
| US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
| US9822124B2 (en) | 2014-07-14 | 2017-11-21 | Incyte Corporation | Bicyclic heteroaromatic carboxamide compounds useful as Pim kinase inhibitors |
| WO2016196244A1 (en) | 2015-05-29 | 2016-12-08 | Incyte Corporation | Pyridineamine compounds useful as pim kinase inhibitors |
| AR105967A1 (es) | 2015-09-09 | 2017-11-29 | Incyte Corp | Sales de un inhibidor de pim quinasa |
| US9920032B2 (en) | 2015-10-02 | 2018-03-20 | Incyte Corporation | Heterocyclic compounds useful as pim kinase inhibitors |
| MA45122A (fr) * | 2016-05-24 | 2019-04-10 | Constellation Pharmaceuticals Inc | Inhibiteurs hétérocycliques de cbp/ep300 et leur utilisation dans le traitement du cancer |
| WO2019113487A1 (en) | 2017-12-08 | 2019-06-13 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
| CN117838695A (zh) | 2018-04-13 | 2024-04-09 | 住友制药肿瘤公司 | 用于治疗骨髓增殖性肿瘤和与癌症相关的纤维化的pim激酶抑制剂 |
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| WO2020157709A1 (en) | 2019-02-01 | 2020-08-06 | Pfizer Inc. | Combination of a cdk inhibitor and a pim inhibitor |
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| CN113195469B (zh) * | 2019-02-19 | 2024-05-24 | 四川科伦博泰生物医药股份有限公司 | 含氮并环化合物、其制备方法及用途 |
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