BR112016017981B1 - Compostos derivados de azaindola, inibidor de jak3, composição farmacêutica e agente compreendendo ditos compostos, e uso dos mesmos para tratar uma doença que envolve jak3 - Google Patents

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Publication number

BR112016017981B1

BR112016017981B1 BR112016017981-1A BR112016017981A BR112016017981B1 BR 112016017981 B1 BR112016017981 B1 BR 112016017981B1 BR 112016017981 A BR112016017981 A BR 112016017981A BR 112016017981 B1 BR112016017981 B1 BR 112016017981B1

Authority

BR

Brazil

Prior art keywords

group

compound

substituted

optionally

alkyl

Prior art date

2014-02-04

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 398
• 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 title claims abstract description 32
• 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 title claims abstract description 31
• 201000010099 disease Diseases 0.000 title claims abstract description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 20
• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
• 229940123241 Janus kinase 3 inhibitor Drugs 0.000 title claims description 9
• 239000008177 pharmaceutical agent Substances 0.000 title abstract description 7
• 150000003839 salts Chemical class 0.000 claims abstract description 74
• 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 27
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 17
• 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 16
• -1 1H-pyrazolyl group Chemical class 0.000 claims description 143
• 125000004169 (C1-C6) alkyl group Chemical class 0.000 claims description 107
• 125000000623 heterocyclic group Chemical group 0.000 claims description 107
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 80
• 125000005843 halogen group Chemical group 0.000 claims description 77
• 125000003277 amino group Chemical group 0.000 claims description 74
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 70
• 229920006395 saturated elastomer Polymers 0.000 claims description 66
• 125000000882 C2-C6 alkenyl group Chemical class 0.000 claims description 43
• 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 41
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 39
• 229910052757 nitrogen Inorganic materials 0.000 claims description 35
• 125000002950 monocyclic group Chemical group 0.000 claims description 33
• XTKIUCRGMPJXJD-UHFFFAOYSA-N N-[3-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)cyclohex-3-en-1-yl]prop-2-enamide Chemical compound C1(=CC=CC=C1)C1=CNC2=NC=CC(=C21)C=1CC(CCC=1)NC(C=C)=O XTKIUCRGMPJXJD-UHFFFAOYSA-N 0.000 claims description 32
• 125000004043 oxo group Chemical group O=* 0.000 claims description 30
• 125000003601 C2-C6 alkynyl group Chemical class 0.000 claims description 29
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 26
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
• BNBOVEZUEKTTKM-UHFFFAOYSA-N N-[3-[3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]cyclohex-3-en-1-yl]prop-2-enamide Chemical compound N1N=CC(=C1)C1=CNC2=NC=CC(=C21)C=1CC(CCC=1)NC(C=C)=O BNBOVEZUEKTTKM-UHFFFAOYSA-N 0.000 claims description 23
• 125000000815 N-oxide group Chemical group 0.000 claims description 23
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 23
• 238000004519 manufacturing process Methods 0.000 claims description 23
• 125000005842 heteroatom Chemical group 0.000 claims description 22
• 125000002971 oxazolyl group Chemical class 0.000 claims description 22
• 125000004076 pyridyl group Chemical class 0.000 claims description 22
• 125000002541 furyl group Chemical class 0.000 claims description 21
• 229910052717 sulfur Inorganic materials 0.000 claims description 21
• 229910052760 oxygen Inorganic materials 0.000 claims description 20
• 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• 125000000335 thiazolyl group Chemical class 0.000 claims description 19
• 125000001781 1,3,4-oxadiazolyl group Chemical class 0.000 claims description 18
• 125000004520 1,3,4-thiadiazolyl group Chemical class 0.000 claims description 18
• 125000000842 isoxazolyl group Chemical class 0.000 claims description 18
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• 125000004504 1,2,4-oxadiazolyl group Chemical class 0.000 claims description 16
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
• 125000000596 cyclohexenyl group Chemical class C1(=CCCCC1)* 0.000 claims description 16
• 125000002433 cyclopentenyl group Chemical class C1(=CCCC1)* 0.000 claims description 16
• 125000004852 dihydrofuranyl group Chemical class O1C(CC=C1)* 0.000 claims description 16
• 125000006376 (C3-C10) cycloalkyl group Chemical class 0.000 claims description 15
• 125000005043 dihydropyranyl group Chemical class O1C(CCC=C1)* 0.000 claims description 15
• BDRSFADBPYMDRE-UHFFFAOYSA-N N-[3-[3-(2-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]cyclohex-3-en-1-yl]prop-2-enamide Chemical compound COC1=NC=CC=C1C1=CNC2=NC=CC(=C21)C=1CC(CCC=1)NC(C=C)=O BDRSFADBPYMDRE-UHFFFAOYSA-N 0.000 claims description 13
• 208000009329 Graft vs Host Disease Diseases 0.000 claims description 11
• 208000024908 graft versus host disease Diseases 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 10
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 9
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
• 239000003795 chemical substances by application Substances 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 201000011510 cancer Diseases 0.000 claims description 7
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
• 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 6
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
• XFTGKNXBMAMHRM-UHFFFAOYSA-N N-[3-[3-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]cyclohex-3-en-1-yl]prop-2-enamide Chemical compound O1C(=NN=C1)C1=CNC2=NC=CC(=C21)C=1CC(CCC=1)NC(C=C)=O XFTGKNXBMAMHRM-UHFFFAOYSA-N 0.000 claims description 6
• KQVAGNCPVKHVCN-UHFFFAOYSA-N N-[3-[3-(furan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]cyclohex-3-en-1-yl]prop-2-enamide Chemical compound O1C(=CC=C1)C1=CNC2=NC=CC(=C21)C=1CC(CCC=1)NC(C=C)=O KQVAGNCPVKHVCN-UHFFFAOYSA-N 0.000 claims description 6
• 201000004681 Psoriasis Diseases 0.000 claims description 6
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 6
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 5
• 208000023275 Autoimmune disease Diseases 0.000 claims description 5
• 208000015943 Coeliac disease Diseases 0.000 claims description 5
• 208000035473 Communicable disease Diseases 0.000 claims description 5
• 206010012442 Dermatitis contact Diseases 0.000 claims description 5
• DADPKXFXEMGZEU-UHFFFAOYSA-N N-[3-[3-[4-(hydroxymethyl)furan-2-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]cyclohex-3-en-1-yl]prop-2-enamide Chemical compound OCC=1C=C(OC=1)C1=CNC2=NC=CC(=C21)C=1CC(CCC=1)NC(C=C)=O DADPKXFXEMGZEU-UHFFFAOYSA-N 0.000 claims description 5
• 206010052779 Transplant rejections Diseases 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• 208000026935 allergic disease Diseases 0.000 claims description 5
• 208000010247 contact dermatitis Diseases 0.000 claims description 5
• 206010012601 diabetes mellitus Diseases 0.000 claims description 5
• 208000015181 infectious disease Diseases 0.000 claims description 5
• 230000003612 virological effect Effects 0.000 claims description 5
• NKVHCPHXVBDHHM-UHFFFAOYSA-N N-[3-[3-(1,3-oxazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]cyclohex-3-en-1-yl]prop-2-enamide Chemical compound O1C=NC=C1C1=CNC2=NC=CC(=C21)C=1CC(CCC=1)NC(C=C)=O NKVHCPHXVBDHHM-UHFFFAOYSA-N 0.000 claims description 4
• AWBYWCWAFOGCLC-UHFFFAOYSA-N N-[3-[3-(2,5-dihydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]cyclohex-3-en-1-yl]prop-2-enamide Chemical compound O1CC(=CC1)C1=CNC2=NC=CC(=C21)C=1CC(CCC=1)NC(C=C)=O AWBYWCWAFOGCLC-UHFFFAOYSA-N 0.000 claims description 4
• 208000012902 Nervous system disease Diseases 0.000 claims description 4
• 229910052705 radium Inorganic materials 0.000 claims description 4
• 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 3
• VDBLHBHEFIDWDQ-UHFFFAOYSA-N N-[3-[3-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]cyclopent-3-en-1-yl]prop-2-enamide Chemical compound O1C(=NN=C1)C1=CNC2=NC=CC(=C21)C=1CC(CC=1)NC(C=C)=O VDBLHBHEFIDWDQ-UHFFFAOYSA-N 0.000 claims description 3
• 201000005787 hematologic cancer Diseases 0.000 claims description 3
• 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 2
• 206010066476 Haematological malignancy Diseases 0.000 claims 1
• 230000001363 autoimmune Effects 0.000 claims 1
• 210000000653 nervous system Anatomy 0.000 claims 1
• 230000000694 effects Effects 0.000 abstract description 21
• 125000005334 azaindolyl group Chemical class N1N=C(C2=CC=CC=C12)* 0.000 abstract description 13
• 238000010521 absorption reaction Methods 0.000 abstract description 3
• 239000000203 mixture Substances 0.000 description 273
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 240
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 234
• 239000011541 reaction mixture Substances 0.000 description 187
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 172
• 239000000047 product Substances 0.000 description 110
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 108
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 106
• 239000000243 solution Substances 0.000 description 97
• 238000006243 chemical reaction Methods 0.000 description 96
• 230000002829 reductive effect Effects 0.000 description 93
• 238000005160 1H NMR spectroscopy Methods 0.000 description 90
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
• 238000000034 method Methods 0.000 description 86
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 81
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 80
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
• 238000010898 silica gel chromatography Methods 0.000 description 69
• 239000012044 organic layer Substances 0.000 description 68
• 238000000746 purification Methods 0.000 description 63
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 58
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 56
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 52
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 51
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
• 239000007864 aqueous solution Substances 0.000 description 51
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 43
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
• 239000002904 solvent Substances 0.000 description 41
• 125000001424 substituent group Chemical group 0.000 description 38
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 36
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
• 238000005859 coupling reaction Methods 0.000 description 31
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 29
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 28
• 235000017557 sodium bicarbonate Nutrition 0.000 description 28
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
• 230000008878 coupling Effects 0.000 description 27
• 238000010168 coupling process Methods 0.000 description 27
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 26
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
• 238000010790 dilution Methods 0.000 description 24
• 239000012895 dilution Substances 0.000 description 24
• HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 22
• 238000000926 separation method Methods 0.000 description 22
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
• 238000002955 isolation Methods 0.000 description 20
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 20
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
• 239000002585 base Substances 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• 235000019270 ammonium chloride Nutrition 0.000 description 18
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• 230000002401 inhibitory effect Effects 0.000 description 18
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• WORJEOGGNQDSOE-ASTXPPQBSA-N trichloro(deuterio)methane;trideuterio(deuteriooxy)methane Chemical compound [2H]C(Cl)(Cl)Cl.[2H]OC([2H])([2H])[2H] WORJEOGGNQDSOE-ASTXPPQBSA-N 0.000 description 17
• UCNGGGYMLHAMJG-UHFFFAOYSA-N 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C)C=C1B1OC(C)(C)C(C)(C)O1 UCNGGGYMLHAMJG-UHFFFAOYSA-N 0.000 description 16
• 108090000765 processed proteins & peptides Proteins 0.000 description 16
• 235000011121 sodium hydroxide Nutrition 0.000 description 16
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
• 239000002253 acid Chemical group 0.000 description 15
• QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 14
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• SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 14
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• WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 13
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
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• 125000006239 protecting group Chemical group 0.000 description 13
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 12
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• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
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• GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 12
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• 230000035484 reaction time Effects 0.000 description 12
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• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
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• 125000000217 alkyl group Chemical group 0.000 description 11
• XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 11
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• PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 11
• YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 10
• JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 10
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• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
• 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 10
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• IUKYKMHCKDLTJC-DTWKUNHWSA-N tert-butyl n-[(1s,3r)-3-hydroxycyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](O)C1 IUKYKMHCKDLTJC-DTWKUNHWSA-N 0.000 description 1
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• 238000010998 test method Methods 0.000 description 1
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• 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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• 125000003831 tetrazolyl group Chemical group 0.000 description 1
• 125000004149 thio group Chemical group *S* 0.000 description 1
• 150000003606 tin compounds Chemical class 0.000 description 1
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• 230000007704 transition Effects 0.000 description 1
• GOWNSHUNTJWVOM-UHFFFAOYSA-N tributyl(1,3-thiazol-5-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CN=CS1 GOWNSHUNTJWVOM-UHFFFAOYSA-N 0.000 description 1
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• TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
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• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
• VHNLOVHBZCOTDI-UHFFFAOYSA-K tripyrrolidin-1-yl(triazolo[4,5-b]pyridin-3-yloxy)phosphanium phosphate Chemical compound [O-]P([O-])([O-])=O.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=NC=CC=C2N=N1.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=NC=CC=C2N=N1.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=NC=CC=C2N=N1 VHNLOVHBZCOTDI-UHFFFAOYSA-K 0.000 description 1
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• DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 1
• 125000005500 uronium group Chemical group 0.000 description 1
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• 210000000707 wrist Anatomy 0.000 description 1