ES2968222T3 - Agentes inhibidores para la tirosina cinasa de Bruton - Google Patents

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Publication number

ES2968222T3

ES2968222T3 ES19732766T ES19732766T ES2968222T3 ES 2968222 T3 ES2968222 T3 ES 2968222T3 ES 19732766 T ES19732766 T ES 19732766T ES 19732766 T ES19732766 T ES 19732766T ES 2968222 T3 ES2968222 T3 ES 2968222T3

Authority

ES

Spain

Prior art keywords

alkyl

methyl

membered monocyclic

amino

occurrence

Prior art date

2018-05-14

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.)

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• 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title claims abstract description 6
• 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title claims abstract 3
• 230000002401 inhibitory effect Effects 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 160
• 150000003839 salts Chemical class 0.000 claims abstract description 88
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 120
• 125000005843 halogen group Chemical group 0.000 claims description 89
• 125000000217 alkyl group Chemical group 0.000 claims description 69
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 67
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 60
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
• 125000003342 alkenyl group Chemical group 0.000 claims description 34
• 229920006395 saturated elastomer Polymers 0.000 claims description 32
• 125000000304 alkynyl group Chemical group 0.000 claims description 29
• 229910052731 fluorine Inorganic materials 0.000 claims description 27
• 125000000623 heterocyclic group Chemical group 0.000 claims description 26
• 229910052739 hydrogen Inorganic materials 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 18
• 239000011737 fluorine Substances 0.000 claims description 18
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 14
• 125000001072 heteroaryl group Chemical group 0.000 claims description 14
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 13
• 208000035475 disorder Diseases 0.000 claims description 13
• 125000002950 monocyclic group Chemical group 0.000 claims description 13
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 125000003118 aryl group Chemical group 0.000 claims description 10
• 125000002837 carbocyclic group Chemical group 0.000 claims description 10
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 8
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 8
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 230000005764 inhibitory process Effects 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 6
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 6
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
• 125000000597 dioxinyl group Chemical group 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 125000003566 oxetanyl group Chemical group 0.000 claims description 5
• 125000004193 piperazinyl group Chemical group 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 5
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 5
• UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims description 4
• BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 4
• YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 claims description 4
• FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 4
• MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 claims description 4
• 208000023275 Autoimmune disease Diseases 0.000 claims description 4
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
• 125000002393 azetidinyl group Chemical group 0.000 claims description 4
• 125000005879 dioxolanyl group Chemical group 0.000 claims description 4
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 4
• ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 4
• 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 4
• 125000003965 isoxazolidinyl group Chemical group 0.000 claims description 4
• 125000005880 oxathiolanyl group Chemical group 0.000 claims description 4
• 125000000160 oxazolidinyl group Chemical group 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 150000003536 tetrazoles Chemical class 0.000 claims description 4
• 125000001984 thiazolidinyl group Chemical group 0.000 claims description 4
• 125000001166 thiolanyl group Chemical group 0.000 claims description 4
• NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 3
• 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 claims description 3
• 201000006417 multiple sclerosis Diseases 0.000 claims description 3
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• 125000005458 thianyl group Chemical group 0.000 claims description 3
• SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims 1
• RLFZYIUUQBHRNV-UHFFFAOYSA-N 2,5-dihydrooxadiazole Chemical compound C1ONN=C1 RLFZYIUUQBHRNV-UHFFFAOYSA-N 0.000 claims 1
• 125000001153 fluoro group Chemical group F* 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 32
• 238000004519 manufacturing process Methods 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 456
• 238000003786 synthesis reaction Methods 0.000 description 449
• 230000015572 biosynthetic process Effects 0.000 description 444
• 239000007787 solid Substances 0.000 description 274
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 230
• 239000011541 reaction mixture Substances 0.000 description 229
• 235000019439 ethyl acetate Nutrition 0.000 description 227
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 215
• 239000000243 solution Substances 0.000 description 203
• -1 biaryl compounds Chemical class 0.000 description 181
• 239000013058 crude material Substances 0.000 description 167
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
• 238000010898 silica gel chromatography Methods 0.000 description 130
• 238000005160 1H NMR spectroscopy Methods 0.000 description 120
• 239000003208 petroleum Substances 0.000 description 105
• 239000000203 mixture Substances 0.000 description 103
• 239000012071 phase Substances 0.000 description 93
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 86
• 238000002953 preparative HPLC Methods 0.000 description 85
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 83
• 238000005481 NMR spectroscopy Methods 0.000 description 80
• 238000000746 purification Methods 0.000 description 80
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 74
• 239000011734 sodium Substances 0.000 description 74
• 239000012043 crude product Substances 0.000 description 69
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 64
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 61
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 44
• XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 41
• 239000000284 extract Substances 0.000 description 40
• 239000000706 filtrate Substances 0.000 description 37
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
• 150000003840 hydrochlorides Chemical class 0.000 description 36
• 239000012267 brine Substances 0.000 description 35
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 35
• YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 34
• DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 34
• 239000003921 oil Substances 0.000 description 34
• 235000019198 oils Nutrition 0.000 description 34
• 239000008346 aqueous phase Substances 0.000 description 32
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 30
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 29
• 239000012074 organic phase Substances 0.000 description 29
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 27
• 238000006243 chemical reaction Methods 0.000 description 26
• VAELWSLNTRVXQS-UHFFFAOYSA-N 1,3-oxazole-4-carboxamide Chemical compound NC(=O)C1=COC=N1 VAELWSLNTRVXQS-UHFFFAOYSA-N 0.000 description 25
• 239000010410 layer Substances 0.000 description 22
• 239000012044 organic layer Substances 0.000 description 22
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• 239000000725 suspension Substances 0.000 description 21
• 229940055764 triaz Drugs 0.000 description 20
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
• RAHXPTQEUZIGJK-UHFFFAOYSA-N 5-tert-butyl-N-[[2-chloro-4-[4-[(1-methylpyrazol-4-yl)amino]-1,3,5-triazin-2-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide Chemical compound N(C=1C=NN(C=1)C)C1=NC=NC(=N1)C1=CC=C(C(Cl)=C1)CNC(=O)C1=NOC(=N1)C(C)(C)C RAHXPTQEUZIGJK-UHFFFAOYSA-N 0.000 description 16
• 150000001412 amines Chemical class 0.000 description 16
• 239000000047 product Substances 0.000 description 16
• 238000003756 stirring Methods 0.000 description 16
• 239000002253 acid Substances 0.000 description 15
• YEJAJYAHJQIWNU-UHFFFAOYSA-N azelastine hydrochloride Chemical compound Cl.C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 YEJAJYAHJQIWNU-UHFFFAOYSA-N 0.000 description 15
• 239000012230 colorless oil Substances 0.000 description 14
• 229910052700 potassium Inorganic materials 0.000 description 14
• 239000011591 potassium Substances 0.000 description 14
• LKYNGTHMKCTTQC-UHFFFAOYSA-N 1,2-oxazole-3-carboxamide Chemical compound NC(=O)C=1C=CON=1 LKYNGTHMKCTTQC-UHFFFAOYSA-N 0.000 description 13
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 13
• 239000012298 atmosphere Substances 0.000 description 13
• IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 13
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
• 238000012799 strong cation exchange Methods 0.000 description 12
• DSIBSRXKQRYPJP-UHFFFAOYSA-N 1,2-oxazole-5-carboxamide Chemical compound NC(=O)C1=CC=NO1 DSIBSRXKQRYPJP-UHFFFAOYSA-N 0.000 description 11
• PLCMVACJJSYDFV-UHFFFAOYSA-N 1,3-oxazole-2-carboxamide Chemical compound NC(=O)C1=NC=CO1 PLCMVACJJSYDFV-UHFFFAOYSA-N 0.000 description 11
• 239000007821 HATU Substances 0.000 description 11
• 239000007864 aqueous solution Substances 0.000 description 11
• 125000004452 carbocyclyl group Chemical group 0.000 description 11
• 125000004432 carbon atom Chemical group C* 0.000 description 11
• 239000000460 chlorine Substances 0.000 description 11
• 239000012065 filter cake Substances 0.000 description 11
• AKWIAIDKXNKXDI-UHFFFAOYSA-N 1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=CNC=1 AKWIAIDKXNKXDI-UHFFFAOYSA-N 0.000 description 10
• 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• RLOQBKJCOAXOLR-UHFFFAOYSA-N 1h-pyrrole-2-carboxamide Chemical compound NC(=O)C1=CC=CN1 RLOQBKJCOAXOLR-UHFFFAOYSA-N 0.000 description 9
• GRCKZPRATXWWAC-UHFFFAOYSA-N 5-[1-(fluoromethyl)cyclopropyl]-N-[[2-methyl-4-[4-[(1-methylpyrazol-4-yl)amino]-1,3,5-triazin-2-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide Chemical compound CN1C=C(NC2=NC(=NC=N2)C2=CC(C)=C(CNC(=O)C3=NOC(=N3)C3(CF)CC3)C=C2)C=N1 GRCKZPRATXWWAC-UHFFFAOYSA-N 0.000 description 9
• XUZPISJJYDZYNH-UHFFFAOYSA-N ClC1=NC(=NC=N1)NC1=NN(C=C1)C Chemical compound ClC1=NC(=NC=N1)NC1=NN(C=C1)C XUZPISJJYDZYNH-UHFFFAOYSA-N 0.000 description 9
• HONOCSADKMFXPU-UHFFFAOYSA-N ClC1=NC(=NC=N1)NC=1C=NN(C=1)C Chemical compound ClC1=NC(=NC=N1)NC=1C=NN(C=1)C HONOCSADKMFXPU-UHFFFAOYSA-N 0.000 description 9
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
• 229910052938 sodium sulfate Inorganic materials 0.000 description 9
• 235000011152 sodium sulphate Nutrition 0.000 description 9
• 239000002904 solvent Substances 0.000 description 9
• AJURQKSKUJQYHO-UHFFFAOYSA-N 5-tert-butyl-N-[[2-methyl-4-[4-[(1-methylpyrazol-3-yl)amino]-1,3,5-triazin-2-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide Chemical compound N1=CN=C(N=C1C1=CC(C)=C(CNC(=O)C2=NOC(=N2)C(C)(C)C)C=C1)NC=1C=CN(N=1)C AJURQKSKUJQYHO-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• 238000001816 cooling Methods 0.000 description 8
• 239000000377 silicon dioxide Substances 0.000 description 8
• 125000001544 thienyl group Chemical group 0.000 description 8
• KPYCHKKYQZRCMG-UHFFFAOYSA-N 1-tert-butyl-4-fluoro-N-[[2-methyl-4-[4-[(1-methylpyrazol-3-yl)amino]-1,3,5-triazin-2-yl]phenyl]methyl]pyrazole-3-carboxamide Chemical compound N1=CN=C(N=C1C1=CC(C)=C(CNC(=O)C=2C(F)=CN(N=2)C(C)(C)C)C=C1)NC=1C=CN(N=1)C KPYCHKKYQZRCMG-UHFFFAOYSA-N 0.000 description 7
• VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 7
• 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 description 7
• 241000124008 Mammalia Species 0.000 description 7
• 239000007832 Na2SO4 Substances 0.000 description 7
• 238000003556 assay Methods 0.000 description 7
• 125000004122 cyclic group Chemical group 0.000 description 7
• 201000010099 disease Diseases 0.000 description 7
• 239000005457 ice water Substances 0.000 description 7
• 238000001871 ion mobility spectroscopy Methods 0.000 description 7
• NIZLCZAQXYDEAP-GOSISDBHSA-N 3-tert-butyl-N-[(5R)-8-[4-[(1-methylpyrazol-3-yl)amino]-1,3,5-triazin-2-yl]-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-1,2,4-oxadiazole-5-carboxamide Chemical compound CN1C=CC(NC2=NC(=NC=N2)C2=CC3=C(C=C2)[C@@H](CCN(CC(F)(F)F)C3)NC(=O)C2=NC(=NO2)C(C)(C)C)=N1 NIZLCZAQXYDEAP-GOSISDBHSA-N 0.000 description 6
• PVPBDHFPWYRRFM-UHFFFAOYSA-N 3-tert-butyl-N-[[2-chloro-4-[4-[(1-methylpyrazol-3-yl)amino]-1,3,5-triazin-2-yl]phenyl]methyl]-1,2,4-oxadiazole-5-carboxamide Chemical compound C(C)(C)(C)C1=NOC(=N1)C(=O)NCC1=C(C=C(C=C1)C1=NC=NC(=N1)NC1=NN(C=C1)C)Cl PVPBDHFPWYRRFM-UHFFFAOYSA-N 0.000 description 6
• CCLMPZVVAADLMR-UHFFFAOYSA-N 4-bromo-2-chloro-3-fluoro-N-methoxy-N-methylbenzamide Chemical compound BrC1=C(C(=C(C(=O)N(C)OC)C=C1)Cl)F CCLMPZVVAADLMR-UHFFFAOYSA-N 0.000 description 6
• FTBHXXCQCOAUJZ-UHFFFAOYSA-N 4-bromo-2-chloro-3-fluorobenzaldehyde Chemical compound Fc1c(Br)ccc(C=O)c1Cl FTBHXXCQCOAUJZ-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• 229910021529 ammonia Inorganic materials 0.000 description 6
• 238000004440 column chromatography Methods 0.000 description 6
• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• 238000002360 preparation method Methods 0.000 description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
• 238000005406 washing Methods 0.000 description 6
• RVUGWAUXCFDHQV-CVDFKLHSSA-N (NE,S)-N-[(4-bromo-2-chloro-3-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide Chemical compound BrC1=C(C(=C(\C=N\[S@@](=O)C(C)(C)C)C=C1)Cl)F RVUGWAUXCFDHQV-CVDFKLHSSA-N 0.000 description 5
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