TW202016097A - 布魯頓氏酪胺酸激酶之抑制劑 - Google Patents

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Publication number

TW202016097A

TW202016097A TW108116422A TW108116422A TW202016097A TW 202016097 A TW202016097 A TW 202016097A TW 108116422 A TW108116422 A TW 108116422A TW 108116422 A TW108116422 A TW 108116422A TW 202016097 A TW202016097 A TW 202016097A

Authority

TW

Taiwan

Prior art keywords

alkyl

methyl

membered

occurrence

group

Prior art date

2018-05-14

Links

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• 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title claims description 3
• 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title claims 2
• 230000002401 inhibitory effect Effects 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 157
• 150000003839 salts Chemical class 0.000 claims abstract description 89
• 238000000034 method Methods 0.000 claims abstract description 27
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 315
• -1 1-fluoro-2-methylpropan-2-yl Chemical group 0.000 claims description 293
• 125000000217 alkyl group Chemical group 0.000 claims description 231
• 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 123
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 117
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 116
• 125000005843 halogen group Chemical group 0.000 claims description 96
• 125000001620 monocyclic carbocycle group Chemical group 0.000 claims description 91
• 229910052739 hydrogen Inorganic materials 0.000 claims description 88
• 229910052799 carbon Inorganic materials 0.000 claims description 80
• 229920006395 saturated elastomer Polymers 0.000 claims description 45
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 44
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 34
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 33
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 33
• 125000000623 heterocyclic group Chemical group 0.000 claims description 31
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
• 238000006467 substitution reaction Methods 0.000 claims description 25
• 229910052731 fluorine Inorganic materials 0.000 claims description 23
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 22
• 235000019000 fluorine Nutrition 0.000 claims description 21
• 125000004122 cyclic group Chemical group 0.000 claims description 18
• 125000002950 monocyclic group Chemical group 0.000 claims description 18
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
• 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 12
• 125000000304 alkynyl group Chemical group 0.000 claims description 12
• 125000003118 aryl group Chemical group 0.000 claims description 12
• 239000011737 fluorine Substances 0.000 claims description 12
• 125000001153 fluoro group Chemical group F* 0.000 claims description 12
• 125000001072 heteroaryl group Chemical group 0.000 claims description 12
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• 229910052757 nitrogen Inorganic materials 0.000 claims description 10
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 125000000532 dioxanyl group Chemical group 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 9
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 8
• BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 8
• 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
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
• 229910052736 halogen Inorganic materials 0.000 claims description 8
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 7
• 150000002367 halogens Chemical class 0.000 claims description 7
• 125000005880 oxathiolanyl group Chemical group 0.000 claims description 7
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• 125000002393 azetidinyl group Chemical group 0.000 claims description 6
• 229910052801 chlorine Inorganic materials 0.000 claims description 6
• 208000035475 disorder Diseases 0.000 claims description 6
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 6
• 125000003566 oxetanyl group Chemical group 0.000 claims description 6
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
• 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 208000023275 Autoimmune disease Diseases 0.000 claims description 5
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 5
• 230000005764 inhibitory process Effects 0.000 claims description 5
• 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 5
• 125000003965 isoxazolidinyl group Chemical group 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 125000000160 oxazolidinyl group Chemical group 0.000 claims description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
• 125000001984 thiazolidinyl group Chemical group 0.000 claims description 5
• 125000004001 thioalkyl 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
• 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
• NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 4
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
• ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 4
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 4
• 150000003536 tetrazoles Chemical class 0.000 claims description 4
• 201000006417 multiple sclerosis Diseases 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 abstract description 3
• 238000003786 synthesis reaction Methods 0.000 description 513
• 230000015572 biosynthetic process Effects 0.000 description 503
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 404
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 211
• 239000011541 reaction mixture Substances 0.000 description 208
• 235000019439 ethyl acetate Nutrition 0.000 description 201
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 199
• 239000007787 solid Substances 0.000 description 162
• 239000013058 crude material Substances 0.000 description 154
• 239000000243 solution Substances 0.000 description 153
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 149
• 238000010898 silica gel chromatography Methods 0.000 description 120
• 239000003208 petroleum Substances 0.000 description 96
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 91
• 239000012071 phase Substances 0.000 description 89
• 239000000203 mixture Substances 0.000 description 88
• 238000002953 preparative HPLC Methods 0.000 description 84
• CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 80
• 238000000746 purification Methods 0.000 description 75
• 239000012043 crude product Substances 0.000 description 72
• 239000011734 sodium Substances 0.000 description 72
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 63
• LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 63
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 62
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 59
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 56
• KUQYIVLMCIOKSG-UHFFFAOYSA-N 3-[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-5-carboxamide Chemical compound CN1C=C(NC2=NC(=NC=N2)C2=CC(C)=C(CNC(=O)C3=NC(=NO3)C3(CF)CC3)C=C2)C=N1 KUQYIVLMCIOKSG-UHFFFAOYSA-N 0.000 description 47
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
• 239000000284 extract Substances 0.000 description 38
• 239000000460 chlorine Substances 0.000 description 34
• KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 33
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 33
• ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 33
• 239000008346 aqueous phase Substances 0.000 description 31
• 239000012267 brine Substances 0.000 description 31
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
• 239000000706 filtrate Substances 0.000 description 30
• 150000001412 amines Chemical class 0.000 description 29
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 29
• 239000003921 oil Substances 0.000 description 28
• 235000019198 oils Nutrition 0.000 description 28
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
• 239000012074 organic phase Substances 0.000 description 27
• 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 25
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
• 239000010410 layer Substances 0.000 description 22
• 239000012044 organic layer Substances 0.000 description 20
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 18
• VAELWSLNTRVXQS-UHFFFAOYSA-N 1,3-oxazole-4-carboxamide Chemical compound NC(=O)C1=COC=N1 VAELWSLNTRVXQS-UHFFFAOYSA-N 0.000 description 17
• 238000006243 chemical reaction Methods 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• 239000012299 nitrogen atmosphere Substances 0.000 description 14
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
• 239000002585 base Substances 0.000 description 13
• 150000002148 esters Chemical class 0.000 description 13
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 125000004432 carbon atom Chemical group C* 0.000 description 12
• 238000012799 strong cation exchange Methods 0.000 description 12
• 239000012230 colorless oil Substances 0.000 description 11
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
• 239000007821 HATU Substances 0.000 description 10
• GMQUEDBQYNHEEM-UHFFFAOYSA-N [B].[B].CC(C)(O)C(C)(C)O.CC(C)(O)C(C)(C)O Chemical compound [B].[B].CC(C)(O)C(C)(C)O.CC(C)(O)C(C)(C)O GMQUEDBQYNHEEM-UHFFFAOYSA-N 0.000 description 10
• 239000012065 filter cake Substances 0.000 description 10
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• 238000003756 stirring Methods 0.000 description 10
• FYOWKGSBHOFLLM-UHFFFAOYSA-N 2h-oxadiazole-3-carboxamide Chemical compound NC(=O)N1NOC=C1 FYOWKGSBHOFLLM-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
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
• 238000001816 cooling Methods 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 229910052700 potassium Inorganic materials 0.000 description 9
• 239000011591 potassium Substances 0.000 description 9
• 125000001544 thienyl group Chemical group 0.000 description 9
• LKYNGTHMKCTTQC-UHFFFAOYSA-N 1,2-oxazole-3-carboxamide Chemical compound NC(=O)C=1C=CON=1 LKYNGTHMKCTTQC-UHFFFAOYSA-N 0.000 description 8
• CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 8
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 8
• 201000010099 disease Diseases 0.000 description 8
• 150000003840 hydrochlorides Chemical class 0.000 description 8
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
• PLCMVACJJSYDFV-UHFFFAOYSA-N 1,3-oxazole-2-carboxamide Chemical compound NC(=O)C1=NC=CO1 PLCMVACJJSYDFV-UHFFFAOYSA-N 0.000 description 7
• SZMPXSZRPMZQPS-UHFFFAOYSA-N 2h-1,3-oxazole-3-carboxamide Chemical compound NC(=O)N1COC=C1 SZMPXSZRPMZQPS-UHFFFAOYSA-N 0.000 description 7
• FTBHXXCQCOAUJZ-UHFFFAOYSA-N 4-bromo-2-chloro-3-fluorobenzaldehyde Chemical compound Fc1c(Br)ccc(C=O)c1Cl FTBHXXCQCOAUJZ-UHFFFAOYSA-N 0.000 description 7
• 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 7
• VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 7
• 241000124008 Mammalia Species 0.000 description 7
• 239000005457 ice water Substances 0.000 description 7
• DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 7
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
• VMCICDADKZXNHW-UHFFFAOYSA-N 1h-triazin-2-amine Chemical compound NN1NC=CC=N1 VMCICDADKZXNHW-UHFFFAOYSA-N 0.000 description 6
• GQLSWQNJXOSVNE-UHFFFAOYSA-N 4-bromo-2-chloro-3-methylbenzoic acid Chemical compound CC=1C(=C(C(=O)O)C=CC=1Br)Cl GQLSWQNJXOSVNE-UHFFFAOYSA-N 0.000 description 6
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
• 235000011114 ammonium hydroxide Nutrition 0.000 description 6
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
• SKKTUOZKZKCGTB-UHFFFAOYSA-N butyl carbamate Chemical compound CCCCOC(N)=O SKKTUOZKZKCGTB-UHFFFAOYSA-N 0.000 description 6
• 239000002904 solvent Substances 0.000 description 6
• 238000005406 washing Methods 0.000 description 6
• LTWSKQYBNYYNRN-UHFFFAOYSA-N 1,2,4-oxadiazole-3-carboxamide Chemical compound NC(=O)C=1N=CON=1 LTWSKQYBNYYNRN-UHFFFAOYSA-N 0.000 description 5
• AKWIAIDKXNKXDI-UHFFFAOYSA-N 1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=CNC=1 AKWIAIDKXNKXDI-UHFFFAOYSA-N 0.000 description 5
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
• KRZOBVQVWLVGOG-UHFFFAOYSA-N OC(=O)c1ccc(Br)c(F)c1Cl Chemical compound OC(=O)c1ccc(Br)c(F)c1Cl KRZOBVQVWLVGOG-UHFFFAOYSA-N 0.000 description 5
• 125000002619 bicyclic group Chemical group 0.000 description 5
• 125000004452 carbocyclyl group Chemical group 0.000 description 5
• 239000002552 dosage form Substances 0.000 description 5
• BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
• 125000002541 furyl group Chemical group 0.000 description 5
• 150000002430 hydrocarbons Chemical group 0.000 description 5
• 125000002971 oxazolyl group Chemical group 0.000 description 5
• 238000002360 preparation method Methods 0.000 description 5
• 125000003373 pyrazinyl group Chemical group 0.000 description 5
• RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 5
• 125000000335 thiazolyl group Chemical group 0.000 description 5
• DSIBSRXKQRYPJP-UHFFFAOYSA-N 1,2-oxazole-5-carboxamide Chemical compound NC(=O)C1=CC=NO1 DSIBSRXKQRYPJP-UHFFFAOYSA-N 0.000 description 4
• YUBCFDODRUHARN-UHFFFAOYSA-N 1,3,5-triazin-2-ylazanium;chloride Chemical compound [Cl-].[NH3+]C1=NC=NC=N1 YUBCFDODRUHARN-UHFFFAOYSA-N 0.000 description 4
• BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 description 4
• RLOQBKJCOAXOLR-UHFFFAOYSA-N 1h-pyrrole-2-carboxamide Chemical compound NC(=O)C1=CC=CN1 RLOQBKJCOAXOLR-UHFFFAOYSA-N 0.000 description 4
• ATWKXXGBCZWOCX-UHFFFAOYSA-N 4-bromo-3-fluoro-2-methylbenzonitrile Chemical compound CC1=C(F)C(Br)=CC=C1C#N ATWKXXGBCZWOCX-UHFFFAOYSA-N 0.000 description 4
• 229940124291 BTK inhibitor Drugs 0.000 description 4
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
• 241001465754 Metazoa Species 0.000 description 4
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
• 108010009978 Tec protein-tyrosine kinase Proteins 0.000 description 4
• 230000002378 acidificating effect Effects 0.000 description 4
• 239000007864 aqueous solution Substances 0.000 description 4
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
• 125000005303 dithiazolyl group Chemical group S1SNC(=C1)* 0.000 description 4
• 125000002883 imidazolyl group Chemical group 0.000 description 4
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