WO2015022926A1 - 新規な縮合ピリミジン化合物又はその塩 - Google Patents
新規な縮合ピリミジン化合物又はその塩 Download PDFInfo
- Publication number
- WO2015022926A1 WO2015022926A1 PCT/JP2014/071158 JP2014071158W WO2015022926A1 WO 2015022926 A1 WO2015022926 A1 WO 2015022926A1 JP 2014071158 W JP2014071158 W JP 2014071158W WO 2015022926 A1 WO2015022926 A1 WO 2015022926A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- group
- oxazol
- pyrimidine
- carboxamide
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims abstract description 76
- -1 pyrimidine compound Chemical class 0.000 title claims description 500
- 150000001875 compounds Chemical class 0.000 claims abstract description 413
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 75
- 125000001424 substituent group Chemical group 0.000 claims description 68
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 67
- 229910052757 nitrogen Inorganic materials 0.000 claims description 54
- 125000005843 halogen group Chemical group 0.000 claims description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 125000003277 amino group Chemical group 0.000 claims description 47
- DYMCRSCIKQMSRP-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine-5-carboxamide Chemical compound N1C=NC=C2C(C(=O)N)=CN=C21 DYMCRSCIKQMSRP-UHFFFAOYSA-N 0.000 claims description 39
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 36
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000004434 sulfur atom Chemical group 0.000 claims description 23
- 125000002950 monocyclic group Chemical group 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 239000000523 sample Substances 0.000 claims description 13
- YSNNXWDSOJMVRP-CYBMUJFWSA-N 4-amino-N-(5-chloro-1,3-benzoxazol-2-yl)-1-[(3R)-1-(2-methylprop-2-enoyl)piperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl)[C@H]1CN(CCC1)C(C(=C)C)=O YSNNXWDSOJMVRP-CYBMUJFWSA-N 0.000 claims description 12
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 12
- 125000005647 linker group Chemical group 0.000 claims description 12
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- 125000003367 polycyclic group Chemical group 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- JWILNBUIJCSTLC-CYBMUJFWSA-N 4-amino-N-(5-cyano-1,3-benzoxazol-2-yl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CCC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)C#N JWILNBUIJCSTLC-CYBMUJFWSA-N 0.000 claims description 10
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 229910052721 tungsten Inorganic materials 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
- 229940124291 BTK inhibitor Drugs 0.000 claims description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- WHIIKUILMHWFPN-OAHLLOKOSA-N 4-amino-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]-N-(5-thiophen-2-yl-1,3-benzoxazol-2-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CCC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)C=1SC=CC1 WHIIKUILMHWFPN-OAHLLOKOSA-N 0.000 claims description 7
- IHYICVDVTRVQAD-UHFFFAOYSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-(1-prop-2-enoylpiperidin-4-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 IHYICVDVTRVQAD-UHFFFAOYSA-N 0.000 claims description 5
- LWIXMILEZATMDL-UHFFFAOYSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-(1-prop-2-enoylpyrrolidin-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 LWIXMILEZATMDL-UHFFFAOYSA-N 0.000 claims description 5
- ICBNFZRGYFGZLT-UHFFFAOYSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[3-(prop-2-enoylamino)propyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)NCCCN1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 ICBNFZRGYFGZLT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 5
- DQCRVSBQFSKPIO-UHFFFAOYSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-(1-prop-2-enoylazetidin-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(C1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 DQCRVSBQFSKPIO-UHFFFAOYSA-N 0.000 claims description 4
- LSWUMDGBEKRQHO-UHFFFAOYSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[2-(prop-2-enoylamino)ethyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)NCCN1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 LSWUMDGBEKRQHO-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- SCQLYOZUYSYZHC-CYBMUJFWSA-N 4-amino-1-[(3R)-1-[(E)-but-2-enoyl]piperidin-3-yl]-N-(5-chloro-1,3-benzoxazol-2-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl)[C@H]1CN(CCC1)C(C=CC)=O SCQLYOZUYSYZHC-CYBMUJFWSA-N 0.000 claims description 3
- RDMBWZLISCEKQQ-LLVKDONJSA-N 4-amino-1-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]-N-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)C(F)(F)F RDMBWZLISCEKQQ-LLVKDONJSA-N 0.000 claims description 3
- JQQNLSUBSWECQL-UHFFFAOYSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[(1-prop-2-enoylazetidin-3-yl)methyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(C1)CN1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 JQQNLSUBSWECQL-UHFFFAOYSA-N 0.000 claims description 3
- JOLWLHDMAIYLGC-UHFFFAOYSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[(1-prop-2-enoylpiperidin-3-yl)methyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(CCC1)CN1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 JOLWLHDMAIYLGC-UHFFFAOYSA-N 0.000 claims description 3
- TYRODWLXPZYVKN-UHFFFAOYSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[(1-prop-2-enoylpiperidin-4-yl)methyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)CN1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 TYRODWLXPZYVKN-UHFFFAOYSA-N 0.000 claims description 3
- LWIXMILEZATMDL-NSHDSACASA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[(3S)-1-prop-2-enoylpyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@H](CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 LWIXMILEZATMDL-NSHDSACASA-N 0.000 claims description 3
- OXZZHHRPRXUIEV-UHFFFAOYSA-N 4-amino-N-(5-chloro-1,3-benzoxazol-2-yl)-1-(1-prop-2-enoylpyrrolidin-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl OXZZHHRPRXUIEV-UHFFFAOYSA-N 0.000 claims description 3
- BBUDVNYJKYGCFW-UHFFFAOYSA-N 4-amino-N-(5-chloro-1,3-benzoxazol-2-yl)-1-[(1-prop-2-enoylazetidin-3-yl)methyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(C1)CN1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl BBUDVNYJKYGCFW-UHFFFAOYSA-N 0.000 claims description 3
- MBTQEKOQTVSXTJ-UHFFFAOYSA-N 4-amino-N-(5-fluoro-1,3-benzoxazol-2-yl)-1-(1-prop-2-enoylpyrrolidin-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)F MBTQEKOQTVSXTJ-UHFFFAOYSA-N 0.000 claims description 3
- GWSCKTFTVOIUTB-UHFFFAOYSA-N 4-amino-N-(5-fluoro-1,3-benzoxazol-2-yl)-1-[(1-prop-2-enoylpiperidin-4-yl)methyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)CN1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)F GWSCKTFTVOIUTB-UHFFFAOYSA-N 0.000 claims description 3
- WGURSOWMEPINOA-LLVKDONJSA-N 4-amino-N-(7-chloro-1,3-benzoxazol-2-yl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CCC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1Cl WGURSOWMEPINOA-LLVKDONJSA-N 0.000 claims description 3
- VGIMMCQWTWCCBO-QGZVFWFLSA-N 4-amino-N-[5-(4-chlorophenyl)-1,3-benzoxazol-2-yl]-1-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)C1=CC=C(C=C1)Cl VGIMMCQWTWCCBO-QGZVFWFLSA-N 0.000 claims description 3
- CLBMDOIIODQDOI-GOSISDBHSA-N 4-amino-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoyl]piperidin-3-yl]-N-(5-thiophen-2-yl-1,3-benzoxazol-2-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)C=1SC=CC1)[C@H]1CN(CCC1)C(C=CCN(C)C)=O CLBMDOIIODQDOI-GOSISDBHSA-N 0.000 claims description 2
- WJIJTAXDEGINAG-HXUWFJFHSA-N 4-amino-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoyl]pyrrolidin-3-yl]-N-(5-phenyl-1,3-benzoxazol-2-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)C1=CC=CC=C1)[C@H]1CN(CC1)C(C=CCN(C)C)=O WJIJTAXDEGINAG-HXUWFJFHSA-N 0.000 claims description 2
- SYACMYUIHQGCPO-CQSZACIVSA-N 4-amino-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoyl]pyrrolidin-3-yl]-N-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)C(F)(F)F)[C@H]1CN(CC1)C(C=CCN(C)C)=O SYACMYUIHQGCPO-CQSZACIVSA-N 0.000 claims description 2
- DDWOKHFHOQZXSM-GFCCVEGCSA-N 4-amino-1-[(3R)-1-[(E)-but-2-enoyl]pyrrolidin-3-yl]-N-(5-chloro-1,3-benzoxazol-2-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl)[C@H]1CN(CC1)C(C=CC)=O DDWOKHFHOQZXSM-GFCCVEGCSA-N 0.000 claims description 2
- NMNXKWKEUXECEB-CQSZACIVSA-N 4-amino-1-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]-N-(5-thiophen-2-yl-1,3-benzoxazol-2-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)C=1SC=CC1 NMNXKWKEUXECEB-CQSZACIVSA-N 0.000 claims description 2
- DLGLFSDRZNEFAE-CYBMUJFWSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[(3R)-1-[(E)-but-2-enoyl]piperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=CC=C1)[C@H]1CN(CCC1)C(C=CC)=O DLGLFSDRZNEFAE-CYBMUJFWSA-N 0.000 claims description 2
- WUMMDJMYFAWMBN-GFCCVEGCSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CCC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 WUMMDJMYFAWMBN-GFCCVEGCSA-N 0.000 claims description 2
- LWIXMILEZATMDL-LLVKDONJSA-N 4-amino-N-(1,3-benzoxazol-2-yl)-1-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=CC=C1 LWIXMILEZATMDL-LLVKDONJSA-N 0.000 claims description 2
- ZSROCQQOHDQNRD-CYBMUJFWSA-N 4-amino-N-(4-methyl-1,3-benzoxazol-2-yl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CCC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C(=CC=C1)C ZSROCQQOHDQNRD-CYBMUJFWSA-N 0.000 claims description 2
- IDKTVJOAWRRCQP-CQSZACIVSA-N 4-amino-N-(5,6-dimethyl-1,3-benzoxazol-2-yl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CCC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C(=C1)C)C IDKTVJOAWRRCQP-CQSZACIVSA-N 0.000 claims description 2
- DZGSRSRWZYZELH-GFCCVEGCSA-N 4-amino-N-(5-bromo-1,3-benzoxazol-2-yl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1C[C@@H](CCC1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)Br DZGSRSRWZYZELH-GFCCVEGCSA-N 0.000 claims description 2
- OERZDMFYTZVXBP-UHFFFAOYSA-N 4-amino-N-(5-chloro-1,3-benzoxazol-2-yl)-1-(1-prop-2-enoylazetidin-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(C1)N1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl OERZDMFYTZVXBP-UHFFFAOYSA-N 0.000 claims description 2
- BAZLMPWIGYDUQP-UHFFFAOYSA-N 4-amino-N-(5-chloro-1,3-benzoxazol-2-yl)-1-[(1-prop-2-enoylpiperidin-4-yl)methyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)CN1N=C(C=2C1=NC=NC2N)C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl BAZLMPWIGYDUQP-UHFFFAOYSA-N 0.000 claims description 2
- LSCBIFHNPDMWIW-OAHLLOKOSA-N 4-amino-N-(5-chloro-1,3-benzoxazol-2-yl)-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoyl]piperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl)[C@H]1CN(CCC1)C(C=CCN(C)C)=O LSCBIFHNPDMWIW-OAHLLOKOSA-N 0.000 claims description 2
- VAHPHFUKSVSWLN-CQSZACIVSA-N 4-amino-N-(5-chloro-1,3-benzoxazol-2-yl)-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoyl]pyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl)[C@H]1CN(CC1)C(C=CCN(C)C)=O VAHPHFUKSVSWLN-CQSZACIVSA-N 0.000 claims description 2
- AKSBYWGFGIJRFN-GOSISDBHSA-N 4-amino-N-(5-chloro-1,3-benzoxazol-2-yl)-1-[(3R)-1-[(E)-4-piperidin-1-ylbut-2-enoyl]piperidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C(=O)NC=2OC1=C(N2)C=C(C=C1)Cl)[C@H]1CN(CCC1)C(C=CCN1CCCCC1)=O AKSBYWGFGIJRFN-GOSISDBHSA-N 0.000 claims description 2
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- 125000004076 pyridyl group Chemical group 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
Definitions
- the present invention relates to a novel condensed pyrimidine compound having a Bruton's tyrosine kinase (BTK) inhibitory action or a salt thereof, and a pharmaceutical composition containing the same.
- BTK Bruton's tyrosine kinase
- Bruton's tyrosine kinase is a protein kinase belonging to Tec kinase family, and plays an important role in the control of proliferation, survival, differentiation and activation of B cells downstream of the B cell receptor (BCR) signal.
- BCR B cell receptor
- Non-receptor tyrosine kinase Non-patent Document 1. Inhibitors capable of controlling the activity of BTK are thought to be useful as therapeutic agents for diseases associated with abnormal enhancement of the BTK signal pathway (for example, cancer).
- Non-patent Document 2 Non-patent Document 2
- JAK3 Janus kinase 3
- EGFR epidermal growth factor
- apoptosis inhibition apoptosis inhibition
- An object of the present invention is to provide a novel compound or a salt thereof that selectively and strongly inhibits BTK as compared with EGFR, and a pharmaceutical composition containing the same.
- a compound group represented by the following formula (I) exhibits excellent inhibitory activity and kinase selectivity for BTK, and BTK such as cancer. Has been found to be useful as a medicament for treating diseases in which the drug is involved, and the present invention has been completed.
- A represents — (CH 2 ) n —X—, — (CH 2 ) m —NH—, or — (C 3 -C 7 cycloalkylene) —NH—;
- n represents an integer of 0 to 2;
- m represents an integer of 1 to 4;
- X represents a nitrogen-containing C3-C10 heterocycloalkylene which may have a substituent;
- Y represents —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ;
- W and Z each independently represent N or CH;
- R 1 represents an amino group which may have a substituent;
- R 2 and R 3 are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 alkoxy group, or a substituent.
- C3-C7 cycloalkyl group which may have, C6-C14 aromatic hydrocarbon group which may have a substituent, which may have a substituent, selected from a nitrogen atom, an oxygen atom and a sulfur atom
- R 4 , R 5 , R 6 and R 7 are the same or different and each represents a hydrogen atom or a C1-C6 alkyl group which may have a substituent.
- the present invention also provides a probe comprising a compound represented by the above general formula (I) or a salt thereof, a detectable label or affinity tag, and a linker, wherein the linker comprises the compound and the label or tag.
- a connected probe is provided.
- this invention provides the BTK inhibitor which uses the compound or its salt represented with the said general formula (I) as an active ingredient.
- this invention provides the pharmaceutical composition containing the compound or its salt represented by the said general formula (I).
- the present invention also provides an antitumor agent comprising the compound represented by the above general formula (I) or a salt thereof as an active ingredient.
- the present invention also provides a compound represented by the above general formula (I) or a salt thereof for tumor therapy.
- the present invention also provides use of a compound represented by the above general formula (I) or a salt thereof for the production of an antitumor agent.
- the present invention also provides a method for treating a tumor, characterized by administering a compound represented by the above general formula (I) or a salt thereof.
- PCI-32765 in the clinical stage is known as a BTK inhibitor.
- PCI-32765 has a phenoxyphenyl group, but differs greatly in that it does not have a benzoxazole group or an oxazolopyridine group, which is a feature of the compound of the present invention.
- the compound of the present invention has a feature that it has a higher BTK selectivity than PCI-32765 (Comparative Example Compound 1).
- the compounds described in Patent Documents 1 and 2 do not have a benzoxazole group or an oxazolopyridine group, which is a feature of the compound of the present invention, and are greatly different in structure.
- a novel compound represented by the above general formula (I) or a salt thereof useful as a BTK inhibitor is provided. It has been clarified that the compound of the present invention or a salt thereof has excellent BTK selective inhibitory activity and exhibits a growth inhibitory effect on cancer cell lines. Furthermore, since the compound of the present invention or a salt thereof selectively and strongly inhibits BTK as compared with EGFR, side effects can be reduced and safety can be expected.
- the compound of the present invention or a salt thereof has advantages in that it exhibits good liver microsomal stability as compared with conventional BTK inhibitors, can be expected to have good blood exposure, and has no concern about Cyp inhibition.
- the compound of the present invention or a salt thereof is useful as an agent for preventing and / or treating cancer.
- the compound of the present invention or a salt thereof can inhibit cancer and tumor bone metastasis.
- the compound represented by the above formula (I) of the present invention has a 1H-pyrazolo [3,4-d] pyrimidine skeleton or 7H-pyrrolo substituted with a benzoxazole group or an oxazolopyridine group via an amide bond. It is a compound having a [2,3-d] pyrimidine skeleton, and is a novel compound not described in any of the above prior art documents.
- examples of the “substituent” include a halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, halogenoalkyl group, cycloalkyl group, cycloalkyl-alkyl group, aralkyl group, alkenyl group, alkynyl.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- alkyl group may be linear or branched.
- cycloalkyl group examples include C3-C7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- cycloalkylene refers to divalent cycloalkyl.
- cycloalkyl-alkyl group includes a C3-C7 cycloalkyl-substituted C1-C4 alkyl group such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a cycloheptylmethyl group. Can be mentioned.
- examples of the “aralkyl group” include C7-C13 aralkyl groups such as a benzyl group, a phenethyl group, a naphthylmethyl group, and a fluorenylmethyl group.
- the “alkenyl group” may be linear, branched or cyclic, and means an unsaturated hydrocarbon group having at least one double bond, such as a vinyl group, an allyl group, 1-propenyl group, 2-methyl-2-propenyl group, isopropenyl group, 1-, 2- or 3-butenyl group, 2-, 3- or 4-pentenyl group, 2-methyl-2-butenyl group, 3 C2-C6 alkenyl groups such as -methyl-2-butenyl group, 5-hexenyl group, 1-cyclopentenyl group, 1-cyclohexenyl group, 3-methyl-3-butenyl group and the like can be mentioned.
- alkynyl group may be any of linear, branched or cyclic, and means an unsaturated hydrocarbon group having at least one triple bond, such as an ethynyl group, 1- or 2 -C2-C6 alkynyl group such as -propynyl group, 1-, 2- or 3-butynyl group, 1-methyl-2-propynyl group.
- alkoxy group may be linear or branched, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyl C1-C6 alkoxy groups such as oxy group, isopentyloxy group and hexyloxy group can be mentioned.
- halogenoalkoxy group is a linear or branched alkoxy group having 1 to 13 carbon atoms and having 1 to 13 carbon atoms (halogeno C1-C6 alkoxy group).
- cycloalkoxy group examples include C3-C7 cycloalkoxy groups such as cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, and cycloheptyloxy group.
- cycloalkyl-alkoxy group includes C3-C7 cycloalkyl-substituted C1-C4 alkoxy groups such as cyclopropylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, cyclohexylmethoxy group and cycloheptylmethoxy group. Can be mentioned.
- examples of the “aralkyloxy group” include C7-C13 aralkyloxy groups such as benzyloxy group, phenethyloxy group, naphthylmethyloxy group, and fluorenylmethyloxy group.
- alkylthio group may be either linear or branched, for example, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, Examples thereof include C1-C6 alkylthio groups such as tert-butylthio group, n-pentylthio group, isopentylthio group, and hexylthio group.
- the “cycloalkyl-alkylthio group” includes a C3-C7 cycloalkyl-substituted C1-C4 alkylthio group such as a cyclopropylmethylthio group, a cyclobutylmethylthio group, a cyclopentylmethylthio group, a cyclohexylmethylthio group, and a cycloheptylmethylthio group.
- a C3-C7 cycloalkyl-substituted C1-C4 alkylthio group such as a cyclopropylmethylthio group, a cyclobutylmethylthio group, a cyclopentylmethylthio group, a cyclohexylmethylthio group, and a cycloheptylmethylthio group.
- the “monoalkylamino group” includes methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, tert-butylamino group, n-pentyl group.
- Examples thereof include an amino group monosubstituted by a linear or branched C1-C6 alkyl group such as an amino group, an isopentylamino group, and a hexylamino group.
- dialkylamino group includes dimethylamino group, diethylamino group, di (n-propyl) amino group, diisopropylamino group, di (n-butyl) amino group, isobutylamino group, di (tert-butyl).
- an amino group di-substituted with a linear or branched C1-C6 alkyl group such as an amino group, a di (n-pentyl) amino group, a diisopentylamino group, and a dihexylamino group.
- alkylcarbonyl group includes methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl. And a linear or branched (C1-C6 alkyl) carbonyl group.
- the “arylcarbonyl group” includes phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl, 2,3-dihydro-1,4-dio (C6-C14 aryl) carbonyl groups such as xanaphthalenylcarbonyl, indanylcarbonyl and phenanthrylcarbonyl.
- acyloxy group means an alkylcarbonyloxy group or an arylcarbonyloxy group.
- alkylcarbonyloxy group includes methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentyl.
- Examples thereof include a linear or branched (C1-C6 alkyl) carbonyloxy group such as carbonyloxy, isopentylcarbonyloxy, hexylcarbonyloxy and the like.
- the “arylcarbonyloxy group” includes phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2, 3 And (C6-C14 aryl) carbonyloxy groups such as -dihydro-1,4-dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy and phenanthrylcarbonyloxy.
- alkoxycarbonyl group may be linear or branched, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl.
- (C1-C6 alkoxy) carbonyl groups such as tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group and hexyloxycarbonyl group.
- examples of the “aralkyloxycarbonyl group” include (C7-C13 aralkyl) oxycarbonyl groups such as benzyloxycarbonyl group, phenethyloxycarbonyl group, naphthylmethyloxycarbonyl group, and fluorenylmethyloxycarbonyl group. .
- the “saturated heterocyclic group” is a saturated heterocyclic group having a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and specifically includes a morpholino group, a 1-pyrrolidinyl group, Examples include a piperidino group, a piperazinyl group, a 4-methyl-1-piperazinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothiophenyl group, a thiazolidinyl group, and an oxazolidinyl group.
- Cyclic group specifically imidazolyl group, thienyl group, furyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group , Pyrimidinyl group, pyridazinyl group, indolyl group, isoindolyl group, indazolyl group, triazolopyridyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzothienyl group, benzofuranyl group, purinyl group, quinolyl group, isoquinolyl group, quinazolinyl Group, quinoxalyl group, Dioxy phenyl group, ethylene dioxy phenyl group, dihydrobenz
- the “saturated heterocyclic oxy group” is a saturated heterocyclic oxy group having a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, specifically, a morpholinyloxy group, 1 -Pyrrolidinyloxy group, piperidinooxy group, piperazinyloxy group, 4-methyl-1-piperazinyloxy group, tetrahydrofuranyloxy group, tetrahydropyranyloxy group, tetrahydrothiophenyloxy group, thiazolidinyloxy Group and oxazolidinyloxy group.
- CA-CB indicates that the substituent has C to B carbon atoms.
- C1-C6 alkyl group represents an alkyl group having 1 to 6 carbon atoms
- C6-C14 aromatic hydrocarbon oxy group represents an oxy group to which an aromatic hydrocarbon group having 6 to 14 carbon atoms is bonded.
- a to B member means that the number of atoms constituting the ring (number of ring members) is A to B.
- “4 to 10-membered saturated heterocyclic group” means a saturated heterocyclic group having 4 to 10 ring members.
- A represents — (CH 2 ) n —X—, — (CH 2 ) m —NH—, or — (C 3 -C 7 cycloalkylene) —NH—.
- N represents an integer of 0 to 2, but 0 is more preferable.
- M represents an integer of 1 to 4, more preferably 2 or 3, and even more preferably 2.
- Examples of the C3-C7 cycloalkylene include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene, and cyclohexylene is more preferable.
- X represents a nitrogen-containing C3-C10 heterocycloalkylene which may have a substituent, and more specifically includes at least one nitrogen atom which may have a substituent in the ring, and A divalent heterocycloalkyl having 3 to 10 carbon atoms (nitrogen-containing C3-C10 heterocycloalkylene) containing 0 to 2 heteroatoms of the same or different types selected from an oxygen atom or a sulfur atom in the ring; More specifically, azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, morpholinylene, octahydroquinolinylene, octahydroindolinene and the like can be mentioned.
- heterocycloalkylene having 3 to 5 carbon atoms which may have a substituent and contains one nitrogen atom in the ring, more preferably azetidinylene, pyrrolidinylene, Or piperidinylene, more preferably 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperidinylene.
- substituent on these heterocycloalkylenes include those described above, but are preferably unsubstituted.
- the nitrogen atom of the nitrogen-containing C3-C10 heterocycloalkylene group represented by X is preferably bonded to the carbonyl group of —COY in the general formula (I). Further, the nitrogen atom of the nitrogen-containing C3-C5 heterocycloalkylene group represented by X is preferably bonded to the carbonyl group of —COY in the general formula (I).
- A is more preferably — (CH 2 ) n —X—.
- Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ) or —C ⁇ C—R 7 .
- W and Z are each independently N or CH, preferably Z is N and W is N, or Z is CH and W is N or CH.
- examples of the “substituent” in the “amino group optionally having substituent (s)” represented by R 1 include the substituents as described above, but are preferably unsubstituted.
- the “amino group optionally having substituent (s)” represented by R 1 is preferably an amino group.
- the “halogen atom” represented by R 2 or R 3 is preferably a fluorine atom, a chlorine atom, or a bromine atom.
- the “C1-C6 alkyl group” in the “optionally substituted C1-C6 alkyl group” represented by R 2 or R 3 is preferably a C1-C4 alkyl group, A methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group is more preferable, and a methyl group or an ethyl group is more preferable.
- the “substituent” in the “optionally substituted C1-C6 alkyl group” represented by R 2 or R 3 is preferably an unsubstituted, halogen atom, or C1-C4 alkoxy group, and more preferably Is unsubstituted, a fluorine atom, or a methoxy group.
- the number of substituents is not particularly limited, but is preferably 1 to 3 when the substituent is a halogen atom, and preferably 1 when the substituent is a C1-C4 alkoxy group.
- the “optionally substituted C1-C6 alkyl group” represented by R 2 or R 3 is preferably a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, or a C1-C4 alkoxy-substituted C1-C6 alkyl group. More preferably a C1-C4 alkyl group, a halogeno C1-C4 alkyl group, or a C1-C4 alkoxy-substituted C1-C4 alkyl group, still more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group.
- N-butyl group isobutyl group, tert-butyl group, trifluoromethyl group, trichloromethyl group, methoxyethyl group, or ethoxyethyl group, and more preferably a methyl group, a trifluoromethyl group, or a methoxyethyl group It is.
- the “C1-C6 alkoxy group” in the “optionally substituted C1-C6 alkoxy group” represented by R 2 or R 3 is preferably “C1-C4 alkoxy group”. More preferably, it is a methoxy group, an ethoxy group, an isopropoxy group, or an n-butoxy group, and more preferably a methoxy group.
- the “substituent” in the “optionally substituted C1-C6 alkoxy group” represented by R 2 or R 3 include the substituents as described above, but are preferably unsubstituted.
- the “optionally substituted C1-C6 alkoxy group” represented by R 2 or R 3 is preferably a C1-C6 alkoxy group, more preferably a C1-C4 alkoxy group, still more preferably A methoxy group, an ethoxy group, an isopropoxy group, or an n-butoxy group, more preferably a methoxy group.
- the “C3-C7 cycloalkyl group” in the “optionally substituted C3-C7 cycloalkyl group” represented by R 2 or R 3 is preferably C3-C6 cycloalkyl More preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
- Examples of the “substituent” in the “C3-C7 cycloalkyl group optionally having substituent (s)” represented by R 2 or R 3 include the substituents as described above, but are preferably unsubstituted. .
- the “optionally substituted C3-C7 cycloalkyl group” represented by R 2 or R 3 is preferably a C3-C6 cycloalkyl group, more preferably a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group. Or a cyclohexyl group.
- the “C6-C14 aromatic hydrocarbon group” in the “optionally substituted C6-C14 aromatic hydrocarbon group” represented by R 2 or R 3 is preferably a phenyl group A naphthyl group, more preferably a phenyl group.
- the “substituent” in the “optionally substituted C6-C14 aromatic hydrocarbon group” represented by R 2 or R 3 is preferably unsubstituted or a halogen atom, more preferably none. Substitution or chlorine atom or fluorine atom. When it has a substituent, the number of the substituent is not particularly limited, but is preferably 1 to 3.
- the “optionally substituted C6-C14 aromatic hydrocarbon group” represented by R 2 or R 3 is preferably a phenyl group or a naphthyl group which may be unsubstituted or substituted with a halogen atom. More preferably a phenyl group, a chlorophenyl group, a fluorophenyl group, a dichlorophenyl group, or a trichlorophenyl group, still more preferably a phenyl group or a chlorophenyl group, and particularly preferably a phenyl group or a 4-chlorophenyl group.
- R 2 or R 3 which may have a substituent and contains 1 to 3 of the same or different heteroatoms selected from nitrogen, oxygen and sulfur atoms 4 4 to 10-membered containing 1 to 3 of the same or different heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the “ ⁇ 10-membered monocyclic or polycyclic unsaturated heterocyclic group”
- the “monocyclic or polycyclic unsaturated heterocyclic group” is preferably a 4 to 6-membered monocyclic unsaturated heterocyclic group containing one nitrogen atom, oxygen atom or sulfur atom, and more A 4- to 6-membered monocyclic unsaturated heterocyclic group containing one sulfur atom is preferable, a thienyl group is more preferable, and a 2-thienyl group is more preferable.
- a 4- to 10-membered monocyclic group which may have a substituent and is represented by 1 to 3 of the same or different heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, represented by R 2 or R 3
- substituents include the above-mentioned substituents, but are preferably unsubstituted.
- a 4- to 10-membered monocyclic group which may have a substituent and is represented by 1 to 3 of the same or different heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, represented by R 2 or R 3
- a “polycyclic unsaturated heterocyclic group” is preferably a 4- to 6-membered monocyclic unsaturated heterocyclic group containing one nitrogen atom, oxygen atom or sulfur atom, more preferably sulfur.
- the “C1-C6 alkyl group” in the “optionally substituted C1-C6 alkyl group” represented by R 4 , R 5 , or R 6 is preferably C1-C4.
- An alkyl group more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group, and even more preferably a methyl group.
- the “substituent” in the “optionally substituted C1-C6 alkyl group” represented by R 4 , R 5 or R 6 is preferably unsubstituted or two C1-C4 alkyl groups.
- a substituted amino group (the C1-C4 alkyl group may form a 4- to 8-membered heterocycloalkyl group together with the nitrogen atom to which they are bonded), more preferably unsubstituted, a dimethylamino group, A methylethylamino group, a diethylamino group, a methylisopropylamino group, a 1-piperidinyl group, or a 1-pyrrolidinyl group;
- the “optionally substituted C1-C6 alkyl group” has a substituent, the number of substituents is not particularly limited, but is preferably one.
- the “optionally substituted C1-C6 alkyl group” represented by R 4 , R 5 , or R 6 is preferably a C1-C4 alkyl group or two C1-C4 alkyl groups.
- a C1-C4 alkyl group substituted with an amino group (the C1-C4 alkyl group may form a 4- to 8-membered heterocycloalkyl group together with the nitrogen atom to which they are bonded), and more preferably.
- the “C1-C6 alkyl group” in the “optionally substituted C1-C6 alkyl group” represented by R 7 is preferably a C1-C4 alkyl group, more preferably A methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group, and more preferably a methyl group.
- Examples of the “substituent” in the “C1-C6 alkyl group optionally having substituent (s)” represented by R 7 include the substituents as described above, but are preferably unsubstituted.
- A is — (CH 2 ) n —X—; n is 0; X is nitrogen-containing C3-C10 heterocycloalkylene (wherein the nitrogen atom is bonded to the carbonyl group of —COY of the general formula (I)); Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ; W and Z are each independently N or CH; R 1 is an amino group; R 2 and R 3 are the same or different and each represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, or a substituent.
- C3-C7 cycloalkyl group which may have, C6-C14 aromatic hydrocarbon group which may have a substituent, which may have a substituent, selected from a nitrogen atom, an oxygen atom and a sulfur atom
- A is — (CH 2 ) n —X—; n is 0; X is azetidinylene, pyrrolidinylene, or piperidinylene; Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ; W and Z are each independently N or CH; R 1 is an amino group; R 2 and R 3 are the same or different and each represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, or a substituent.
- C3-C7 cycloalkyl group which may have, C6-C14 aromatic hydrocarbon group which may have a substituent, which may have a substituent, selected from a nitrogen atom, an oxygen atom and a sulfur atom
- C3-C7 cycloalkyl group which may have, C6-C14 aromatic hydrocarbon group which may have a substituent, which may have a substituent, selected from a nitrogen atom, an oxygen atom and a sulfur atom
- A is — (CH 2 ) n —X—; n is 0; X is azetidinylene, pyrrolidinylene, or piperidinylene; Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ; W and Z are independently N or CH; R 1 is an amino group; One of R 2 and R 3 is a hydrogen atom or a C1-C6 alkyl group, and the other is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C4 alkoxy-substituted C1-C6 alkyl group , A C1-C6 alkoxy group, a phenyl group optionally substituted with a halogen atom, a 4-6 membered monocyclic unsaturated
- A is — (CH 2 ) n —X—; n is 0; X is azetidinylene, pyrrolidinylene, or piperidinylene (wherein the nitrogen atom is bonded to the carbonyl group of —COY of the general formula (I)); Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ; W and Z are independently N or CH; R 1 is an amino group; One of R 2 and R 3 is a hydrogen atom or a C1-C6 alkyl group, and the other is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C4 alkoxy-substituted C1-C6 alkyl group , A C1-C6 alkoxy
- A is — (CH 2 ) n —X—; n is 0; X is 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperidinylene (wherein the nitrogen atom is bonded to the carbonyl group of —COY in the general formula (I)); Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ;
- Z is N
- W is N
- Z is CH
- W is N or CH
- R 1 is an amino group;
- One of R 2 and R 3 is a hydrogen atom or a C1-C4 alkyl group, and the other is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a halogeno C1-C4 alkyl group, a C1-C4 alkoxy-substituted C1
- A is — (CH 2 ) n —X—; n is 0; X is 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperidinylene; Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ;
- Z is N, W is N; when Z is CH, W is N or CH;
- R 1 is an amino group;
- One of R 2 and R 3 is a hydrogen atom or a methyl group, and the other is a hydrogen atom, halogen atom, methyl group, trifluoromethyl group, methoxyethyl group, methoxy group, phenyl group, 4-chlorophenyl group, 2-thienyl A group or a cyano group;
- A is — (CH 2 ) n —X—; n is 0; X is 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperidinylene (wherein the nitrogen atom is bonded to the carbonyl group of —COY in the general formula (I)); Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ;
- Z is N
- W is N
- Z is CH
- W is N or CH
- R 1 is an amino group;
- One of R 2 and R 3 is a hydrogen atom or a methyl group, and the other is a hydrogen atom, halogen atom, methyl group, trifluoromethyl group, methoxyethyl group, methoxy group, phenyl group, 4-chlorophenyl group, 2-thienyl A group or a cyano group
- A is — (CH 2 ) n —X—; n is 0; R 1 is an amino group;
- R 2 and R 3 is a hydrogen atom or a methyl group, and the other is a hydrogen atom, a halogen atom, a trifluoromethyl group, a methoxyethyl group, a phenyl group, a 2-thienyl group, or a cyano group;
- Z is N and W is N
- X is 1,3-piperidinylene
- Y is a vinyl group
- Z is CH and W is N, X is 1,3-pyrrolidinylene or 1,3-piperidinylene, Y is —C (R 4 ) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C— (R 7 )
- Y is —C ⁇ C— (R 7 )
- R 7 is a methyl group
- Z is CH and W is CH
- X is 1,3-azetidinylene or 1,3-pyrrolidinylene
- R 4 , R 5 and R 6 are the same or different and each represents a hydrogen atom, dimethylaminomethyl group, methylethylaminomethyl group, diethylaminomethyl group, methylisopropylaminomethyl group, 1-piperidinylmethyl group or 1-
- a compound or a salt thereof which is a pyrrolidinylmethyl group is more preferable.
- A is — (CH 2 ) n —X—; n is 0; R 1 is an amino group;
- R 2 and R 3 is a hydrogen atom or a methyl group, and the other is a hydrogen atom, a halogen atom, a trifluoromethyl group, a methoxyethyl group, a phenyl group, a 2-thienyl group, or a cyano group;
- Y is —C ⁇ C— (R 7 )
- R 7 is a methyl group
- X is 1,3-azetidinylene or 1,3-pyrrolidinylene (wherein the nitrogen atom is bonded to the carbonyl group of —COY in the general formula (I))
- R 4 , R 5 and R 6 are the same or different and each represents a hydrogen atom, dimethylaminomethyl group, methylethylaminomethyl group, diethylaminomethyl group, methylisopropylaminomethyl group, 1-piperidinylmethyl group or 1-
- a compound or a salt thereof which is a pyrrolidinylmethyl group is more preferable.
- A is — (CH 2 ) n —X—; n is 0; X is 1,3-piperidinylene; Y is a vinyl group; Z is CH; W is N; R 1 is an amino group; A compound or a salt thereof, in which one of R 2 and R 3 is a hydrogen atom and the other is a hydrogen atom, a halogen atom, or a cyano group, is more preferable.
- A is — (CH 2 ) n —X—; n is 0; X is 1,3-piperidinylene (wherein the nitrogen atom is bonded to the carbonyl group of —COY in the general formula (I)); Y is a vinyl group; Z is CH; W is N; R 1 is an amino group; A compound or a salt thereof, in which one of R 2 and R 3 is a hydrogen atom and the other is a hydrogen atom, a halogen atom, or a cyano group, is more preferable.
- A is — (CH 2 ) n —X—; n is 0; X is 1,3-piperidinylene; Y is a vinyl group; Z is CH; W is N; R 1 is an amino group; A compound or a salt thereof in which one of R 2 and R 3 is a hydrogen atom and the other is a hydrogen atom or a halogen atom is more preferable.
- A is — (CH 2 ) n —X—; n is 0; X is 1,3-piperidinylene (wherein the nitrogen atom is bonded to the carbonyl group of —COY in the general formula (I)); Y is a vinyl group; Z is CH; W is N; R 1 is an amino group; A compound or a salt thereof in which one of R 2 and R 3 is a hydrogen atom and the other is a hydrogen atom or a halogen atom is more preferable.
- Examples of the compound of the present invention include, but are not limited to, compounds produced in Examples described later.
- suitable compounds of the present invention include the following: (1) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Pyrimidine-3-carboxamide (Example Compound 1) (2) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-bromobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Pyrimidine-3-carboxamide (Example compound 2) (3) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1H-pyra
- the probe according to the present invention comprises a detectable label or affinity tag combined with the compound of the present invention, and a linker.
- the linker connects the compound of the present invention and the label or tag.
- the detectable label or affinity tag is not particularly limited as long as the binding between the probe according to the present invention and BTK can be detected, but it is desirable to have a functional group capable of binding to the linker moiety by alkylation or amidation.
- BODIPY (registered trademark) FL BODIPY (registered trademark) R6G, BODIPY (registered trademark) TMR, BODIPY (registered trademark) 581/591, BODIPY (registered trademark) TR and the like are luminophores, and biotin and the like are conjugated groups. can give. More preferred are BODIPY (registered trademark) FL and biotin.
- the linker is not particularly limited as long as it can connect the label or tag to the compound of the present invention. It is desirable.
- the probe according to the present invention is preferably 4-amino-N- (benzo [d] oxazol-2-yl) -1-((R) -1-((E) -4- (4- (2- (5-((3aS, 4S, 6aR) -2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl) piperazin-1-yl) but-2-enoyl ) Piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide, or (R, E) -7- (3-((2- (4- (4- (3- ( 4-Amino-3- (benzo [d] oxazol-2-ylcarbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) -4-oxobut-2-en-
- the probe according to the present invention can be detected by, for example, co-processing with a sample such as in blood or spleen, or by co-processing with a cell extract derived from blood, spleen or the like to detect the binding state of the compound of the present invention and BTK.
- biochemical techniques emission, fluorescence, etc.
- Step 1 This step is a step of synthesizing the benzoxazole compound represented by the general formula (III) from the aminophenol represented by the general formula (II).
- reagents used include cyano compounds such as bromocyanide, chlorocyanide, iodocyan, and 1,1-carbonimidoylbis-1H-imidazole.
- the reaction is carried out using 0.5 to 5 mol, preferably 0.9 to 1.5 mol, of a cyano compound per 1 mol of the compound represented by the general formula (II).
- the said cyano compound can be manufactured according to a commercial item or a well-known method.
- the solvent used in the reaction is not particularly limited as long as it does not adversely influence the reaction.
- alcohols for example, methanol, ethanol, etc.
- hydrocarbons for example, benzene, toluene, xylene, etc.
- halogenated hydrocarbons Eg, methylene chloride, chloroform, 1,2-dichloroethane, etc.
- nitriles eg, acetonitrile, etc.
- ethers eg, dimethoxyethane, tetrahydrofuran, etc.
- aprotic polar solvents eg, N, N—
- Dimethylformamide dimethylsulfoxide, hexamethylphosphoramide, etc.
- water or a mixture thereof.
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 to 120 ° C., preferably 0 to 90 ° C.
- the compound represented by the general formula (III) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.
- L 3 and L 4 represent a leaving group; P 1 represents a protective group for an amino group contained in A; W, A , Y, Z, R 1 , R 2 and R 3 represent It is synonymous. ]
- Step 2 This step is a step of producing a compound represented by the general formula (VII) using the compound represented by the general formula (IV) and the general formula (V) or the general formula (VI). .
- the compound represented by formula (V) is used as an alkylating reagent, it can be produced in the presence of a base.
- L 4 includes a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonic acid ester, a p-toluenesulfonic acid ester, and the like. Can be manufactured.
- the compound represented by the general formula (V) can be used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula (IV).
- the base include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, sodium hydride, potassium hydride and other inorganic bases, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine. , 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like, and the amount of the base used is 1 to 1 mol of the compound represented by the general formula (IV).
- 100 mol can be used, preferably 2 to 10 mol.
- the solvent N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile, etc. may be used singly or in combination. it can.
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.
- the general formula (VI) When the general formula (VI) is used as an alkylating reagent, it can be produced using a Mitsunobu reaction.
- This step can be carried out according to a generally known method (for example, Chemical Reviews, Vol. 109, p. 2551, 2009).
- phosphine reagent For example, in the presence of Mitsunobu Reagents, phosphine reagent, the reaction is adversely affected. It can be carried out in a solvent that does not reach.
- This step is usually carried out using 1 to 10 mol, preferably 1 to 5 mol, of the compound represented by the general formula (VI) per 1 mol of the compound represented by the general formula (IV).
- Examples of the Mitsunobu reagent include diethyl azodicarboxylate and diisopropyl azodicarboxylate.
- the amount of Mitsunobu reagent used is 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula (IV).
- Examples of the phosphine reagent include triphenylphosphine and tributyphosphine.
- the phosphine reagent is used in an amount of 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of the compound represented by the general formula (IV).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- reaction temperature is usually ⁇ 78 to 200 ° C., preferably 0 to 50 ° C.
- reaction time is usually 5 minutes to 3 days, preferably 10 minutes to 10 hours.
- the compound represented by the general formula (VII) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. The product can be subjected to the next step without separation and purification.
- Step 3 the compound represented by the general formula (VII) is added in a solvent that does not adversely influence the reaction in the presence of an alcohol, for example, a transition metal and, optionally, a base, in a carbon monoxide atmosphere.
- the compound represented by the general formula (VIII) is produced.
- the leaving group represented by L 3 is a bromine atom or an iodine atom, and the compound can be produced according to a commercially available product or a known method.
- the pressure of carbon monoxide is usually 1 to 10 atmospheres, preferably 1 to 5 atmospheres.
- the amount of the alcohol compound to be used can be 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula (VII).
- the alcohol compound include methanol, ethanol, propanol, isopropyl alcohol, diethylaminoethanol, isobutanol, 4- (2-hydroxyethyl) morpholine, 3-morpholinopropanol, diethylaminopropanol and the like.
- transition metal catalyst examples include a palladium catalyst (eg, palladium acetate, tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis ( Diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, etc.), and a ligand (eg, triphenylphosphine, xanthophos, tri-tert-butylphosphine, etc.) is added as necessary.
- a palladium catalyst eg, palladium acetate, tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis ( Diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, etc.
- the amount of the transition metal catalyst used varies depending on the type of catalyst, but is usually 0.0001 to 1 mol, preferably 0.001 to 0.5 mol, relative to 1 mol of the compound represented by the general formula (VII). is there.
- the amount of the ligand used is usually 0.0001 to 4 mol, preferably 0.01 to 2 mol, per 1 mol of the compound represented by the general formula (VII).
- the said reaction can add a base as needed.
- the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyl.
- Organic bases such as disilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, butyllithium, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride Is mentioned.
- the amount of the base to be used is generally 0.1 to 50 mol, preferably 1 to 20 mol, per 1 mol of the compound represented by the general formula (VII).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- hydrocarbons for example, benzene, toluene, xylene and the like
- nitriles for example, acetonitrile and the like
- ethers for example, dimethoxyethane
- Tetrahydrofuran 1,4-dioxane, etc.
- alcohols eg, methanol, ethanol, etc.
- aprotic polar solvents eg, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, hexamethylphosphoramide, etc.
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 150 ° C. After this reaction, it becomes a mixture of the carboxylic acid compound (VIII) and the ester corresponding to the alcohol used, so that it undergoes a hydrolysis reaction and is converted to a compound represented by the general formula (VIII).
- Hydrolysis is carried out using a base such as diethylamine, diisopropylamine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium. Examples thereof include organic bases such as hexamethyldisilazide and butyllithium, and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydroxide.
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- hydrocarbons for example, benzene, toluene, xylene and the like
- nitriles for example, acetonitrile and the like
- ethers for example, dimethoxyethane
- Tetrahydrofuran 1,4-dioxane, etc.
- alcohols eg, methanol, ethanol, etc.
- aprotic polar solvents eg, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, hexamethylphosphoramide, etc.
- Water or a mixture thereof for example, hydrocarbons (for example, benzene, toluene, xylene and the like), nitriles (for example, acetonitrile and the like), ethers (for example, dimethoxyethane) , Tetrahydrofuran, 1,4-dio
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 150 ° C.
- the compound represented by the general formula (VIII) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without separation and purification.
- Step 4 This step is a step for producing a compound represented by the general formula (IX) by carrying out an amidation reaction using the compounds represented by the general formula (VIII) and the general formula (III).
- a suitable condensing agent or activator as an amidating reagent, 0.5 to 10 mol, preferably 1 Performed using ⁇ 3 moles.
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- reaction temperature is usually ⁇ 78 to 200 ° C., preferably 0 to 50 ° C.
- reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.
- the said reaction can add a base as needed.
- the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium Hexamethyldisilazide, potassium hexamethyldisilazide, diazabicycloundecene, diazabicyclononene, organic bases such as butyllithium, or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, hydrogen And inorganic bases such as sodium hydride.
- the addition amount is 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of the compound represented by the general formula (VIII).
- the compound represented by the general formula (IX) thus obtained can be isolated and purified by a known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can utilize for manufacture of this invention compound (I), without separating and refining.
- L 3 represents a leaving group
- Step 5 the compound represented by the general formula (VII) is adversely affected by the reaction in the presence of compound (III) in the presence of compound (III), for example, with a transition metal and a base as necessary.
- This is a step of producing a compound represented by the general formula (IX) by carrying out in a solvent not present.
- the leaving group represented by L 3 is a bromine atom or an iodine atom, and the compound can be produced according to a commercially available product or a known method.
- the pressure of carbon monoxide is 1 to 10 atmospheres, preferably 1 to 5 atmospheres.
- transition metal catalyst examples include a palladium catalyst (eg, palladium acetate, tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis ( Diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, etc.), and a ligand (eg, triphenylphosphine, xanthophos, tri-tert-butylphosphine, etc.) is added as necessary.
- a palladium catalyst eg, palladium acetate, tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis ( Diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, etc.
- the amount of the transition metal catalyst used varies depending on the type of catalyst, but is usually 0.0001 to 1 mol, preferably 0.001 to 0.5 mol, relative to 1 mol of the compound represented by the general formula (IX). is there.
- the amount of the ligand used is usually 0.0001 to 4 mol, preferably 0.01 to 2 mol, per 1 mol of the compound represented by the general formula (VII).
- the said reaction can add a base as needed.
- Examples of the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyl.
- Organic bases such as disilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, butyllithium, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride Is mentioned.
- the amount of the base to be used is generally 0.1-50 mol, preferably 1-20 mol, per 1 mol of the compound represented by the general formula (VII).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- hydrocarbons for example, benzene, toluene, xylene and the like
- nitriles for example, acetonitrile and the like
- ethers for example, dimethoxyethane
- Tetrahydrofuran 1,4-dioxane, etc.
- alcohols eg, methanol, ethanol, etc.
- aprotic polar solvents eg, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, hexamethylphosphoramide, etc.
- Water or a mixture thereof for example, hydrocarbons (for example, benzene, toluene, xylene and the like), nitriles (for example, acetonitrile and the like), ethers (for example, dimethoxyethane) , Tetrahydrofuran, 1,4-dio
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 150 ° C.
- the compound represented by the general formula (IX) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can utilize for manufacture of this invention compound (I), without separating and refining.
- Step 6 This step is a step for producing a compound represented by the general formula (X) by deprotecting the amino group protection of the compound represented by the general formula (IX).
- Examples of the deprotection method include generally known methods such as Protective Groups in Organic Synthesis, T. et al. W. It can be performed by the method described in Greene, John Wiley & Sons (1981) or a method analogous thereto.
- An example of a protecting group is tert-butyloxycarbonyl.
- a tert-butyloxycarbonyl group is used as the protecting group
- deprotection under acidic conditions is preferred, and examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, tosylic acid and the like.
- deprotection using a Lewis acid is also preferable, and examples include trimethylsilyl iodine, boron trifluoride / diethyl ether complex, and the like.
- the amount of the acid to be used is preferably 1 to 100 mol per 1 mol of compound (IX).
- the solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
- the reaction temperature is 0 to 120 ° C., preferably 0 to 90 ° C.
- the compound represented by the general formula (X) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.
- Step 7 the compound represented by the general formula (X) and a carboxylic acid represented by Y—COOH or Y—C ( ⁇ O) —L (L represents a chlorine atom or a bromine atom)
- a carboxylic acid represented by Y-COOH is used as an amidating reagent
- 0.5 to 10 moles of carboxylic acid is used per 1 mole of the compound represented by the general formula (X) in the presence of a suitable condensing agent. It is preferably carried out using 1 to 3 moles.
- the said carboxylic acid can be manufactured according to a commercial item or a well-known method.
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide N-methylpyrrolidinone, dimethyl sulfoxide, etc., or a mixed solvent thereof is preferred.
- the reaction temperature is usually ⁇ 78 to 200 ° C., preferably 0 to 50 ° C.
- the reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.
- condensing agent examples include diphenyl phosphate azide, N, N′-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt, 4- (4,6-dimethoxy-1,3,5-triazine-2 -Yl) -4-methylmorpholinium chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole, 2-chloro-1,3-dimethylimidazolinium chloride, O- (7-azabenzotriazo-1-yl) -N, N, N ′, N′-tetramethylhexauronium hexafluorophosphate, etc.
- the said reaction can add a base as needed.
- the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium
- organic bases such as hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium
- inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.
- the addition amount is 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of the compound represented by the general formula (X).
- an acid halide represented by Y—C ( ⁇ O) —L (L represents a chlorine atom or a bromine atom) is used as an amidating reagent, with respect to 1 mol of the compound represented by the general formula (X),
- the acid halide is used in an amount of 0.5 to 5 mol, preferably 0.9 to 1.1 mol.
- the said acid halide can be manufactured according to a commercial item or a well-known method.
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- reaction temperature is usually ⁇ 78 to 200 ° C., preferably ⁇ 20 to 50 ° C.
- reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.
- said reaction can add a base as needed.
- Bases include, for example, triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butylate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexa
- organic bases such as methyl disilazide, potassium hexamethyl disilazide, and butyl lithium
- inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.
- the addition amount can be 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of the compound represented by the general formula (X).
- the compound represented by the general formula (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. .
- Step 8 Step 9 This step is a step for producing a compound represented by the general formula (XII) in the same manner as in Production Method 4, Steps 6 and 7 to the compound represented by the general formula (VIII). is there.
- Step 10 This step is a step for producing the compound represented by the general formula (I) by the same procedure as in Production Method 2 and Step 4 for the compound represented by the general formula (XII).
- the compound represented by the general formula (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. .
- Step 11 In this step, a compound represented by the general formula (X) and a carboxylic acid represented by “Linker-CH ⁇ CH—COOH” or “Linker-CH ⁇ CH—CO—L” (L is chlorine
- This is a step of producing a compound represented by the general formula (XIII) by an amidation reaction with an acid halide represented by the formula (XIII).
- This reaction can be carried out with reference to production method 4 step 7.
- the Linker part is a part that connects the Reporter part and the compound, and preferably has an appropriate length, physical properties that do not greatly affect the compound, and a functional group that can extend the Reporter part.
- the Linker part for example,
- reporter part examples include BODIPY (registered trademark) FL, BODIPY (registered trademark) R6G, BODIPY (registered trademark) TMR, BODIPY (registered trademark) 581/591, BODIPY (registered trademark) TR, and the like, and biotin, etc. Is given as a union.
- L 3 represents a leaving group: P 1 , W, A, Y, Z, R 1 , R 2 and R 3 are as defined above.
- Steps 13 and 14 This step is a step of producing a compound represented by the general formula (XV) from the compound represented by the general formula (VII) by the same operation as in Production Method 4, Steps 6 and 7.
- Step 15 This step is a step for producing the general formula (I) in the same manner as in Production Method 3 and Step 5 on the compound represented by the general formula (XVI).
- the compound represented by the general formula (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. .
- amino groups, imino groups, hydroxyl groups, carboxyl groups, carbonyl groups and amide groups, and functional groups having active protons such as indole are protected at appropriate steps in each production method.
- the protecting group can be removed after introducing a protecting group into the functional group using a conventional reagent or according to a conventional method.
- the “protecting group for amino group or imino group” is not particularly limited as long as it has the function.
- benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, Aralkyl groups such as p-nitrobenzyl group, benzhydryl group, trityl group and cumyl group; for example, lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, trifluoroacetyl group and trichloroacetyl group;
- Benzoyl group for example, arylalkanoyl group such as phenylacetyl group and phenoxyacetyl group; for example, lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, tert-butoxycarbonyl group;
- the “hydroxyl-protecting group” is not particularly limited as long as it has the function, but for example, a lower alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group; A lower alkylsilyl group such as a butyldimethylsilyl group; a lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydropyranyl group; a trimethylsilylethoxymethyl group; a benzyl group, a p-methoxybenzyl Aralkyl groups such as a group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group; for example, acyl groups such as formyl group, acetyl group, trifluoroacetyl group, etc.
- the “carboxyl-protecting group” is not particularly limited as long as it has the function, but for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group; Halo lower alkyl groups such as 1,2-trichloroethyl group; for example, lower alkenyl groups such as allyl group; for example, trimethylsilylethoxymethyl group; for example, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group, trityl group, etc. And the like, and particularly preferred are methyl group, ethyl group, tert-butyl group, allyl group, benzyl group, p-methoxybenzyl group, trimethylsilylethoxymethyl group and the like.
- the “carbonyl-protecting group” is not particularly limited as long as it has the function, and examples thereof include ketals such as ethylene ketal, trimethylene ketal, dimethyl ketal, ethylene acetal, trimethylene acetal, dimethyl acetal, and acetals. Can be mentioned.
- the method for removing the protecting group varies depending on the type of the protecting group and the stability of the target compound.
- the method described in the literature Protective Groups in Organic Synthesis, 3rd edition, by TW Greene, John Wiley & Sons) 1999
- a method analogous thereto eg solvolysis using acids or bases, ie for example 0.01 mol to large excess of acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid etc., or equimolar to
- a large excess of base preferably potassium hydroxide, calcium hydroxide or the like is allowed to act
- chemical reduction using a metal hydride complex or the like or catalytic reduction using a palladium-carbon catalyst, Raney nickel catalyst, or the like.
- the compound of the present invention can be easily isolated and purified by ordinary separation means.
- Examples of such means include solvent extraction, recrystallization, preparative reverse phase high performance liquid chromatography, column chromatography, preparative thin layer chromatography and the like.
- the compound of the present invention has an isomer such as an optical isomer, a stereoisomer, a positional isomer or a rotational isomer
- a mixture of any isomers is also included in the compound of the present invention.
- an optical isomer exists in the compound of the present invention
- an optical isomer resolved from a racemate is also included in the compound of the present invention.
- Each of these isomers can be obtained as a single compound by synthetic methods and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.).
- the compound of the present invention or a salt thereof may be in the form of a crystal, and it is included in the compound of the present invention or a salt thereof regardless of whether the crystal form is single or polymorphic.
- the crystal can be produced by crystallization by applying a crystallization method known per se.
- the compound of the present invention or a salt thereof may be a solvate (such as a hydrate) or a non-solvate, and both are included in the compound of the present invention or a salt thereof.
- a compound labeled with an isotope eg, 3 H, 14 C, 35 S, 125 I, etc. is also encompassed in the compound of the present invention or a salt thereof.
- a prodrug of the compound of the present invention or a salt thereof is a compound that is converted into the compound of the present invention or a salt thereof by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed, etc.
- the prodrug of the compound of the present invention or a salt thereof can be converted into the compound of the present invention or a salt thereof under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, pages 163 to 198. It may change.
- the compound of the present invention or a salt thereof has excellent BTK inhibitory activity and is useful as an antitumor agent. In addition, it has an excellent selectivity for BTK, and has the advantage that there are few side effects due to inhibition of other kinases.
- the compound of the present invention or a salt thereof has excellent BTK inhibitory activity.
- BTK includes human or non-human mammal BTK, preferably human BTK.
- the term “BTK” includes isoforms.
- this invention compound or its salt is useful as a pharmaceutical for the prevention or treatment of the disease in which BTK is related by the outstanding BTK inhibitory activity.
- Diseases involving BTK include diseases in which the rate of onset is reduced, symptoms are ameliorated, alleviated, and / or completely cured by deleting, suppressing and / or inhibiting BTK function. Examples of such diseases include, but are not limited to, cancer and tumors. The target cancer or tumor is not particularly limited.
- epithelial cancer for example, respiratory cancer, digestive cancer, genital cancer, secretory cancer, etc.
- sarcoma hematopoietic cell line.
- Tumors, central nervous system tumors, peripheral nerve tumors and the like, and hematopoietic cell tumors are preferable.
- the type of tumor organ is not particularly limited, for example, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer,
- Examples include ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, blood tumor, multiple myeloma, skin cancer, brain tumor, mesothelioma and the like.
- the hematopoietic cell line tumor is preferably acute leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, lymphoblastic lymphoma, myeloproliferative tumor, chronic lymphocytic leukemia, small lymph Spherical lymphoma, myelodysplastic syndrome, follicular lymphoma, MALT lymphoma, marginal zone lymphoma, lymphoid plasma cell lymphoma, Waldenstrom macroglobulinemia, mantle cell lymphoma, diffuse large B-cell lymphoma, bar Kit lymphoma, extranodal NK / T cell lymphoma, Hodgkin lymphoma, multiple myeloma, etc.
- B lymphoblastic leukemia / lymphoma follicular lymphoma, mantle cell lymphoma, nodal follicular marginal zone lymphoma, diffuse large B cell lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia, small lymphocyte Hematologic tumors such as metastatic lymphoma, Waldenstrom macroglobulinemia, extranodal NK / T cell lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, acute myeloid leukemia, acute lymphocytic leukemia.
- a pharmaceutical carrier can be blended as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment. Any of injections, suppositories, ointments, patches and the like may be used. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
- the pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, coating agents, etc. in solid preparations, solvents in liquid preparations, dissolution aids , Suspending agents, isotonic agents, pH adjusting agents / buffering agents, soothing agents and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, flavoring / flavoring agents, stabilizers and the like can be used as necessary.
- excipient examples include lactose, sucrose, D-mannitol, starch, crystalline cellulose, calcium silicate and the like.
- binder examples include hydroxypropyl cellulose, methyl cellulose, polyvinyl pyrrolidone, candy powder, hypromellose and the like.
- disintegrant examples include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch and the like.
- lubricant examples include talc, magnesium stearate, sucrose fatty acid ester, stearic acid, sodium stearyl fumarate and the like.
- Examples of the coating agent include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, sucrose, and the like.
- Examples of the solvent include water, propylene glycol, and physiological saline.
- Examples of the solubilizer include polyethylene glycol, ethanol, ⁇ -cyclodextrin, macrogol 400, polysorbate 80 and the like.
- Suspending agents include carrageenan, crystalline cellulose / carmellose sodium, and polyoxyethylene hydrogenated castor oil.
- Examples of the isotonic agent include sodium chloride, glycerin, potassium chloride and the like.
- Examples of the pH regulator / buffering agent include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate and the like.
- Examples of soothing agents include procaine hydrochloride and lidocaine.
- Examples of preservatives include ethyl paraoxybenzoate, cresol, benzalkonium chloride, and the like.
- Examples of the antioxidant include sodium sulfite, ascorbic acid, natural vitamin E and the like.
- Examples of the colorant include titanium oxide, iron sesquioxide, edible blue No. 1, copper chlorophyll and the like.
- Examples of flavoring and flavoring agents include aspartame, saccharin, sucralose, l-menthol, and mint flavor.
- Examples of the stabilizer include sodium pyrosulfite, sodium edetate, erythorbic acid, magnesium oxide, dibutylhydroxytoluene and the like.
- an excipient When preparing an oral solid preparation, an excipient, if necessary, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. are added to the compound of the present invention. Tablets, coated tablets, granules, powders, capsules and the like can be produced by the method.
- a pH adjuster, buffer, stabilizer, tonicity agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods. Can be manufactured.
- the amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which the compound is to be applied, or its dosage form, but generally 0 for oral dosage forms per dosage unit form. .05 to 1000 mg, 0.01 to 500 mg for injections, and 1 to 1000 mg for suppositories.
- the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally.
- the dose may be 0.05 to 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into 2 to 3 times a day.
- the NMR spectrum was measured using an AL400 (400 MHz; JEOL), Mercury 400 (400 MHz; Agilent Technology) spectrometer, or an Inova 400 (400 MHz; Agilent Technology) spectrometer equipped with an OM NMR probe (Protasis).
- AL400 400 MHz; JEOL
- Mercury 400 400 MHz; Agilent Technology
- Inova 400 400 MHz; Agilent Technology
- OM NMR probe Protasis
- Step 1 Synthesis of (S) -tert-butyl 3- (methylsulfonyloxy) piperidine-1-carboxylate 20 g of (S) -N-Boc-3-piperidinol was dissolved in 100 ml of toluene and heated to 0 ° C. Then, 21 ml of triethylamine and 9.2 ml of methanesulfonyl chloride were added. After stirring for 1 hour under ice cooling, ethyl acetate and water were added, and the organic layer was separated.
- the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous ammonium chloride solution and water, and then dried over anhydrous sodium sulfate.
- the solvent was distilled off under reduced pressure to obtain 26.8 g of the title compound as a colorless solid.
- Step 2 Synthesis of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate International Publication WO2007 / 14.6 g of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine synthesized by the method described in the pamphlet of No. 126841, (S) -tert-butyl 3 obtained in Step 1 A suspension of 150 ml of DMA containing 25 g of-(methylsulfonyloxy) piperidine-1-carboxylate and 69 g of potassium carbonate was heated to 100 ° C.
- Step 1 Synthesis of (S) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate 935 mg of (S)-( ⁇ )-N-Boc-3-pyrrolidinol was dissolved in 15 ml of chloroform, ice Under cooling, 1.04 ml of triethylamine and 467 ⁇ l of methanesulfonyl chloride were added. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added, and the organic layer was separated.
- Step 2 Synthesis of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate
- Step 3 Synthesis of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid 2.0 g of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in step 2; 3.1 ml of 2-diethylaminoethanol and 163 mg of Pd (PPh 3 ) 2 Cl 2 were dissolved in 20 ml of NMP, and the system was replaced with carbon monoxide, followed by heating to 120 ° C.
- Example 1 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of pyrimidine-3-carboxamide (Example Compound 1) (Step 1) (R) -tert-butyl-3- (4-amino-3-((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) Synthesis of -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate (R) -4-amino-1- (1- (tert-butyloxy) obtained in Synthesis
- Example 2 50 mg of CDI was added to a suspension of 94 mg of THF in 4 ml of THF after adding carbonyl) piperidin-3-yl) -1H-pyrazolo [3,4-d
- Step 2 Synthesis of Example Compound 1 (R) -tert-butyl-3- (4-amino-3- (5-chlorobenzo [d] oxazol-2-ylcarbonyl)-obtained in (Step 1) 1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate (5.6 mg) was added with 4N-hydrochloric acid / 1,4-dioxane (1 ml), and the mixture was stirred for 1 hour, and then the solvent was removed with an evaporator.
- Example 3 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1H-pyrazolo Synthesis of [3,4-d] pyrimidine-3-carboxamide (Example Compound 3) (Step 1) Synthesis of 5- (thiophen-2-yl) benzo [d] oxazol-2-amine 5-Bromobenzo [d] Oxazol-2-amine (100 mg), potassium phosphate (249 mg), and thiophen-2-ylboronic acid (90 mg) were suspended in DME (2.5 ml) and water (0.5 ml), and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) Dichloride-dichloromethane (38 mg) was added, and the mixture was heated in a microwave reactor at 140 ° C.
- Step 2 (R) -tert-butyl-3- (4-amino-3-((5- (thiophen-2-yl) benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3 , 4-d] pyrimidin-1-yl) piperidine-1-carboxylate (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidine-3- obtained in Synthesis Example 2 Yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid 10 mg of CDI was added to a suspension of 19 mg of THF 2 ml, and the mixture was stirred at room temperature for 2 hours.
- Step 3 Synthesis of Example Compound 3 ((R) -tert-butyl-3- (4-amino-3-((5- (thiophen-2-yl) benzo [d ] Oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate (9 mg) was added with 1 ml of 4N-hydrochloric acid / 1,4-dioxane and stirred for 1 hour.
- Example 4 (R) -4-Amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1-methacryloylpiperidin-3-yl) -1H-pyrazolo [3,4-d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 4) According to Example 1, the title compound was obtained as a white solid using methacrylic chloride instead of acrylic chloride.
- Example 5 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) piperidin-3-yl) -1H- Synthesis of Pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 5) According to Example 1, using crotonic acid chloride instead of acrylic chloride, the title compound was obtained as a white solid.
- Example 6 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-cyanobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 6) (Step 1) (R) -tert-butyl-3- (4-amino-3-((5-cyanobenzo [d] oxazol-2-yl) carbamoyl) Synthesis of -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate (R) -4-amino-1- (1- (tert-butyloxy) obtained in Synthesis Example 2 Carbonyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid (2.32 g) was dissolved in DMA (25 ml), CDI
- Step 2 Synthesis of Example Compound 6 (R) -tert-butyl-3- (4-amino-3-((5-cyanobenzo [d] oxazol-2-yl) carbamoyl)-obtained in Step 1 2.1 g of 1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate was suspended in 10 ml of dichloromethane, and 10 ml of TFA was added at room temperature. After stirring for 2 hours, TFA was removed by an evaporator. Further, azeotropy was performed with toluene, and 20 ml of NMP and 2 ml of water were added to the residue, followed by ice cooling.
- Example 7 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-methoxybenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] Synthesis of Pyrimidine-3-carboxamide (Example Compound 7) According to Example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) of Synthesis Example 2 The title compound was obtained as a light brown solid from -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and 5-methoxybenzo [d] oxazol-2-amine.
- Example 8 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5- (2-methoxyethyl) benzo [d] oxazol-2-yl) -1H-pyrazolo [ Synthesis of 3,4-d] pyrimidine-3-carboxamide (Example Compound 8) According to Example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidine of Synthesis Example 2 was used.
- Example 9 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (oxazolo [4,5-b] pyridin-2-yl) -1H-pyrazolo [3,4 d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 9) According to Example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl of Synthesis Example 2 was used. ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and oxazolo [4,5-b] pyridin-2-amine gave the title compound as a white solid.
- Example 10 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (4-methylbenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 10) According to Example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl)-of Synthesis Example 2 The title compound was obtained as a white solid from 1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and 4-methylbenzo [d] oxazol-2-amine.
- Example 11 (R) -4-Amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1- (1-methacryloylpiperidin-3-yl) -1H-pyrazolo [3,4-d ] Synthesis of Pyrimidine-3-carboxamide (Example Compound 11) According to Example 6, (R) -4-amino-N- (5-fluorobenzo [d] oxazole obtained in Example 12 (Step 2) The title compound was obtained as a white solid using -2-yl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide and methacrylic chloride instead of acrylic chloride. .
- Example 12 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] Synthesis of pyrimidine-3-carboxamide (Example Compound 12) (Step 1) (R) -tert-butyl-3- (4-amino-3-((5-fluorobenzo [d] oxazol-2-yl) Synthesis of carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate (R) -4-amino-1- (1- (tert-) obtained in Synthesis Example 2 Butyloxycarbonyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid 895 mg of CDI was added to a solution of 1.0 g of
- Step 2 (R) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine Synthesis of -3-carboxamide (R) -tert-butyl-3- (4-amino-3- (5-fluorobenzo [d] oxazol-2-ylcarbonyl) -1H-pyrazolo [3] obtained in Step 1 , 4-d] pyrimidin-1-yl) piperidine-1-carboxylate and 5.5 g of sodium iodide were suspended in 30 ml of acetonitrile, and 4.7 ml of trimethylsilyl chloride was added at room temperature.
- Step 3 Synthesis of Example Compound 12 (R) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1- (piperidin-3-yl) obtained in Step 2
- 1 g of 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide and 2.1 g of potassium carbonate were dissolved in 20 ml of NMP and 2 ml of water and stirred under ice cooling.
- 0.4 ml of acrylic chloride was added and stirred for 1 hour. Water was added, the pH was adjusted with hydrochloric acid, and the precipitated solid was collected by filtration.
- the solid collected by filtration was purified by silica gel chromatography (eluent: chloroform-methanol) to obtain 1.79 g of the title compound as a white solid.
- Example 13 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxamide (Example Compound 13) (Step 1) (R) -tert-butyl-3- (4-amino-3-((benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo Synthesis of [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3] obtained in Synthesis Example 1 , 4-d] pyrimidin-1-yl) piperidine-1-carboxylate 300 mg was dissolved in 3 ml NMP.
- Step 2 Synthesis of Example Compound 13 (R) -tert-Butyl-3- (4-amino-3-((benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo obtained in Step 1
- 5 g of [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate was suspended in 50 ml of acetonitrile, and 7.85 g of sodium iodide was added. Under stirring at room temperature, 6.65 ml of trimethylsilyl chloride was added dropwise and stirred for 1 hour. After adding 87.5 ml of water and 12.5 ml of 5N sodium hydroxide aqueous solution, the mixture was ice-cooled. 0.895 ml of acrylic chloride was added dropwise and stirred for 1 hour under ice cooling. Water was added and the resulting solid was collected by filtration, washed with water and dried to give 4.13 g of the title compound as a white solid.
- Example 14 (R, E) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [ Synthesis of 3,4-d] pyrimidine-3-carboxamide (Example Compound 14) According to Example 13, the title compound was obtained as a white solid using crotonic acid chloride instead of acrylic chloride.
- Example 16 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4-ethyl (methyl) amino) but-2-enoyl) piperidine Synthesis of -3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 16) According to Example 15, (E) -4- (dimethylamino) but-2-ene The title compound was obtained as a white solid by using (E) -4- (ethyl (methyl) amino) but-2-enoic acid hydrochloride instead of the hydrochloride salt.
- Example 17 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4-diethylamino) but-2-enoyl) piperidin-3-yl ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 17) Synthesis of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride according to Example 15 The title compound was obtained as a white solid by using (E) -4- (diethylamino) but-2-enoic acid hydrochloride instead.
- Example 18 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4-isopropyl (methyl) amino) but-2-enoyl) piperidine Synthesis of (-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 18) According to Example 15, (E) -4- (dimethylamino) but-2-ene The title compound was obtained as a white solid by using (E) -4- (isopropyl (methyl) amino) but-2-enoic acid hydrochloride instead of the hydrochloride salt.
- Example 19 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) Synthesis of Piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 19) According to Example 15, (E) -4- (dimethylamino) but-2- The title compound was obtained as a white solid by using (E) -4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride instead of enoic acid hydrochloride.
- Example 20 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (piperidin-1-yl) but-2-enoyl) Synthesis of Piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 20) According to Example 15, (E) -4- (dimethylamino) but-2- The title compound was obtained as a white solid by using (E) -4- (piperidin-1-yl) but-2-enoic acid hydrochloride instead of enoic acid hydrochloride.
- Example 21 (R, E) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) buta- Synthesis of 2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 21) Obtained in Example 3 (Step 2) according to Example 15 (R) -tert-butyl-3- (4-amino-3-((5- (thiophen-2-yl) benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4 d] Pyrimidin-1-yl) piperidine-1-carboxylate was used to give the title compound as a white solid.
- Example 22 (R) -4-Amino-N- (benzo [d] oxazol-2-yl) -1- (1-but-2-inoyl) piperidin-3-yl) -1H-pyrazolo [3,4 -D] Synthesis of Pyrimidine-3-carboxamide (Example Compound 22) According to Example 15, (R) -tert-butyl-3- (4-amino-3-) obtained in Example 13 (Step 1) was used.
- Example 23 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5,6-dimethylbenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4 -D] Synthesis of Pyrimidine-3-carboxamide (Example Compound 23) (Step 1) (R) -1- (1-Acyloxypiperidin-3-yl) -4-amino-1H-pyrazolo [3,4 d] Synthesis of pyrimidine-3-carboxylic acid 4 g of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid in Synthesis Example 3 -Hydrochloric acid / 1,4-dioxane (15 ml) was added, and the mixture was stirred at room temperature for 1 hour.
- Step 2 Synthesis of Example Compound 23 (R) -1- (1-Acyloxypiperidin-3-yl) -4-amino-1H-pyrazolo [3,4-d] pyrimidine obtained in Step 1 above -5 mg of -3-carboxylic acid was dissolved in 150 ⁇ l of DMF. To the solution, 8.26 ⁇ l of diisopropylethylamine, 3.85 mg of 5,6-dimethylbenzo [d] oxazol-2-amine, and 9 mg of HATU were added. After stirring overnight, 850 ⁇ l of DMSO was added and purified by reverse phase preparative HPLC purification (water / acetonitrile (0.1% formic acid)) to give 1.2 mg of the title compound as a white solid.
- Example 24 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 24) (Step 1) (R) -tert-butyl-3- (4-amino-3-((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) Synthesis of -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyridine-1-carboxylate (R) -4-amino-1- (1- (tert-butyloxy) obtained in Synthesis Example 3 Carbonyl (56 mg) was added to a solution of 100 mg of DMF in 5 ml of DMF and stirred at room temperature for 1 hour.
- Example 25 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) pyrrolidin-3-yl) -1H- Synthesis of pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 25) According to Example 24, the title compound was obtained as a white solid using crotonic acid chloride instead of acrylic chloride.
- Example 26 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (3-methylbut-2-enoyl) pyrrolidin-3-yl)- Synthesis of 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 26) According to Example 24, the title compound was converted to white using 3-methylbut-2-enoyl chloride instead of acryl chloride. Obtained as a solid.
- Example 27 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxamide (Example Compound 27) According to Example 24, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1H- of Synthesis Example 3 The title compound was obtained as a white solid from pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and benzo [d] oxazol-2-amine.
- Example 29 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-methylbenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 29) According to Example 24, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl)-of Synthesis Example 3 The title compound was obtained as a pale yellow solid from 1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and 5-methylbenzo [d] oxazol-2-amine.
- Example 30 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] Synthesis of Pyrimidine-3-carboxamide (Example Compound 30) According to Example 24, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) of Synthesis Example 3 The title compound was obtained as a pale yellow solid from -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and 5-fluorobenzo [d] oxazol-2-amine.
- Example 31 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (4-chlorophenyl) benzo [d] oxazol-2-yl) -1H-pyrazolo [3 , 4-d] pyrimidine-3-carboxamide
- Example Compound 31 (Step 1) Synthesis of 5- (4-chlorophenyl) benzo [d] oxazol-2-amine
- thiophene The title compound was obtained as a white solid by using 4-chlorophenylboronic acid instead of -2-ylboronic acid.
- Example 32 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidine-3 Synthesis of —yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 32) (R) -tert-butyl-3- (4- Amino-3-((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate to 15 mg of 4N hydrochloric acid / 1 1.5 ml of 1,4-dioxane was added and stirred for 10 minutes.
- Example 33 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4-ethyl (methyl) amino) but-2-enoyl) pyrrolidine Synthesis of -3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 33) According to Example 32, (E) -4- (dimethylamino) but-2-ene The title compound was obtained as a white solid by using (E) -4- (ethyl (methyl) amino) but-2-enoic acid hydrochloride instead of the hydrochloride salt.
- Example 34 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4-diethylamino) but-2-enoyl) piperidin-3-yl ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 34) Synthesis of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride according to Example 32 The title compound was obtained as a white solid by using (E) -4- (diethylamino) but-2-enoic acid hydrochloride instead.
- Example 35 (R, E) -4-Amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4-isopropyl (methyl) amino) but-2-enoyl) pyrrolidine Synthesis of (3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 35) According to Example 32, (E) -4- (dimethylamino) but-2-ene The title compound was obtained as a white solid by using (E) -4- (isopropyl (methyl) amino) but-2-enoic acid hydrochloride instead of the hydrochloride salt.
- Example 36 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) Synthesis of (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 36) According to Example 32, (E) -4- (dimethylamino) but-2- The title compound was obtained as a white solid by using (E) -4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride instead of enoic acid hydrochloride.
- Example 37 (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (piperidin-1-yl) but-2-enoyl) Synthesis of (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 37) According to Example 32, (E) -4- (dimethylamino) but-2- The title compound was obtained as a white solid by using (E) -4- (piperidin-1-yl) but-2-enoic acid hydrochloride instead of enoic acid hydrochloride.
- Example 38 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-methoxybenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] Synthesis of Pyrimidine-3-carboxamide (Example Compound 38) According to Example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) of Synthesis Example 3 The title compound was obtained as a white solid from -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and 5-methoxybenzo [d] oxazol-2-amine.
- Example 39 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-cyanobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 39) According to Example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl)-of Synthesis Example 3 The title compound was obtained as a white solid from 1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and 5-cyanobenzo [d] oxazol-2-amine.
- Example 40 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (2-methoxyethyl) benzo [d] oxazol-2-yl) -1H-pyrazolo [ Synthesis of 3,4-d] pyrimidine-3-carboxamide (Example Compound 40) According to Example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidine of Synthesis Example 3 Obtained as a pale yellow solid from -3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid and 5- (2-methoxyethyl) benzo [d] oxazol-2-amine.
- Example 41 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] Synthesis of Pyrimidine-3-carboxamide (Example Compound 41) (Step 1) (R) -tert-Butyl-3- (4-amino-3-((5-phenylbenzo [d] oxazol-2-yl) Synthesis of carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate (R) -4-amino-1- (1- (tert-butyloxycarbonyl) of Synthesis Example 3 ) 20 mg of pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid was suspended in 1 ml of THF
- Step 2 Synthesis of Example Compound 41 (R) -tert-butyl-3- (4-amino-3-((5-phenylbenzo [d] oxazol-2-yl) carbamoyl obtained in Step 1 above) ) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate (12.8 mg) was added with 1.5 ml of 4N-hydrochloric acid / 1,4-dioxane and stirred for 1 hour. Thereafter, the solvent was removed, and azeotropic distillation was performed with 1 ml of toluene.
- Example 42 (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidine- Synthesis of 3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 42) (R) -tert-butyl-3- (4) obtained in Step 1 of Example 41 -Amino-3-((5-phenylbenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate to 5 mg of N-hydrochloric acid 1 ml of 1,4-dioxane was added and stirred for 30 minutes.
- Example 43 (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (trifluoromethyl) benzo [d] oxazol-2-yl) -1H-pyrazolo [3 , 4-d] pyrimidine-3-carboxamide (Example Compound 43) (Step 1) (R) -tert-butyl-3- (4-amino-3-((5- (trifluoromethyl) benzo [ d] Synthesis of Oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate (R) -4-amino-1- ( 32 mg of 1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid was suspended in 2 ml of THF, and
- Step 2 Synthesis of Example 43 Compound (R) -tert-butyl-3- (4-amino-3-((5- (trifluoromethyl) benzo [d] oxazole-2) obtained in Step 1 above -Il) Carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-carboxylate was added to 500 mg of dichloromethane, and further 200 ⁇ l of trifluoroacetic acid was added and stirred for 30 minutes. Thereafter, the solvent was removed, and azeotropic distillation was performed with 1 ml of toluene.
- Example 44 (R, E) -4-amino-N- (5- (trifluoromethyl) benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2- Synthesis of enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 44) (R) -tert-butyl- obtained in Step 1 of Example 43 3- (4-Amino-3-((5- (trifluoromethyl) benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1 -To 500 mg of carboxylate, 500 ⁇ l of dichloromethane was added, and 200 ⁇ l of trifluoroacetic acid was further added and stirred for 30 minutes.
- Example 45 1- (1-acryloylazetidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 Synthesis of Carboxamide (Example Compound 45) (Step 1) tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate Synthesis of tert-butyl 3-hydroxyazetidine-1-carboxylate (240 mg) in chloroform (2 ml) was added triethylamine (290 ⁇ l) and methanesulfonyl chloride (130 ⁇ l) at 0 ° C.
- Step 2 Synthesis of 4-amino-1- (1- (tert-butyloxycarbonyl) azetidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid obtained in Step 1 Further, 262 mg of tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate was dissolved in 10 ml of methanol and 1 ml of triethylamine.
- Step 3 tert-butyl-3- (4-amino-3-((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl)
- Azetidine-1-carboxylate 4-Amino-1- (1- (tert-butyloxycarbonyl) azetidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine- obtained in Step 2 above 42 mg of 3-carboxylic acid was dissolved in 3 ml of DMF, 24 mg of CDI was added, and the mixture was stirred overnight at room temperature.
- Step 2 Synthesis of tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate
- Step 3 tert-butyl 3- (4-amino-5-((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine
- -1-carboxylate tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate obtained in Step 2 above 32 mg of rate, 20 mg of 5-chlorobenzo [d] oxazol-2-amine, 28 ⁇ l of diazabicycloundecene were dissolved in 1 ml of DMF, and further 9 mg of 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane And stirred for 1.5 hours at 80 ° C.
- Step 4 Synthesis of Example Compound 46 tert-butyl 3- (4-amino-5-((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrolo [
- Example 47 (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (dimethylamino) but-2-enoyl) azetidin-3-yl ) Synthesis of 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 47) tert-butyl 3- (4-amino-5-((5- 1 ml of 4N-hydrochloric acid / 1,4-dioxane was added to 5 mg of chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate.
- Example 48 (R) -7- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7H-pyrrolo [2,3-d] Synthesis of Pyrimidine-5-carboxamide (Example Compound 48) (Step 1) (R) -tert-Butyl 3- (4-Chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl ) Synthesis of pyrrolidine-1-carboxylate 5.00 g of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine synthesized by the method described in International Publication WO2005 / 042556 (S) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (19.1 g) and cesium carbonate (23.5 g) were suspended in acetonitrile (
- Step 2 (R) -tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate obtained in Step 1 above (R) -tert-butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate was added to 40 g of 28% aqueous ammonia. The reaction solution was stirred at 100 ° C. for 1.5 hours in a microwave reactor. The solid precipitated after stirring for 1 hour under ice-cooling was collected by filtration and washed with cold methanol to obtain 3.91 g of the title compound as a white solid.
- Step 4 Synthesis of Example Compound 48 (R) -tert-butyl 3- (4-amino-5-((5-chlorobenzo [d] oxazol-2-yl) carbamoyl)-obtained in Step 3 above
- To 20 mg of 7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate 1 ml of 4N-hydrochloric acid / 1,4-dioxane was added and stirred for 1 hour. Thereafter, the solvent was removed, and azeotropic distillation was performed with 1 ml of toluene.
- Example 49 (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl ) Synthesis of 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 49) (R) -tert-butyl 3- (4-amino-5-) obtained in Step 3 of Example 48 ((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate to 13 mg of 4N-hydrochloric acid / 1,4-dioxane 1 ml was added and stirred for 1 hour.
- Example 50 (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (ethyl (methyl) amino) but-2-enoyl) pyrrolidine- 3-yl) Synthesis of 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 50) According to Example 49, (E) -4- (dimethylamino) but-2-enoic acid The title compound was obtained as a white solid by using (E) -4- (ethyl (methyl) amino) but-2-enoic acid hydrochloride instead of the salt.
- Example 51 (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (diethylamino) but-2-enoyl) pyrrolidin-3-yl) Synthesis of 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 51) According to Example 49, instead of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride The title compound was obtained as a white solid by using (E) -4- (diethylamino) but-2-enoic acid hydrochloride.
- Example 52 (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (isopropyl (methyl) amino) but-2-enoyl) pyrrolidine- 3-yl) Synthesis of 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 52) According to Example 49, (E) -4- (dimethylamino) but-2-enoic acid The title compound was obtained as a white solid using (E) -4- (isopropyl (methyl) amino) but-2-enoic acid hydrochloride instead of the salt.
- Example 53 (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) pyrrolidine- Synthesis of 3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 53) According to Example 49, (E) -4- (dimethylamino) but-2-enoic acid The title compound was obtained as a white solid by using (E) -4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride instead of the salt.
- Example 57 (E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (ethyl (methyl) amino) but-2-enoyl) pyrrolidine -3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 57) According to Example 56, (E) -4- (dimethylamino) but-2-enoic acid The title compound was obtained as a white solid by using (E) -4- (ethyl (methyl) amino) but-2-enoic acid hydrochloride instead of the hydrochloride salt.
- Example 58 (E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (diethylamino) but-2-enoyl) pyrrolidin-3-yl ) Synthesis of 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 58) According to Example 56, instead of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride The title compound was obtained as a white solid by using (E) -4- (diethylamino) but-2-enoic acid hydrochloride.
- Example 59 (E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (isopropyl (methyl) amino) but-2-enoyl) pyrrolidine -3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 59) According to Example 56, (E) -4- (dimethylamino) but-2-enoic acid The title compound was obtained as a white solid by using (E) -4- (isopropyl (methyl) amino) but-2-enoic acid hydrochloride instead of the hydrochloride salt.
- Example 61 (E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (piperidin-1-yl) but-2-enoyl) ) Synthesis of pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Example Compound 61) According to Example 56, (E) -4- (dimethylamino) but-2- The title compound was obtained as a white solid by using (E) -4- (piperidin-1-yl) but-2-enoic acid hydrochloride instead of enoic acid hydrochloride.
- Example 64 (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (7-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 64) (Step 1) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxylic acid (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] obtained in Synthesis Example 2 To 10 g of pyrimidine-3-carboxylic acid was added 50 mL of 4N-hydrochloric acid / 1,4-dioxane, and the mixture was stirred for 1 hour, and then the solvent was removed with
- Example 65 (S) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxamide (Example Compound 65) (Step 1) Synthesis of (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (R) -N-Boc- according to Synthesis Example 3 The title oily compound was obtained from 3-pyrrolidinol.
- Step 2 Synthesis of (S) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate Synthesis Example 3 ( According to Step 2), the title compound is obtained from 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate. A pale yellow solid was obtained.
- Step 3 (S) -1- (3- (4-Amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-ene- Synthesis of 1-one (S) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-carboxy obtained in Step 2 Chloroform 5mL and trifluoroacetic acid 1.7ml were added to the rate 500mg, and after stirring for 1 hour, the solvent was removed with an evaporator.
- Step 4 (S) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine Synthesis of -3-carboxamide (S) -1- (3- (4-Amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolopyrrolidine-1 obtained in Step 3 -Il) 20 mg of prop-2-en-1-one was dissolved in 520 mL of DMF, 13 mg of benzo [d] oxazol-2-amine, 3.65 mg of PdCl 2 (PPh 3) 2 and 23 ⁇ L of DBU were added, and 120 carbon dioxide atmosphere was added.
- Example 67 1-((1-acryloylpiperidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 Synthesis of Carboxamide (Example Compound 67) (Step 1) tert-butyl 3-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidine-1 Synthesis of carboxylate According to Synthesis Example 3 (Step 2), 300 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and tert-butyl 3- (bromomethyl) pyrrolidine-1-carboxylate From 416 mg, 375 mg of the pale yellow solid of the title compound was obtained.
- Step 2 1- (3-((4-Amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop-2-en-1 Synthesis of —one According to Step 3 of Example 65, tert-butyl-3-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl obtained in Step 1 228 mg of a pale yellow solid of the title compound was obtained from 375 mg of)) methyl) piperidine-1-carboxylate.
- Step 3 1-((1-acryloylpiperidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxamide 1- (3-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl obtained in Step 2 according to Step 4 of Example 65) 1.4 mg of a white solid of the title compound was obtained from 10 mg)) methyl) piperidin-1-yl) prop-2-en-1-one.
- Step 2 1- (4-((4-Amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop-2-en-1 Synthesis of —one According to Step 3 of Example 65, tert-butyl 4-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) obtained in Step 1 From 120 mg of methyl) piperidine-1-carboxylate, 85 mg of a pale yellow solid of the title compound was obtained.
- Step 3 1-((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxamide 1- (4-((4-Amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) obtained in Step 2 according to Step 4 of Example 65 3.12 mg of the white solid of the title compound was obtained from 10 mg)) methyl) piperidin-1-yl) prop-2-en-1-one.
- Example 69 1- (1-acryloylpiperidin-4-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide ( Synthesis of Example Compound 69) (Step 1) Synthesis of tert-butyl 4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate Synthesis According to Example 3 (Step 2), a pale yellow solid of the title compound was obtained from 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and tert-butyl 4-bromopiperidine-1-carboxylate. It was.
- Step 2 1- (4- (4-Amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one Synthesis According to Step 3 of Example 65, tert-butyl 4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1- obtained in Step 1 The pale yellow solid of the title compound was obtained from the carboxylate.
- Step 3 1- (1-acryloylpiperidin-4-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
- Step 4 of Example 65 1- (4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1 obtained in Step 3 was obtained.
- -Ill 2.4 mg of the white solid of the title compound was obtained from 10 mg of prop-2-en-1-one.
- Example 70 1-((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxamide (Example Compound 70) (Step 1) Synthesis of tert-butyl 3-((methylsulfonyloxy) methyl) azetidine-1-carboxylate According to Synthesis Example 3, tert-butyl 3- (hydroxymethyl) ) The title oily compound was obtained from azetidine-1-carboxylate.
- Step 2 Synthesis of tert-butyl 3-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) azetidine-1-carboxylate Synthesis Example 3 (Step According to 2), 200 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and tert-butyl 3-((methylsulfonyloxy) methyl) azetidine-1-carboxyl obtained in step 1 The pale yellow solid of the title compound was obtained from the rate.
- Step 3 1- (3-((4-Amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) azetidin-1-yl) propyl-2-ene-1 Synthesis of —one According to Step 3 of Example 65, tert-butyl 3-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) obtained in Step 2 A pale yellow solid of the title compound was obtained from methyl) azetidine-1-carboxylate.
- Example 71 1-((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3- Synthesis of Carboxamide (Example Compound 71) (Step 1) Synthesis of (1R, 4R) -4-((tert-butoxycarbonyl) amino) cyclohexylmethanesulfonate According to Synthesis Example 3, tert-butyl (1R, 4R)- 780 mg of the title oily compound was obtained from 500 mg of 4-cyclohexyl carbamate.
- Step 2 Synthesis of tert-butyl ((1S, 4S) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexylcarbamamate Synthesis Example 3 According to (Step 2), 630 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and (1R, 4R) -4-((tert-butoxycarbonyl) amino obtained in Step 1 ) From 780 mg of cyclohexylmethanesulfonate, 614 mg of a pale yellow solid of the title compound was obtained.
- Step 3 Synthesis of N-((1S, 4S) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide
- Step of Example 65 Tert-butyl ((1S, 4S) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexylcarbama obtained in Step 2 From 200 mg of mate, 137 mg of a pale yellow solid of the title compound was obtained.
- Step 4 1-((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 —Synthesis of Carboxamide N-((1S, 4S) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine obtained in Step 3 according to Step 4 of Example 65 2.08 mg of the white solid of the title compound was obtained from 10 mg of -1-yl) cyclohexyl) acrylamide.
- Example 72 1-((1R, 4R) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3- Synthesis of carboxamide (Example Compound 72) (Step 1) Synthesis of (1S, 4S) -4-((tert-butoxycarbonyl) amino) cyclohexyl methanesulfonate According to Synthesis Example 3, tert-butyl (1S, 4S)- 704 mg of the title oily compound was obtained from 500 mg of 4-cyclohexyl carbamate.
- Step 2 Synthesis of tert-butyl ((1R, 4R) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexylcarbamamate Synthesis Example 3 According to (Step 2), 570 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and (1S, 4S) -4-((tert-butoxycarbonyl) amino obtained in Step 1 ) From 704 mg of cyclohexylmethanesulfonate, 375 mg of a pale yellow solid of the title compound was obtained.
- Step 3 Synthesis of N-((1R, 4R) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide
- Step of Example 65 Tert-butyl ((1R, 4R) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexylcarbama obtained in Step 2 90 mg of the pale yellow solid of the title compound was obtained from 200 mg of the mate.
- Step 4 1-((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 —Synthesis of Carboxamide N-((1S, 4S) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine obtained in Step 3 according to Step 4 of Example 65 A white solid of the title compound (3.43 mg) was obtained from 10 mg of -1-yl) cyclohexyl) acrylamide.
- Example 73 (S, E) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Example Compound 73) (Step 1) (S) -tert-butyl 3- (4-amino-3- (benzo [d] Oxazol-2-ylcarbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in Step 2 of Example 65 according to Step 4 of Example 65 ( The title compound was obtained from S) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate.
- Step 2 (S, E) -amino-N- (benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) Synthesis of -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
- (S) -tert-butyl 3- (4-amino-3- (benzo [d ] 13.8 mg of a white solid of the title compound was obtained from 20 mg of oxazol-2-ylcarbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate.
- Step 2 Synthesis of tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidine-1-carboxylate
- Step 3 Step 2 According to the same procedure, 670 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and 774 mg of tert-butyl 3- (methylsulfonyloxy) azetidine-1-carboxylate obtained in Step 1 690 mg of a pale yellow solid was obtained.
- Step 4 1-((1-acryloylazetidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 -Synthesis of carboxamide 1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidine obtained in Step 3 according to Step 4 of Example 65 A white solid of the title compound was obtained from -1-yl) propyl-2-en-1-one.
- Example 75 1-((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d Synthesis of pyrimidine-3-carboxamide (Example Compound 75) (Step 1) 1- (3-((4-Amino-3-) obtained in Step 3 of Example 70 according to Step 4 of Example 65 10 mg iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) azetidin-1-yl) propyl-2-en-1-one and 5-fluorobenzo [d] oxazol-2-amine 5 From 2.2 mg, 3.36 mg of the title compound was obtained as a white solid.
- Example 76 1-((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of Pyrimidine-3-carboxamide (Example Compound 76) (Step 1) 1- (3-((4-amino-3-iodo) obtained in Step 3 of Example 70 according to Step 4 of Example 65 10 mg of 1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) azetidin-1-yl) propyl-2-en-1-one and 5.2 mg of 5-chlorobenzo [d] oxazol-2-amine From 3.76 mg of a white solid of the title compound.
- Example 77 1-((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] Synthesis of pyrimidine-3-carboxamide (Example Compound 77) (Step 1) 1- (4-((4-amino-3-iodo) obtained in Step 2 of Example 68 according to Step 4 of Example 65 3.
- Example 78 1-((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxamide (Example Compound 78) (Step 1) According to Step 4 of Example 65, N-((1S, 4S) -4- (4-amino-) obtained in Step 3 of Example 72 1.93 mg of the white solid of the title compound was obtained from 10 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide and 5.2 mg of 5-chlorobenzo [d] oxazol-2-amine. It was.
- Example 79 1- (1-acryloylazetidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Synthesis of 3-carboxamide (Example Compound 79) (Step 1) 1- (3- (4-Amino-3-iodo-1H—) obtained in Step 3 of Example 74 according to Step 4 of Example 65 From 10 mg of pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) propyl-2-en-1-one and 4.8 mg of 5-fluorobenzo [d] oxazol-2-amine, 2.21 mg of a white solid was obtained.
- Example 80 1-((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine Synthesis of -3-carboxamide (Example Compound 80) (Step 1) 1- (4-((4-Amino-3-iodo-) obtained in Step 2 of Example 68 according to Step 4 of Example 65 From 10 mg of 1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop-2-en-1-one and 5.2 mg of 5-chlorobenzo [d] oxazol-2-amine 4.30 mg of a white solid of the title compound was obtained.
- Example 81 1-((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine Synthesis of -3-carboxamide (Example Compound 81) (Step 1) According to Step 4 of Example 65, N-((1S, 4S) -4- (4-amino) obtained in Step 3 of Example 72 -3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide 10 mg and 5-fluorobenzo [d] oxazol-2-amine 4.8 mg 91 mg was obtained.
- Example 82 1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide ( Synthesis of Example Compound 82) (Step 1) Synthesis of tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate The title oily compound was obtained from N-Boc-3-pyrrolidinol according to Synthesis Example 3. .
- Step 2 Synthesis of tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate
- Step 2 According to the same procedure, 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate gave the pale yellow solid of the title compound.
- Step 3 of 1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one Synthesis According to Step 3 of Example 65, tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1- obtained in Step 2 The title compound was obtained as a white solid from the carboxylate.
- Step 4 1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
- Step 4 of Example 65 1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolopyrrolidine-obtained in Step 3 was obtained.
- 3.9 mg of the title compound was obtained as a white solid from 10 mg of 1-yl) prop-2-en-1-one.
- Example 83 1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 Synthesis of Carboxamide (Example Compound 83) (Step 1) 1- (3- (4-Amino-3-iodo-1H-pyrazolo) obtained in Step 3 of Example 82 according to Step 4 of Example 65 The title compound was obtained from 10 mg of [3,4-d] pyrimidin-1-yl) pyrrolopyrrolidin-1-yl) prop-2-en-1-one and 4.8 mg of 5-fluorobenzo [d] oxazol-2-amine. 4.09 mg was obtained as a white solid.
- Step 3 Synthesis of 1- (3-acrylamidopropyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
- Step 4 the title compound was obtained from 10 mg of N- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) propyl) acrylamide obtained in Step 3. 3.2 mg of a white solid was obtained.
- Step 2 N- (2- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) acrylamide Obtained in Step 1 according to Step 3 of Example 65 From 239 mg of the resulting tert-butyl (2- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) carboxylate, 140 mg of the title compound as a pale yellow solid was obtained.
- Step 3 Synthesis of 1- (2-acrylamidoethyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
- Step 4 the title compound was obtained from 10 mg of N- (2- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) acrylamide obtained in Step 2. Of white solid was obtained.
- Example compounds and Comparative compound 1 are shown in Tables 1 to 44 below.
- Test Example 1 Measurement of BTK Inhibitory Activity (In Vitro)
- FL-Peptide 2 was added to the Perchip Elmer LabChip® series reagent consumables price list.
- the purified recombinant human BTK protein used for the test was purchased from Carna Bioscience.
- the compound of the present invention was serially diluted with dimethyl sulfoxide (DMSO).
- a buffer for kinase reaction (20 mM HEPES (pH 7.5), 2 mM dithiotheol, 0.01% Triton X-100), BTK protein, substrate peptide (final concentration is 1 uM), magnesium chloride (final concentration is 10 mM), ATP (final concentration is 45 uM) and the DMSO solution of the present invention (final concentration of DMSO is 5%) were added and incubated at 25 ° C. for 40 minutes to perform a kinase reaction. The reaction was stopped by adding EDTA to a final concentration of 30 mM.
- the substrate peptide (S) and the phosphorylated peptide (P) that were not phosphorylated with LabChip EZ Reader II (Perkin Elmer) were separated and detected by microchannel capillary electrophoresis.
- the amount of phosphorylation reaction was determined from the peak heights of S and P, and the compound concentration capable of suppressing the phosphorylation reaction by 50% was defined as an IC50 value (nM) and is shown in the table below.
- Test Example 2 BTK inhibition selectivity compared to EGFR kinase inhibitory activity (in vitro) 1) Measurement of BTK inhibitory activity In the same manner as in Test Example 1, measurement of BTK inhibitory activity was measured. 2) Measurement of EGFR inhibitory activity In the setting of the in vitro inhibitory activity measurement method for compounds against EGFR kinase activity, FL-Peptide 22 was measured in the lab kinase price list of Perchip Elmer LabChip (registered trademark) series. Since it was described that it corresponds as a substrate peptide, a biotinylated peptide (biotin-EEPLYWSFPAKKK) was prepared with reference to the amino acid sequence.
- biotinylated peptide biotin-EEPLYWSFPAKKK
- the purified recombinant human EGFR protein used for the test was purchased from Carna Bioscience.
- the compound of the present invention was serially diluted with dimethyl sulfoxide (DMSO).
- DMSO dimethyl sulfoxide
- DMSO solution of the present invention final concentration of DMSO is 2.5%) and incubated at 25 ° C. for 120 minutes for kinase reaction Went. The reaction was stopped by adding EDTA to a final concentration of 24 mM, and then a detection solution containing Eu-labeled anti-phosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA (PerkinElmer) was added. And allowed to stand at room temperature for 2 hours or more.
- the amount of fluorescence when irradiated with excitation light having a wavelength of 337 nm was measured at two wavelengths of 620 nm and 665 nm using PHERAstar FS (BMG LABTECH).
- the amount of phosphorylation reaction was determined from the fluorescence amount ratio of two wavelengths, and the concentration of the compound capable of suppressing the phosphorylation reaction by 50% was defined as an IC50 value (nM).
- IC50 value (nM) concentration of the compound capable of suppressing the phosphorylation reaction by 50% was defined as an IC50 value (nM).
- 3) BTK inhibition selectivity Based on the results obtained in the above 1) and 2), the “EGFR inhibitory activity IC50 value (nM) / BTK inhibitory activity IC50 value (nM)” is calculated, whereby the BTK inhibitory selectivity of the test compound is determined. confirmed.
- the BTK inhibition selectivity for the EGFR kinase of the compound of the present invention is about 7.5 times or more in vitro compared with Comparative Example Compound 1, and the compound of the present invention has excellent BTK inhibition selectivity. It became clear. From this result, it was shown that this invention compound can reduce a side effect rather than a known BTK inhibitor.
- Test Example 3 Growth Inhibitory Activity Measurement Test (In Vitro) on BTK and EGFR-expressing Cell Lines and Comparison of Selectivity TMD8 cells which are a diffuse large B-cell lymphoma line expressing BTK, are 10% bovine. It was suspended in RPMI 1640 medium (Life Technologies) containing fetal serum. A431 cells, an EGFR overexpressing and highly activated human epidermoid carcinoma cell line, were suspended in DMEM and high glucose medium (Life Technologies) containing 10% fetal bovine serum. The cell suspension was seeded in each well of a 384 well flat bottom microplate and cultured at 37 ° C. for 1 day in an incubator containing 5% carbon dioxide gas.
- the compound of the present invention and Comparative Example Compound 1 were dissolved in DMSO, and the test compound was diluted with DMSO to a concentration 500 times the final concentration.
- a DMSO solution of the test compound is diluted with the medium used for suspending each cell, and this is added to each well of the cell culture plate so that the final concentration of DMSO is 0.2%, and 5% carbon dioxide gas is contained.
- Incubator was further cultured at 37 ° C. for 3 days. The cell count was measured before the addition of the compound and after the cultivation for 3 days in the presence of the compound using Celltiter Glo (manufactured by Promega) based on the protocol recommended by Promega.
- the BTK inhibition selectivity of the compound of the present invention for EGFR kinase in the cell growth inhibition rate in vitro is about 8.5 times or more compared to Comparative Compound 1, and the compound of the present invention is only kinase.
- the cells have excellent BTK inhibition selectivity. From this result, it was shown that this invention compound can reduce a side effect rather than a known BTK inhibitor.
- Test Example 4 Evaluation of Antitumor Effect and Body Weight Change Rate
- the mice were divided into 5 animals per group by the random stratification method (Day 1), and oral administration was started.
- Group 1 Comparative compound 1 (100 mg / kg) orally administered once a day
- Group 2 Compound of the present invention (Example compound 13) (50 mg / kg) orally administered once a day
- Group 3 Present invention Compound (Example Compound 12) (50 mg / kg) was orally administered once a day.
- Group 4 The compound of the present invention (Example Compound 6) (50 mg / kg) was orally administered once a day.
- the relative tumor volume (RTV; Relative Tumor Volume) with the tumor volume at the time of grouping as 1 was determined as the tumor growth rate according to the following formula.
- RTV (tumor volume on the day of tumor volume measurement) / (tumor volume at the time of grouping)
- Table 51 shows the average RTV on the 17th day after administration of the control group and the compound administration group (groups 1 to 4).
- BWC Body Weight Change
- BWC (%) ([(mouse weight on the weight measurement day) ⁇ (mouse weight at the time of grouping)] / (mouse weight at the time of grouping)) ⁇ 100
- the compound of the present invention showed a high antitumor effect equivalent to or higher than that of the group administered with Comparative Example Compound 1 at 100 mg / kg in the group administered with 50 mg / kg.
- no toxicity such as weight loss was observed in these compound administration groups. Therefore, it was clarified that the compound of the present invention is an excellent anti-tumor effect at a low dose as compared with Comparative Example Compound 1 and has high safety.
- Test Example 5 Effect of repeated administration of the compound of the present invention on the body weight of SD rats (in vivo) Using Comparative Compound 1 and the compound of the present invention, the effect of repeated administration for 2 weeks on the weight gain of SD rats was compared with that of the solvent administration group. In order to make the average body weight of each group almost uniform, each group was divided into the following 4 groups by random stratification (first day). Group 1: Comparative compound 1 (280 mg / kg) orally administered once a day, Group 2: Compound of the present invention (Example compound 12) (750 mg / kg) orally administered once a day, Group 3: Present invention The compound (Example Compound 13) (750 mg / kg) was orally administered once a day. The body weight change rate (BWC; Body Weight Change) was used as an index representing systemic toxicity due to drug administration. BWC was calculated according to the following formula.
- BWC (%) ([(Rat weight on day 14 of administration) ⁇ (Rat weight at grouping)] / (Rat weight at grouping)) ⁇ 100
- the relative body weight change rate of each compound administration group when the BWC of the solvent administration group was set to 1 was calculated according to the following formula and shown in Table 52.
- Relative body weight change rate (%) (BWC in the compound administration group) / (BWC in the solvent administration group) ⁇ 100
- group 1 which was the group administered with Comparative Example Compound 1 showed a slight increase in the weight gain of the rats compared with the group administered with the solvent
- groups 2 and 3 which were the group administered with the present compound were comparative examples.
- the compound of the present invention has an excellent effect that the side effects are low although the exposure amount is much higher than that of Comparative Compound 1.
- the compound group of the present invention is a compound having an excellent profile with reduced toxicity as compared with Comparative Example Compound 1.
- Test Example 6 Detection with BTK label using fluorescent label compound (in vitro)
- the human B cell lymphoma-derived cell line Ramos was suspended in RPMI 1640 medium containing 10% bovine serum, seeded on a culture plate at a concentration of 2.0 ⁇ 10 6 (cells / well), and then incubated for 24 hours at 37 ° C. CO 2 incubator (SANYO). ).
- Fluorescent label compound (PCI-33380, Non-Patent Document 2) (10 mM stock) of Example Compound P-1 or Comparative Example Compound 1 (10 mM stock) was diluted with DMSO and added to the plate seeded with cells, and the CO 2 incubator for 1 hour. Incubated inside.
- the fluorescent label compound (10 mM stock) was diluted to 2 mM with DMSO, added to each well, and further cultured in a CO 2 incubator for 1 hour. Thereafter, the cells were collected, and 50 ⁇ l (a cell extract (NP-40; Invitrogen) containing 1 ⁇ protease inhibitor (Roche), 1 ⁇ phosphatase cocktail inhibitor (Sigma)) was added to the cell pellet, and 10 It was allowed to stand on ice.
- the amount of protein in the recovered cell extract was quantified with DC protein assay (Biorad), 20 ug of protein per lane was applied to SDS-concentration gradient gel (4-20%) (Wako Pure Chemical Industries), and after electrophoresis, An image of the electrophoresis gel was captured using a Molecular Dynamics Typhoon Scanner (GE Healthcare). Thereafter, Western blotting was performed using i-Blot (Invitrogen), and BTK protein was detected with LAS4000 (GE Healthcare) using BTK antibody (Abcam) (FIG. 1).
- the probe according to the present invention was found to be a useful tool for detecting BTK in an in vitro test.
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Abstract
Description
特許文献1及び2に開示された化合物は、BTKに加えてEGFR(Epidermal Growth Factor Receptor)、JAK3(Janus kinase 3)等に対しても高い阻害活性を示すことが知られている。しかし、このようなマルチキナーゼ阻害剤は、種々のシグナル経路を阻害することで細胞増殖等を抑制するため、さまざまな副作用が懸念される。例えば、EGFRはリガンドである上皮成長因子(Epidermal Growth Factor;EGF)等と結合し、種々の細胞の増殖や生存(アポトーシス阻害等)等に関与していることが知られているが(非特許文献3)、EGFRを標的とした阻害剤では皮膚障害や消化管障害等の副作用が共通して発生することが知られており、これらの副作用は野生型EGFRシグナル経路の阻害と関連しうると広く考えられている(非特許文献4)。
そこで、BTK阻害活性を有しつつEGFR阻害活性が弱い化合物としてPCI-45292が知られている(非特許文献5)。
以上のように副作用低減の観点から、BTKに対して高い阻害活性を持ちつつEGFRのような他のキナーゼに対する阻害活性が低い、選択性の高いBTK阻害剤が望まれる。
nは、0から2の整数を示し;
mは、1から4の整数を示し;
Xは、置換基を有しても良い含窒素C3-C10ヘテロシクロアルキレンを示し;
Yは、-C(R4)=C(R5)(R6)、又は-C≡C-R7を示し;
W及びZは、各々独立してN又はCHを示し;
R1は、置換基を有しても良いアミノ基を示し;
R2及びR3は、同一又は相異なって、水素原子、ハロゲン原子、置換基を有しても良いC1-C6アルキル基、置換基を有しても良いC1-C6アルコキシ基、置換基を有しても良いC3-C7シクロアルキル基、置換基を有しても良いC6-C14芳香族炭化水素基、置換基を有しても良く、窒素原子、酸素原子及び硫黄原子から選択される同種若しくは異種のヘテロ原子を1~3個含む4~10員の単環式若しくは多環式の不飽和複素環式基、又はシアノ基を示し;
R4、R5、R6及びR7は、同一又は相異なって、水素原子、又は置換基を有しても良いC1-C6アルキル基を示す。)で表される化合物又はその塩を提供するものである。
また、本発明は、上記一般式(I)で表される化合物又はその塩を有効成分とするBTK阻害剤を提供するものである。
また本発明は、上記一般式(I)で表される化合物又はその塩を含有する医薬組成物を提供するものである。
また本発明は、上記一般式(I)で表される化合物又はその塩を有効成分とする抗腫瘍剤を提供するものである。
また、本発明は、腫瘍治療のための上記一般式(I)で表される化合物又はその塩を提供するものである。
また本発明は、抗腫瘍剤製造のための、上記一般式(I)で表される化合物又はその塩の使用を提供するものである。
また本発明は、上記一般式(I)で表される化合物又はその塩を投与することを特徴とする腫瘍の治療方法を提供するものである。
また、特許文献1及び2に記載の化合物も、本発明化合物の特徴であるベンゾオキサゾール基又はオキサゾロピリジン基を有しておらず、構造が大きく異なる。
また、本発明化合物に関連する構造を有する化合物として、国際公開第2007/067781号に開示されている化合物が知られている。しかし、ここに開示された化合物はオーロラキナーゼを阻害する化合物であり、BTK阻害活性の有無について記載はない。また、ベンゾオキサゾール基又はオキサゾロピリジン基を有する具体的化合物の開示もない。
本発明化合物又はその塩は、優れたBTK選択的阻害活性を有し、且つ癌細胞株に対する増殖抑制効果を示すことが明らかとなった。さらに本発明化合物又はその塩は、EGFRに比してBTKを選択的に強く阻害することから、副作用を軽減でき安全性の向上が期待できる。
本発明化合物又はその塩は、従来のBTK阻害剤と比較して良好な肝ミクロソームの安定性を示し、良好な血中曝露が期待でき、またCyp阻害の懸念がないという有利な点を有する。
本発明化合物又はその塩は、癌の予防及び/又は治療剤として有用である。
本発明化合物又はその塩は、癌や腫瘍の骨転移を抑制することができる。
好ましくは、置換基を有しても良い、窒素原子を1個環内に含む炭素数3~5のヘテロシクロアルキレン(含窒素C3-C5ヘテロシクロアルキレン)であり、さらに好ましくはアゼチジニレン、ピロリジニレン、又はピペリジニレンであり、さらに好ましくは1,3-アゼチジニレン、1,3-ピロリジニレン、又は1,3-ピペリジニレンである。
これらのヘテロシクロアルキレン上の置換基としては、前記のような置換基が例示されるが、好ましくは無置換である。
一般式(I)中、W及びZは、各々独立してN又はCHであり、好ましくはZがNでWがNであるか、ZがCHでWがN又はCHである。
R1で示される「置換基を有しても良いアミノ基」は、好ましくはアミノ基である。
一般式(I)中、R2又はR3で示される「置換基を有しても良いC1-C6アルキル基」における「C1-C6アルキル基」は、好ましくはC1-C4アルキル基であり、より好ましくはメチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、又はtert-ブチル基であり、さらに好ましくはメチル基、又はエチル基である。
R2又はR3で示される「置換基を有しても良いC1-C6アルキル基」における「置換基」としては、好ましくは無置換、ハロゲン原子、又はC1-C4アルコキシ基であり、さらに好ましくは、無置換、フッ素原子、又はメトキシ基である。置換基を有する場合、置換基の数は特に制限されないが、置換基がハロゲン原子の場合は好ましくは1~3個、置換基がC1-C4アルコキシ基の場合は好ましくは1個である。
R2又はR3で示される「置換基を有しても良いC1-C6アルキル基」は、好ましくはC1-C6アルキル基、ハロゲノC1-C6アルキル基、又はC1-C4アルコキシ置換C1-C6アルキル基であり、より好ましくはC1-C4アルキル基、ハロゲノC1-C4アルキル基、又はC1-C4アルコキシ置換C1-C4アルキル基であり、さらに好ましくはメチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、tert-ブチル基、トリフルオロメチル基、トリクロロメチル基、メトキシエチル基、又はエトキシエチル基であり、さらに好ましくは、メチル基、トリフルオロメチル基、又はメトキシエチル基である。
R2又はR3で示される「置換基を有しても良いC1-C6アルコキシ基」における「置換基」としては、前記のような置換基が例示されるが、好ましくは無置換である。
R2又はR3で示される「置換基を有しても良いC1-C6アルコキシ基」としては、好ましくはC1-C6アルコキシ基であり、より好ましくはC1-C4アルコキシ基であり、さらに好ましくはメトキシ基、エトキシ基、イソプロポキシ基、又はn-ブトキシ基であり、さらに好ましくはメトキシ基である。
R2又はR3で示される「置換基を有しても良いC6-C14芳香族炭化水素基」における「置換基」としては、好ましくは無置換、又はハロゲン原子であり、さらに好ましくは、無置換、又は塩素原子、フッ素原子である。置換基を有する場合、置換基の数は特に制限されないが、好ましくは1~3個である。
R2又はR3で示される「置換基を有しても良いC6-C14芳香族炭化水素基」は、好ましくは無置換、又はハロゲン原子で置換されていても良いフェニル基又はナフチル基であり、より好ましくはフェニル基、クロロフェニル基、フルオロフェニル基、ジクロロフェニル基、又はトリクロロフェニル基であり、さらに好ましくはフェニル基、又はクロロフェニル基であり、特に好ましくはフェニル基、又は4-クロロフェニル基である。
R2又はR3で示される「置換基を有しても良く、窒素原子、酸素原子及び硫黄原子から選択される同種又は異種のヘテロ原子を1~3個含む4~10員の単環式又は多環式の不飽和複素環式基」における「置換基」としては、前記のような置換基が例示されるが、好ましくは無置換である。
R2又はR3で示される「置換基を有しても良く、窒素原子、酸素原子及び硫黄原子から選択される同種又は異種のヘテロ原子を1~3個含む4~10員の単環式又は多環式の不飽和複素環式基」は、好ましくは窒素原子、酸素原子又は硫黄原子を1個含む4~6員の単環式の不飽和複素環式基であり、より好ましくは硫黄原子を1個含む4~6員の単環式の不飽和複素環式基であり、さらに好ましくはチエニル基であり、さらに好ましくは2-チエニル基である。
R7で示される「置換基を有しても良いC1-C6アルキル基」における「置換基」としては、前記のような置換基が例示されるが、好ましくは無置換である。
R7で示される「置換基を有しても良いC1-C6アルキル基」としては、好ましくはC1-C4アルキル基であり、より好ましくはメチル基、エチル基、n-プロピル基、イソプロピル基、又はn-ブチル基であり、さらに好ましくはメチル基である。
一般式(I)中、Yで示される-C(R4)=C(R5)(R6)、又は-C≡C-R7は、特に好ましくは
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、含窒素C3-C10ヘテロシクロアルキレンであり;
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
W及びZが、各々独立してN又はCHであり;
R1がアミノ基であり;
R2及びR3が、同一又は相異なって、水素原子、ハロゲン原子、置換基を有しても良いC1-C6アルキル基、置換基を有しても良いC1-C6アルコキシ基、置換基を有しても良いC3-C7シクロアルキル基、置換基を有しても良いC6-C14芳香族炭化水素基、置換基を有しても良く、窒素原子、酸素原子及び硫黄原子から選択される同種若しくは異種のヘテロ原子を1~3個含む4~10員の単環式若しくは多環式の不飽和複素環式基、又はシアノ基であり;
R4、R5、R6及びR7が、同一又は相異なって、水素原子、又は置換基を有しても良いC1-C6アルキル基である化合物又はその塩が好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、含窒素C3-C10ヘテロシクロアルキレンであり(ここで窒素原子は一般式(I)の-COYのカルボニル基と結合する);
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
W及びZが、各々独立してN又はCHであり;
R1がアミノ基であり;
R2及びR3が、同一又は相異なって、水素原子、ハロゲン原子、置換基を有しても良いC1-C6アルキル基、置換基を有しても良いC1-C6アルコキシ基、置換基を有しても良いC3-C7シクロアルキル基、置換基を有しても良いC6-C14芳香族炭化水素基、置換基を有しても良く、窒素原子、酸素原子及び硫黄原子から選択される同種若しくは異種のヘテロ原子を1~3個含む4~10員の単環式若しくは多環式の不飽和複素環式基、又はシアノ基であり;
R4、R5、R6及びR7が、同一又は相異なって、水素原子、又は置換基を有しても良いC1-C6アルキル基である化合物又はその塩がより好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、アゼチジニレン、ピロリジニレン、又はピペリジニレンであり;
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
W及びZが、各々独立してN又はCHであり;
R1がアミノ基であり;
R2及びR3が、同一又は相異なって、水素原子、ハロゲン原子、置換基を有しても良いC1-C6アルキル基、置換基を有しても良いC1-C6アルコキシ基、置換基を有しても良いC3-C7シクロアルキル基、置換基を有しても良いC6-C14芳香族炭化水素基、置換基を有しても良く、窒素原子、酸素原子及び硫黄原子から選択される同種若しくは異種のヘテロ原子を1~3個含む4~10員の単環式若しくは多環式の不飽和複素環式基、又はシアノ基であり;
R4、R5、R6及びR7が、同一又は相異なって、水素原子、又は置換基を有しても良いC1-C6アルキル基である、化合物又はその塩がより好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、アゼチジニレン、ピロリジニレン、又はピペリジニレンであり(ここで窒素原子は、一般式(I)の-COYのカルボニル基と結合する);
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
W及びZが、各々独立してN又はCHであり;
R1がアミノ基であり;
R2及びR3が、同一又は相異なって、水素原子、ハロゲン原子、置換基を有しても良いC1-C6アルキル基、置換基を有しても良いC1-C6アルコキシ基、置換基を有しても良いC3-C7シクロアルキル基、置換基を有しても良いC6-C14芳香族炭化水素基、置換基を有しても良く、窒素原子、酸素原子及び硫黄原子から選択される同種若しくは異種のヘテロ原子を1~3個含む4~10員の単環式若しくは多環式の不飽和複素環式基、又はシアノ基であり;
R4、R5、R6及びR7が、同一又は相異なって、水素原子、又は置換基を有しても良いC1-C6アルキル基である、化合物又はその塩がより好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、アゼチジニレン、ピロリジニレン、又はピペリジニレンであり;
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
W及びZが、独立してN又はCHであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はC1-C6アルキル基であり、他方が水素原子、ハロゲン原子、C1-C6アルキル基、ハロゲノC1-C6アルキル基、C1-C4アルコキシ置換C1-C6アルキル基、C1-C6アルコキシ基、ハロゲン原子で置換されていても良いフェニル基、硫黄原子を1個含む4~6員の単環式の不飽和複素環式基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5、及びR6が、同一又は相異なって、水素原子、C1-C6アルキル基、2個のC1-C6アルキル基で置換されたアミノ基で置換されているC1-C6アルキル基(C1-C6アルキル基はこれらが結合する窒素原子と共に4~8員環のヘテロシクロアルキル基を形成しても良い。)であり;
Yが-C≡C-R7である場合、
R7が、水素原子又はC1-C6アルキル基である、化合物又はその塩がより好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、アゼチジニレン、ピロリジニレン、又はピペリジニレンであり(ここで窒素原子は、一般式(I)の-COYのカルボニル基と結合する);
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
W及びZが、独立してN又はCHであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はC1-C6アルキル基であり、他方が水素原子、ハロゲン原子、C1-C6アルキル基、ハロゲノC1-C6アルキル基、C1-C4アルコキシ置換C1-C6アルキル基、C1-C6アルコキシ基、ハロゲン原子で置換されていても良いフェニル基、硫黄原子を1個含む4~6員の単環式の不飽和複素環式基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5、及びR6が、同一又は相異なって、水素原子、C1-C6アルキル基、2個のC1-C6アルキル基で置換されたアミノ基で置換されているC1-C6アルキル基(C1-C6アルキル基はこれらが結合する窒素原子と共に4~8員環のヘテロシクロアルキル基を形成しても良い。)であり;
Yが-C≡C-R7である場合、
R7が、水素原子又はC1-C6アルキル基である、化合物又はその塩がより好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、1,3-アゼチジニレン、1,3-ピロリジニレン、又は1,3-ピペリジニレンであり;
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
ZがNのとき、WがNであり、ZがCHのとき、WがN又はCHであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はC1-C4アルキル基であり、他方が水素原子、ハロゲン原子、C1-C4アルキル基、ハロゲノC1-C4アルキル基、C1-C4アルコキシ置換C1-C4アルキル基、C1-C4アルコキシ基、ハロゲン原子で置換されていても良いフェニル基、硫黄原子を1個含む4~6員の単環式の不飽和複素環式基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5、及びR6が、同一又は相異なって、水素原子、C1-C6アルキル基、2個のC1-C6アルキル基で置換されたアミノ基で置換されているC1-C6アルキル基(C1-C6アルキル基はこれらが結合する窒素原子と共に4~8員環のヘテロシクロアルキル基を形成しても良い。)であり;
Yが-C≡C-R7である場合、
R7が、水素原子又はC1-C4アルキル基である、化合物又はその塩がより好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、1,3-アゼチジニレン、1,3-ピロリジニレン、又は1,3-ピペリジニレンであり(ここで、窒素原子は、一般式(I)中の-COYのカルボニル基と結合する);
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
ZがNのとき、WがNであり、ZがCHのとき、WがN又はCHであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はC1-C4アルキル基であり、他方が水素原子、ハロゲン原子、C1-C4アルキル基、ハロゲノC1-C4アルキル基、C1-C4アルコキシ置換C1-C4アルキル基、C1-C4アルコキシ基、ハロゲン原子で置換されていても良いフェニル基、硫黄原子を1個含む4~6員の単環式の不飽和複素環式基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5、及びR6が、同一又は相異なって、水素原子、C1-C6アルキル基、2個のC1-C6アルキル基で置換されたアミノ基で置換されているC1-C6アルキル基(C1-C6アルキル基はこれらが結合する窒素原子と共に4~8員環のヘテロシクロアルキル基を形成しても良い。)であり;
Yが-C≡C-R7である場合、
R7が、水素原子又はC1-C4アルキル基である、化合物又はその塩がより好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、1,3-アゼチジニレン、1,3-ピロリジニレン、又は1,3-ピペリジニレンであり;
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
ZがNのとき、WがNであり、ZがCHのとき、WがN又はCHであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はメチル基であり、他方が水素原子、ハロゲン原子、メチル基、トリフルオロメチル基、メトキシエチル基、メトキシ基、フェニル基、4-クロロフェニル基、2-チエニル基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5及びR6が、同一又は相異なって、水素原子、メチル基、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基、又は1-ピロリジニルメチル基であり;
Yが-C≡C-R7である場合、
R7がメチル基である、化合物又はその塩がより好ましい。
Aが、-(CH2)n-X-であり;
nが、0であり;
Xが、1,3-アゼチジニレン、1,3-ピロリジニレン、又は1,3-ピペリジニレンであり(ここで、窒素原子は、一般式(I)中の-COYのカルボニル基と結合する);
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
ZがNのとき、WがNであり、ZがCHのとき、WがN又はCHであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はメチル基であり、他方が水素原子、ハロゲン原子、メチル基、トリフルオロメチル基、メトキシエチル基、メトキシ基、フェニル基、4-クロロフェニル基、2-チエニル基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5及びR6が、同一又は相異なって、水素原子、メチル基、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基、又は1-ピロリジニルメチル基であり;
Yが-C≡C-R7である場合、
R7がメチル基である、化合物又はその塩がより好ましい。
Aが-(CH2)n-X-であり;
nが0であり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はメチル基であり、他方が水素原子、ハロゲン原子、トリフルオロメチル基、メトキシエチル基、フェニル基、2-チエニル基、又はシアノ基であり;
(1)ZがNで、WがNの場合、
Xが1,3-ピペリジニレンで、
Yがビニル基であり、
(2)ZがCHで、WがNの場合、
Xが1,3-ピロリジニレン、又は1,3-ピペリジニレンで、
Yが-C(R4)=C(R5)(R6)、又は-C≡C-(R7)であり、
Yが-C(R4)=C(R5)(R6)の場合、
R4、R5及びR6が、同一又は相異なって、水素原子、メチル基、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基、又は1-ピロリジニルメチル基であり、
Yが-C≡C-(R7)の場合、
R7がメチル基であり、
(3)ZがCHで、WがCHの場合、
Xが1,3-アゼチジニレン、又は1,3-ピロリジニレンで、
Yが-C(R4)=C(R5)(R6)であり、
R4、R5及びR6が、同一又は相異なって、水素原子、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基又は1-ピロリジニルメチル基である、化合物又はその塩がより好ましい。
Aが-(CH2)n-X-であり;
nが0であり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はメチル基であり、他方が水素原子、ハロゲン原子、トリフルオロメチル基、メトキシエチル基、フェニル基、2-チエニル基、又はシアノ基であり;
(1)ZがNで、WがNの場合、
Xが1,3-ピペリジニレンで(ここで、窒素原子は、一般式(I)中の-COYのカルボニル基と結合する)、
Yがビニル基であり、
(2)ZがCHで、WがNの場合、
Xが1,3-ピロリジニレン、又は1,3-ピペリジニレンで(ここで、窒素原子は、一般式(I)中の-COYのカルボニル基と結合する)、
Yが-C(R4)=C(R5)(R6)、又は-C≡C-(R7)であり、
Yが-C(R4)=C(R5)(R6)の場合、
R4、R5及びR6が、同一又は相異なって、水素原子、メチル基、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基、又は1-ピロリジニルメチル基であり、
Yが-C≡C-(R7)の場合、
R7がメチル基であり、
(3)ZがCHで、WがCHの場合、
Xが1,3-アゼチジニレン、又は1,3-ピロリジニレンで(ここで、窒素原子は、一般式(I)中の-COYのカルボニル基と結合する)、
Yが-C(R4)=C(R5)(R6)であり、
R4、R5及びR6が、同一又は相異なって、水素原子、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基又は1-ピロリジニルメチル基である、化合物又はその塩がより好ましい。
Aが-(CH2)n-X-であり;
nが0であり;
Xが1,3-ピペリジニレンであり;
Yがビニル基であり;
ZがCHであり;
WがNであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子であり、他方が水素原子、ハロゲン原子、又はシアノ基である、化合物又はその塩がより好ましい。
Aが-(CH2)n-X-であり;
nが0であり;
Xが1,3-ピペリジニレンであり(ここで、窒素原子は、一般式(I)中の-COYのカルボニル基と結合する);
Yがビニル基であり;
ZがCHであり;
WがNであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子であり、他方が水素原子、ハロゲン原子、又はシアノ基である、化合物又はその塩がより好ましい。
Aが-(CH2)n-X-であり;
nが0であり;
Xが1,3-ピペリジニレンであり;
Yがビニル基であり;
ZがCHであり;
WがNであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子であり、他方が水素原子、又はハロゲン原子である、化合物又はその塩がより好ましい。
Aが-(CH2)n-X-であり;
nが0であり;
Xが1,3-ピペリジニレンであり(ここで、窒素原子は、一般式(I)中の-COYのカルボニル基と結合する);
Yがビニル基であり;
ZがCHであり;
WがNであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子であり、他方が水素原子、又はハロゲン原子である、化合物又はその塩がより好ましい。
好適な本発明化合物としては、以下のものが例示できる:
(1)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物1)
(2)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-ブロモベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物2)
(3)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物3)
(4)(R)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-メタクリロイルピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物4)
(5)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物5)
(6)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-シアノベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物6)
(7)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-メトキシベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物7)
(8)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-(2-メトキシエチル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物8)
(9)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(オキサゾロ[4,5-b]ピリジン-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物9)
(10)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(4-メチルベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物10)
(11)(R)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1-(1-メタクリロイルピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物11)
(12)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物12)
(13)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物13)
(14)(R,E)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1-(1-(ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物14)
(15)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物15)
(17)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-ジエチルアミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物17)
(18)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-イソプロピル(メチル)アミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物18)
(19)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ピロリジン-1-イル)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物19)
(20)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ピペリジン-1-イル)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物20)
(21)(R,E)-4-アミノ-N-(5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物21)
(22)(R)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1-(1-ブタ-2-イノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物22)
(23)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5,6-ジメチルベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物23)
(24)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物24)
(25)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物25)
(26)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(3-メチルブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物26)
(27)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物27)
(28)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物28)
(29)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-メチルベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物29)
(30)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物30)
(32)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物32)
(33)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-エチル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物33)
(34)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-ジエチルアミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物34)
(35)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-イソプロピル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物35)
(36)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ピロリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物36)
(37)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ピペリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物37)
(38)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-メトキシベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物38)
(39)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-シアノベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物39)
(40)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-(2-メトキシエチル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物40)
(41)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物41)
(42)(R,E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物42)
(43)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-(トリフルオロメチル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物43)
(44)(R,E)-4-アミノ-N-(5-(トリフルオロメチル)ベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物44)
(45)1-(1-アクリロイルアゼチジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物45)
(47)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)アゼチジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物47)
(48)(R)-7-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物48)
(49)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物49)
(50)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(エチル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物50)
(51)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジエチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物51)
(52)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(イソプロピル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物52)
(53)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ピロリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物53)
(54)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ピぺリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物54)
(55)(R)-7-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物55)
(56)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物56)
(57)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(エチル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物57)
(58)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジエチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物58)
(59)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(イソプロピル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物59)
(60)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ピロリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド(実施例化合物60)
(64)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(7-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物64)
(65)(S)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物65)
(66)1-((1-アクリロイルピロリジン-3-イル)メチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物66)
(67)1-((1-アクリロイルピペリジン-3-イル)メチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物67)
(68)1-((1-アクリロイルピペリジン-4-イル)メチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物68)
(69)1-(1-アクリロイルピペリジン-4-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物69)
(70)1-((1-アクリロイルアゼチジン-3-イル)メチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物70)
(71)1-((1S,4S)-4-アクリルアミドシクロヘキシル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物71)
(72)1-((1R,4R)-4-アクリルアミドシクロヘキシル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物72)
(73)(S、E)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物73)
(74)1-(1-アクリロイルアゼチジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物74)
(75)1-((1-アクリロイルアゼチジン-3-イル)メチル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物75)
(77)1-((1-アクリロイルピペリジン-4-イル)メチル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物77)
(78)1-((1S,4S)-4-アクリルアミドシクロヘキシル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物78)
(79)1-(1-アクリロイルアゼチジン-3-イル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物79)
(80)1-((1-アクリロイルピペリジン-4-イル)メチル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物80)
(81)1-((1S,4S)-4-アクリルアミドシクロヘキシル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物81)
(82)1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物82)
(83)1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物83)
(84)1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物84)
(85)1-(3-アクリルアミドプロピル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物85)
(86)1-(2-アクリルアミドエチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド(実施例化合物86)
検出可能なラベルまたは親和性タグとしては、本発明にかかるプローブとBTKの結合を検出できれば特に限定されないが、リンカー部とアルキル化、アミド化等で結合できる官能基を備えていることが望ましい。好ましくはBODIPY(登録商標) FL、BODIPY(登録商標) R6G、BODIPY(登録商標) TMR,BODIPY(登録商標) 581/591、BODIPY(登録商標) TRなどが発光団として、ビオチン等が結合団としてあげられる。より好ましくは、BODIPY(登録商標) FL、ビオチンである。
リンカーとしては、前記ラベル又はタグと本発明化合物を連結する部分できれば特に限定されないが、適度な長さと本発明化合物に大きな影響を与えない物性と、前記ラベル又はタグを伸張できる官能基を備えていることが望ましい。好ましくは
本発明化合物(I)は、例えば、下記の製造法又は実施例に示す方法等により製造することができる。ただし、本発明化合物(I)の製造法はこれら反応例に限定されるものではない。
用いられる試薬としてはブロモシアン、クロロシアン、ヨードシアン、1,1-カルボンイミドイルビス-1H-イミダゾール等のシアノ化合物が例示できる。一般式(II)で表される化合物1モルに対して、シアノ化合物を0.5~5モル、好ましくは0.9~1.5モル用いて行われる。なお、当該シアノ化合物は、市販品、又は公知の方法に準じて製造することができる。反応に用いる溶媒としては、反応に悪影響を及ぼさないものであればよく、例えば、アルコール類(例えば、メタノール、エタノール等)、炭化水素類(例えば、ベンゼン、トルエン、キシレン等)、ハロゲン化炭化水素類(例えば、塩化メチレン、クロロホルム、1,2-ジクロロエタン等)、ニトリル類(例えば、アセトニトリル等)、エーテル類(例えば、ジメトキシエタン、テトラヒドロフラン等)、非プロトン性極性溶媒(例えば、N,N-ジメチルホルムアミド、ジメチルスルホキシド、ヘキサメチルホスホルアミド等)、水あるいはそれらの混合物が用いられる。反応時間は0.1~100時間であり、好ましくは0.5~24時間である。反応温度としては0~120℃であり、好ましくは0~90℃である。
このようにして得られる一般式(III)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製するか又は単離精製することなく、次工程に付すことができる。
一般式(V)で表される化合物をアルキル化試薬として用いる場合、塩基存在下で製造することができる。一般式(V)において、L4は、例えば塩素原子、臭素原子、ヨウ素原子、メタンスルホン酸エステル、p-トルエンスルホン酸エステル等の脱離基が挙げられ、市販品、又は公知の方法に準じて製造することができる。一般式(V)で表される化合物は、一般式(IV)で表される化合物1モルに対して、1~10モル用いることができ、好ましくは1~5モルである。
塩基としては、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化セシウム、水素化ナトリウム、水素化カリウム等の無機塩基やトリメチルアミン、トリエチルアミン、トリプロピルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン、4-(N,N-ジメチルアミノ)ピリジン、ルチジン、コリジン等の有機アミン類が挙げられ、塩基の使用量としては、一般式(IV)で表される化合物1モルに対して、1~100モル用いることができ、好ましくは2~10モルである。
溶媒としてはN,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、ジメチルスルホキシド、テトラヒドロフラン、1,4-ジオキサン、N-メチルピロリジン-2-オン、アセトニトリル、などを単一又は混合して用いることができる。反応時間は0.1~100時間であり、好ましくは0.5~24時間である。反応温度としては0℃~溶媒の沸騰する温度であり、好ましくは0~100℃である。
光延試薬は、例えばジエチルアゾジカルボキシレート、ジイプロピルアゾジカルボキシレート等が例示できる。光延試薬の使用量は、一般式(IV)で表される化合物1モルに対して1~10モル、好ましくは1~5モル用いて行われる。
ホスフィン試薬は、例えばトリフェニルホスフィン、トリブチホスフィンが例示できる。ホスフィン試薬は、一般式(IV)で表される化合物1モルに対して、1~10モル、好ましくは1~5モル用いて行われる。
反応溶媒は、反応に支障のないものであれば、特に限定されないが、例えばトルエン、ベンゼンテトラヒドロフラン、1,4-ジオキサン、ジメチルホルムアミド、ジメチルアセトアミド、N-メチルピロリジノン、ジメチルスルホキシド等又はその混合溶媒等が好適である。
反応温度は、通常、-78~200℃、好ましくは0~50℃である。反応時間は、通常、5分~3日間、好ましくは10分~10時間である。
このようにして得られる一般式(VII)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製するか又は単離精製することなく、次の工程に付すことができる。
一般式(VII)において、L3で表される脱離基としては、臭素原子又はヨウ素原子であり、当該化合物は、市販品、又は公知の方法に準じて製造することができる。
本工程において、一酸化炭素の圧力は、通常1気圧~10気圧であり、好ましくは1気圧~5気圧である。アルコール化合物の使用量は、一般式(VII)で表される化合物1モルに対して、1~10モル用いることができ、好ましくは1~5モルである。アルコール化合物の例としては、メタノール、エタノール、プロパノール、イソプロピルアルコール、ジエチルアミノエタノール、イソブタノール、4-(2-ヒドロキシエチル)モルホリン、3-モルホリノプロパノール、ジエチルアミノプロパノール等があげられる。
本工程で利用可能な遷移金属触媒としては、例えば、パラジウム触媒(例、酢酸パラジウム、トリス(ジベンジリデンアセトン)ジパラジウム、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド、1,1’-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体等)であり、必要に応じて、リガンド(例、トリフェニルホスフィン、キサントホス、トリ-tert-ブチルホスフィン等)を添加する。遷移金属触媒の使用量は、触媒の種類により異なるが、一般式(VII)で表される化合物1モルに対して、通常0.0001~1モル、好ましくは0.001~0.5モルである。リガンドの使用量としては、一般式(VII)で表される化合物1モルに対して、通常0.0001~4モル、好ましくは0.01~2モルである。
反応溶媒は、反応に支障のないものであれば、特に限定されないが、例えば、炭化水素類(例えば、ベンゼン、トルエン、キシレン等)、ニトリル類(例えば、アセトニトリル等)、エーテル類(例えば、ジメトキエタン、テトラヒドロフラン、1,4-ジオキサン等)、アルコール類(例、メタノール、エタノール等)、非プロトン性極性溶媒(例、ジメチルホルムアミド、ジメチルアセトアミド、N-メチルピロリジノン、ジメチルスルホキシド、ヘキサメチルホスホルアミド等)、水あるいはそれらの混合物等が挙げられる。反応時間は0.1~100時間であり、好ましくは0.5~24時間である。反応温度としては0℃~溶媒の沸騰する温度であり、好ましくは0~150℃である。
この反応後にはカルボン酸化合物(VIII)と使用したアルコールに対応したエステル体の混合物となるため、加水分解反応を行い一般式(VIII)で表される化合物に変換処理を行う。加水分解は塩基を用いて行い、例えばジエチルアミン、ジイソプロピルアミン、カリウム-tert-ブチラート、ナトリウム-tert-ブチラート、ナトリウムメトキシド、ナトリウムエトキシド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ブチルリチウム等の有機塩基、又は炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム等の無機塩基が挙げられる。
このようにして得られる一般式(VIII)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製するか又は単離精製することなく、次工程に付すことができる。
アミド化試薬として、適当な縮合剤、または活性化剤の存在下、一般式(VIII)で表される化合物1モルに対して、一般式(III)を0.5~10モル、好ましくは1~3モル用いて行われる。
反応溶媒は、反応に支障のないものであれば、特に限定されないが、例えば、イソプロパノール、tert-ブチルアルコール、トルエン、ベンゼン、塩化メチレン、クロロホルム、テトラヒドロフラン、1,4-ジオキサン、ジメチルホルムアミド、ジメチルアセトアミド、N-メチルピロリジノン、ジメチルスルホキシド等又はその混合溶媒等が好適である。反応温度は、通常、-78~200℃、好ましくは0~50℃である。反応時間は、通常、5分~3日間、好ましくは5分~10時間である。
縮合剤、活性化剤としては、例えばジフェニルリン酸アジド、N,N’-ジシクロヘキシルカルボジイミド、ベンゾトリアゾール-1-イルオキシ-トリスジメチルアミノホスホニウム塩、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロライド、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミドと1-ヒドロキシベンゾトリアゾールの組み合わせ、2-クロロ-1,3-ジメチルイミダゾリニウムクロライド、O-(7-アザベンゾトリアゾ-1-イル)-N,N,N’,N’-テトラメチルヘキサウロニウム ヘキサフルオロホスフェート、1,1-カルボニルジイミダゾール、N-ヒドロキシコハク酸イミド等が挙げられる。
このようにして得られる一般式(IX)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製するか又は単離精製することなく、本発明化合物(I)の製造に利用することができる。
一般式(VII)において、L3で表される脱離基としては、臭素原子又はヨウ素原子であり、当該化合物は、市販品、又は公知の方法に準じて製造することができる。
本工程において、一酸化炭素の圧力は、1気圧~10気圧であり、好ましくは1気圧~5気圧である。
本工程で利用可能な遷移金属触媒としては、例えば、パラジウム触媒(例、酢酸パラジウム、トリス(ジベンジリデンアセトン)ジパラジウム、ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド、1,1’-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体等)であり、必要に応じて、リガンド(例、トリフェニルホスフィン、キサントホス、トリ-tert-ブチルホスフィン等)を添加する。遷移金属触媒の使用量は、触媒の種類により異なるが、一般式(IX)で表される化合物1モルに対して、通常0.0001~1モル、好ましくは0.001~0.5モルである。リガンドの使用量としては、一般式(VII)で表される化合物1モルに対して、通常0.0001~4モル、好ましくは0.01~2モルである。
また、上記反応は必要に応じて塩基を添加することができる。塩基としては、例えばトリエチルアミン、ジイソプロピルエチルアミン、ピリジン、ルチジン、コリジン、4-ジメチルアミノピリジン、N-メチルモルホリン、カリウム-tert-ブチラート、ナトリウム-tert-ブチラート、ナトリウムメトキシド、ナトリウムエトキシド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ブチルリチウム等の有機塩基、又は炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水素化ナトリウム等の無機塩基が挙げられる。塩基の使用量は、一般式(VII)で表される化合物1モルに対して、通常0.1~50モル、好ましくは1~20モルである。
このようにして得られる一般式(IX)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製するか又は単離精製することなく、本発明化合物(I)の製造に利用することができる。
反応に用いる溶媒としては、反応に悪影響を及ぼさないものであればよく、例えば、アルコール類(例えば、メタノール等)、炭化水素類(例えば、ベンゼン、トルエン、キシレン等)、ハロゲン化炭化水素類(例えば、塩化メチレン、クロロホルム、1,2-ジクロロエタン等)、ニトリル類(例えば、アセトニトリル等)、エーテル類(例えば、ジメトキシエタン、テトラヒドロフラン等)、非プロトン性極性溶媒(例えば、N,N-ジメチルホルムアミド、ジメチルスルホキシド、ヘキサメチルホスホルアミド等)あるいはそれらの混合物が用いられる。反応時間は0.1~100時間であり、好ましくは0.5~24時間である。反応温度としては0~120℃であり、好ましくは0~90℃である。
このようにして得られる一般式(X)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製するか又は単離精製することなく、次工程に付すことができる。
アミド化試薬としてY-COOHで表されるカルボン酸を用いる場合、適当な縮合剤の存在下、一般式(X)で表される化合物1モルに対して、カルボン酸を0.5~10モル、好ましくは1~3モル用いて行われる。なお、当該カルボン酸は、市販品、又は公知の方法に準じて製造することができる。
反応溶媒は、反応に支障のないものであれば、特に限定されないが、例えば、イソプロパノール、tert-ブチルアルコール、トルエン、ベンゼン、塩化メチレン、クロロホルム、テトラヒドロフラン、1,4-ジオキサン、ジメチルホルムアミド、ジメチルアセトアミド、N-メチルピロリジノン、ジメチルスルホキシド等又はその混合溶媒等が好適である。反応温度は、通常、-78~200℃、好ましくは0~50℃である。反応時間は、通常、5分~3日間、好ましくは5分~10時間である。
縮合剤としては、例えばジフェニルリン酸アジド、N,N’-ジシクロヘキシルカルボジイミド、ベンゾトリアゾール-1-イルオキシ-トリスジメチルアミノホスホニウム塩、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロライド、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミドと1-ヒドロキシベンゾトリアゾールの組み合わせ、2-クロロ-1,3-ジメチルイミダゾリニウムクロライド、O-(7-アザベンゾトリアゾ-1-イル)-N,N,N’,N’-テトラメチルヘキサウロニウムヘキサフルオロホスフェート等が挙げられる。
また、上記反応は必要に応じて塩基を添加することができる。塩基としては、例えばトリエチルアミン、ジイソプロピルエチルアミン、ピリジン、ルチジン、コリジン、4-ジメチルアミノピリジン、カリウム-tert-ブチラート、ナトリウム-tert-ブチラート、ナトリウムメトキシド、ナトリウムエトキシド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ブチルリチウム等の有機塩基、又は炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水素化ナトリウム等の無機塩基が挙げられる。添加量としては、一般式(X)で表される化合物1モルに対して、1~100モルであり、好ましくは1~10モルである。
反応溶媒は、反応に支障のないものであれば、特に限定されないが、例えば水、トルエン、ベンゼン、塩化メチレン、クロロホルム、テトラヒドロフラン、アセトニトリル、1,4-ジオキサン、ジメチルホルムアミド、ジメチルアセトアミド、N-メチルピロリジノン等又はその混合溶媒等が好適である。反応温度は、通常、-78~200℃、好ましくは-20~50℃である。反応時間は、通常、5分~3日間、好ましくは5分~10時間である。
また、上記反応は必要に応じて塩基を添加することができる。塩基は、例えばトリエチルアミン、ジイソプロピルエチルアミン、ピリジン、ルチジン、コリジン、4-ジメチルアミノピリジン、カリウム-tert-ブチラート、ナトリウム-tert-ブチラート、ナトリウムメトキシド、ナトリウムエトキシド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ブチルリチウム等の有機塩基、又は炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水素化ナトリウム等の無機塩基が挙げられる。添加量としては、一般式(X)で表される化合物1モルに対して、1~100モル用いることができ、好ましくは1~10モルである。
このようにして得られる一般式(I)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製することができる。
このようにして得られる一般式(I)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製することができる。
Linker部はReporter部と化合物を連結する部分で、適度な長さと化合物に大きな影響を与えない物性と、Reporter部を伸張できる官能基を備えているのが望ましい。Linker部としては例えば、
(工程12)本工程は一般式(XIII)で表される化合物にReporter部を伸張することにより、一般式(XIV)で表されるプローブ化合物を合成する反応である。本反応はLinker及びReporterの種類によって、アルキル化、アミド化などを選択することができ、それぞれ製造法2 工程2または製造法4 工程7を参考に実施することができる。
Reporter部はそれを備えたプローブ化合物を、血液中、脾臓中等の検体との共処理または、血液、脾臓等由来の細胞抽出液との共処理することにより、生化学的手法(発光、蛍光等)をもってBTKとの結合状態の検出を容易にするための部位であり、Linker部と上記のようにアルキル化、アミド化等で結合できる官能基を備えていることが望ましい。Reporter部としては例えば、BODIPY(登録商標)FL、BODIPY(登録商標)R6G、BODIPY(登録商標)TMR、BODIPY(登録商標)581/591、BODIPY(登録商標)TRなどが発光団として、ビオチン等が結合団としてあげられる。
本工程は一般式(VII)で表される化合物に製造法4、工程6、7と同様の操作にて一般式(XV)で表される化合物を製造する工程である。
本工程は一般式(XVI)で表される化合物に製造法3、工程5と同様の操作にて一般式(I)を製造する工程である。
このようにして得られる一般式(I)で表される化合物は、公知の分離精製手段、例えば濃縮、減圧濃縮、結晶化、溶媒抽出、再沈殿、クロマトグラフィーなどにより単離精製することができる。
該塩基付加塩としては、例えばナトリウム塩、カリウム塩等のアルカリ金属塩;例えばカルシウム塩、マグネシウム塩等のアルカリ土類金属塩;例えばアンモニウム塩;例えばトリメチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、プロカイン塩、N,N’-ジベンジルエチレンジアミン塩等の有機アミン塩等が挙げられる。
該酸付加塩としては、例えば塩酸塩、硫酸塩、硝酸塩、リン酸塩、過塩素酸塩等の無機酸塩;例えば酢酸塩、ギ酸塩、マレイン酸塩、酒石酸塩、クエン酸塩、アスコルビン酸塩、トリフルオロ酢酸塩等の有機酸塩;例えばメタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のスルホン酸塩等が挙げられる。
また、本発明化合物又はその塩は、その優れたBTK阻害活性により、BTKが関与する疾患の予防や治療のための医薬として有用である。「BTKが関与する疾患」とは、BTKの機能を欠失、抑制及び/又は阻害することによって、発症率の低下、症状の寛解、緩和、及び/又は完治する疾患が挙げられる。このような疾患として、例えば、癌や腫瘍等が挙げられるがこれに限定はされない。対象となる癌や腫瘍は特に制限はされないが、例えば、上皮性癌(例えば、呼吸器系癌、消化器系癌、生殖器系癌、分泌系癌等が挙げられる。)、肉腫、造血細胞系腫瘍、中枢神経系腫瘍、末梢神経腫瘍等が挙げられ、好ましくは、造血細胞系腫瘍(例えば、白血病、多発性骨髄腫、悪性リンパ腫等)である。また、腫瘍の発生臓器の種類も特に制限はされないが、例えば、頭頚部癌、食道癌、胃癌、結腸癌、直腸癌、肝臓癌、胆嚢・胆管癌、胆道癌、膵臓癌、肺癌、乳癌、卵巣癌、子宮頚癌、子宮体癌、腎癌、膀胱癌、前立腺癌、精巣腫瘍、骨・軟部肉腫、血液腫瘍、多発性骨髄腫、皮膚癌、脳腫瘍、中皮腫等が挙げられる。造血細胞系腫瘍としては、好ましくは、急性白血病、急性前骨髄球性白血病、急性リンパ芽球性白血病、慢性骨髄性白血病、リンパ芽球性リンパ腫、骨髄増殖性腫瘍、慢性リンパ性白血病、小リンパ球性リンパ腫、骨髄異形性症候群、濾胞性リンパ腫、MALTリンパ腫、辺縁帯リンパ腫、リンパ形質細胞性リンパ腫、ワルデンストレームマクログロブリン血症、マントル細胞リンパ腫、びまん性大細胞型B細胞リンパ腫、バーキットリンパ腫、節外性NK/T細胞リンパ腫、ホジキンリンパ腫、多発性骨髄腫等である。特に好ましくは、Bリンパ芽球性白血病/リンパ腫、濾胞性リンパ腫、マントル細胞リンパ腫、節性濾胞辺縁帯リンパ腫、びまん性大細胞型B細胞リンパ腫、バーキットリンパ腫、慢性リンパ性白血病、小リンパ球性リンパ腫、ワルデンストレームマクログロブリン血症、節外性NK/T細胞リンパ腫、ホジキンリンパ腫、骨髄異形成症候群、急性骨髄性白血病、急性リンパ性白血病等の血液腫瘍である。
結合剤としては、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン、アメ粉、ヒプロメロース等が挙げられる。
崩壊剤としては、デンプングリコール酸ナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、部分アルファー化デンプン等が挙げられる。
滑沢剤としては、タルク、ステアリン酸マグネシウム、ショ糖脂肪酸エステル、ステアリン酸、フマル酸ステアリルナトリウム等が挙げられる。
コーティング剤としては、エチルセルロース、アミノアルキルメタクリレートコポリマーRS、ヒプロメロース、白糖等が挙げられる。
溶剤としては、水、プロピレングリコール、生理食塩液が挙げられる。
溶解補助剤としては、ポリエチレングリコール、エタノール、α-シクロデキストリン、マクロゴール400、ポリソルベート80等が挙げられる。
懸濁化剤としては、カラギーナン、結晶セルロース・カルメロースナトリウム、ポリオキシエチレン硬化ヒマシ油が挙げられる。
等張化剤としては、塩化ナトリウム、グリセリン、塩化カリウム等が挙げられる。
pH調節剤・緩衝剤としては、クエン酸ナトリウム、塩酸、乳酸、リン酸、リン酸二水素ナトリウム等が挙げられる。
無痛化剤としては、プロカイン塩酸塩、リドカイン等が挙げられる。
防腐剤としては、パラオキシ安息香酸エチル、クレゾール、ベンザルコニウム塩化物等が挙げられる。
抗酸化剤としては、亜硫酸ナトリウム、アスコルビン酸、天然ビタミンE等が挙げられる。
着色剤としては、酸化チタン、三二酸化鉄、食用青色1号、銅クロロフィル等が挙げられる。
矯味・矯臭剤としてはアスパルテーム、サッカリン、スクラロース、l-メントール、ミントフレーバー等が挙げられる。
安定化剤としては、ピロ亜硫酸ナトリウム、エデト酸ナトリウム、エリソルビン酸、酸化マグネシウム、ジブチルヒドロキシトルエン等が挙げられる。
注射剤を調製する場合は、本発明化合物にpH調節剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤等を添加し、常法により皮下、筋肉内及び静脈内用注射剤を製造することができる。
カラム:YMC社製YMC-Triart C18,2.0X50mm,1.9μm
MS検出:ESI positive
UV検出:254及び210nm
カラム流速:0.5mL/min
移動相:水/アセトニトリル(0.1%ギ酸)
インジェクション量:1μL
グラディエント(table 1)
Time(min)Water Acetonitrile
0 95 5
0.1 95 5
2.1 5 95
3.0 STOP
カラム:YMC社製YMC-Actus Triart C18,20×50mm,5μmとYMC社製YMC-Actus Triart C18,20×10mm,5μmを連結したものを使用した。
UV検出:254nm
MS検出:ESI positive
カラム流速:25mL/min
移動相:水/アセトニトリル(0.1%ぎ酸)
インジェクション量:0.1-0.5mL
s:シングレット
d:ダブレット
t:トリプレット
q:カルテット
dd:ダブル ダブレット
dt:ダブル トリプレット
td:トリプル ダブレット
tt:トリプル トリプレット
ddd:ダブル ダブル ダブレット
ddt:ダブル ダブル トリプレット
dtd:ダブル トリプル ダブレット
tdd:トリプル ダブル ダブレット
m:マルチプレット
br:ブロード
brs:ブロードシングレット
CDI:カルボニルジイミダゾール
DMSO-d6:重ジメチルスルホキシド
CDCl3:重クロロホルム
CD3OD:重メタノール
THF:テトラヒドロフラン
DMF:N,N-ジメチルホルムアミド
DMA:N,N-ジメチルアセトアミド
NMP:1-メチル-2-ピロリジノン
DMSO:ジメチルスルホキシド
TFA:トリフルオロ酢酸
WSC:1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩
HOBt:1-ヒドロキシベンゾトリアゾール1水和物
HATU:(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ)メタンイミニウム ヘキサフルオロホスフェート
DIAD:ジイソプロピルアゾジカルボキシレート
TBAF:テトラブチルアンモニウムフルオライド
DIPEA:ジイソプロピルエチルアミン
Boc2O:二炭酸ジ-tert-ブチル
DMAP:ジメチルアミノピリジン
(S)-N-Boc-3-ピぺリジノール20gをトルエン100mlに溶解し、0℃にてトリエチルアミン21ml、メタンスルホニルクロライド9.2mlを加えた。氷冷下にて1時間撹拌したのち、酢酸エチルと水を加え、有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、表題化合物を無色固体として26.8g得た。
国際公開WO2007/126841号パンフレットに記載されている方法にて合成した3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン14.6g、工程1で得られた(S)-tert-ブチル 3-(メチルスルホニルオキシ)ピペリジン-1-カルボキシレート25g、炭酸カリウム69gをDMA150mlの懸濁溶液を100℃に加熱し、10時間撹拌した。室温に冷却後、水300mlを加え生じた固体を濾取し、水で洗浄後、乾燥し表題化合物を黄色固体として26.9g得た。物性値:m/z[M+H]+ 446.2
(S)-(-)-N-Boc-3-ピロリジノール935mgをクロロホルム15mlに溶解し、氷冷下にてトリエチルアミン1.04ml、メタンスルホニルクロライド467μlを加えた。室温にて1.5時間撹拌したのち、酢酸エチルと水を加え、有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、無色油状の表題化合物1.3gを得た。物性値:m/z[M+H]+ 266.1
国際公開WO2007/126841号パンフレットに記載されている方法にて合成した3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン20.0g、工程1で得られた(S)-tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレート23g、炭酸カリウム32gをDMA200mlへ懸濁させた溶液を85℃に加熱し、3時間撹拌した。室温に冷却後、水400mlを加え生じた固体を濾取し、水で洗浄後、乾燥し表題化合物を淡黄色固体として23.5g得た。物性値:m/z[M+H]+ 431.0
上記工程2で得られた(R)-tert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート2.0g、2-ジエチルアミノエタノール3.1ml、Pd(PPh3)2Cl2 163mgを,NMP 20mlに溶解し、系内を一酸化炭素で置換した後、120℃に加熱した。1時間撹拌後、室温まで冷却してメタノールを10ml加えた後、5規定の水酸化ナトリウム水溶液を6ml加え10分撹拌した。水を加えた後、クロロホルムで水層を洗浄し、水層を塩酸でpH4に調整して析出した固体を濾取し、水で洗浄した後、乾燥し表題化合物を淡黄色固体として1.35g得た。物性値:m/z[M+H]+ 349.1
(工程1)(R)-tert-ブチル-3-(4-アミノ-3-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートの合成
合成例2で得られた(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸 94mgのTHF4mlの懸濁溶液にCDI50mgを加え室温で3時間撹拌した。氷冷下5-クロロベンゾ[d]オキサゾール-2-アミン66mgを加え、リチウムヘキサメチルジシラザン-THF1.0M溶液を滴下した。氷冷下30分撹拌後、水を1ml加え、THFを除媒した。残渣に水を4ml加え、生じた固体を濾別し、ヘキサン/酢酸エチル=1/1 5mlで洗浄し、表題化合物を白色固体として106mg得た。物性値:m/z[M+H]+ 513.2
(工程1)で得られた(R)-tert-ブチル-3-(4-アミノ-3-(5-クロロベンゾ[d]オキサゾール-2-イルカルボニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート5.6mgを4N-塩酸/1,4-ジオキサン1mlを加え、1時間撹拌後、エバポレーターで除媒した。残渣にクロロホルム2ml、トリエチルアミン7.6μlを加え氷冷後、塩化アクリル0.9μlを加えた。1.5h撹拌後、飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣をシリカゲルカラムで精製し(展開溶媒:酢酸エチル:メタノール)表題化合物を白色固体として2.6mg得た。
実施例1に準じ、合成例2の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-ブロモベンゾ[d]オキサゾール-2-アミンから表題化合物を白色固体として得た。
(工程1)5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-アミンの合成
5-ブロモベンゾ[d]オキサゾール-2-アミン100mg、リン酸カリウム249mg、チオフェン-2-イルボロン酸90mgをDME2.5ml、水0.5mlに懸濁させ、1,1’-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン38mgを加え、マイクロウェーブ反応装置で140℃、20分間加熱した。反応溶液を除媒し、アミンゲルクロマトグラフィーで精製し(溶出液:クロロホルム/メタノール)、表題化合物を淡茶色固体として93mg得た。物性値:m/z[M+H]+ 216.8
合成例2で得られた(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸 19mgのTHF2mlの懸濁溶液にCDI10mgを加え室温で2時間撹拌した。氷冷下工程1で得られた5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-アミン17mgを加え、リチウムヘキサメチルジシラザン-THF1.0M溶液105μlを滴下した。氷冷下30分撹拌後、水を1ml加え、THFを除媒した。残渣に水を4ml加え、生じた固体を濾別し、ヘキサン/酢酸エチル=1/1 5mlで洗浄し、目的物を淡茶色固体として13mg得た。物性値:m/z[M+H]+ 561.3
(工程2)で得られた((R)-tert-ブチル-3-(4-アミノ-3-((5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート9mgに4N-塩酸/1,4-ジオキサン1mlを加え、1時間撹拌後、エバポレーターで除媒した。残渣にクロロホルム2ml、トリエチルアミン12μlを加え氷冷後、塩化アクリル1.3μlを加えた。1.5h撹拌後、飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として2.1mg得た。
実施例1に準じ、塩化アクリルの代わりに塩化メタクリルを用いて表題化合物を白色固体として得た。
実施例1に準じ、塩化アクリルの代わりにクロトン酸クロリドを用いて表題化合物を白色固体として得た。
(工程1)(R)-tert-ブチル-3-(4-アミノ-3-((5-シアノベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートの合成
合成例2で得られた(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸2.32gをDMA25mlに溶解させ、CDI2.01gを加え、室温で1時間撹拌した。反応溶液に5-シアノベンゾ[d]オキサゾール-2-アミン1.12gを加え、その後ナトリウム-tert-ブチラート1.23gを加えた。室温で2時間撹拌し、水を加えた後、2N塩酸でpHを調節して固体を析出させ濾取して乾燥させ、表題化合物を淡黄色固体として2.66g得た。物性値:m/z[M+H]+ 505.3
工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-シアノベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート2.1gをジクロロメタン10mlに懸濁させ、室温でTFA10mlを加えた。2時間撹拌した後、TFAをエバポレーターで除媒した。さらにトルエンで共沸を行い、残渣をNMP20ml、水2mlを加え氷冷した。炭酸カリウム2.88g、塩化アクリル0.4mlを加え、氷冷下撹拌した。2時間後水、2N塩酸を加えてpHを調整し、生じた固体を濾取した。その後シリカゲルクロマトグラフィー(クロロホルムーメタノール)で精製し、目的物を白色固体として0.7g得た。
実施例6に準じ、合成例2の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-メトキシベンゾ[d]オキサゾール-2-アミンから表題化合物を淡茶色固体として得た。
実施例6に準じ、合成例2の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-(2-メトキシエチル)ベンゾ[d]オキサゾール-2-アミンから表題化合物を白色固体として得た。
実施例6に準じ、合成例2の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸とオキサゾロ[4,5-b]ピリジン-2-アミンから表題化合物を白色固体として得た。
実施例6に準じ、合成例2の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と4-メチルベンゾ[d]オキサゾール-2-アミンから表題化合物を白色固体として得た。
実施例6に準じ、実施例12(工程2)で得られた(R)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1-(ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミドと塩化アクリルの代わりに塩化メタクリルを用いて表題化合物を白色固体として得た。
(工程1)(R)-tert-ブチル-3-(4-アミノ-3-((5-フルオロベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートの合成
合成例2で得られた(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸 1.0gのDMA10mlの溶液にCDI895mgを加え室温で1時間撹拌した。5-フルオロベンゾ[d]オキサゾール-2-アミン462mgを加え、ナトリウム-tert-ブチラートーTHF1.0M溶液9mlを滴下した。室温下30分撹拌後、1N NaOH水溶液10mlを加えてTHFを除媒した。1時間撹拌後、2N HClで晶析させ、水―MeOHを加えて完全に晶析させた後、生じた固体を濾取し、表題化合物1.14gを微黄色固体として得た。物性値:m/z[M+H]+ 497.2
工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-(5-フルオロベンゾ[d]オキサゾール-2-イルカルボニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート3.06gとヨウ化ナトリウム5.5gをアセトニトリル30mlに懸濁させ、室温下トリメチルシリルクロライド4.7mlを加えた。室温下1時間撹拌し、飽和重曹水を加え、固体を析出させた。10分撹拌後固体を濾取し、乾燥させて表題化合物2.07gを薄褐色固体として得た。物性値:m/z[M+H]+ 398.0
工程2で得られた(R)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1-(ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド2gと炭酸カリウム2.1gをNMP20ml、水2mlに溶解させ氷冷下撹拌した。塩化アクリル0.4mlを加え1時間撹拌した。水を加え、塩酸でpHを調整し、析出した固体を濾取した。濾取した固体をシリカゲルクロマトグラフィー(溶出液:クロロホルムーメタノール)で精製し、表題化合物を1.79g白色固体として得た。
(工程1)(R)-tert-ブチル-3-(4-アミノ-3-((ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートの合成
合成例1で得た(R)-tert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート 300mgをNMP3mlに溶解させた。ベンゾ[d]オキサゾール-2-アミン118mg、キサントホス20mg、N-メチルモルホリン0.15mlを加え、脱気操作を行った。その後酢酸パラジウム7.6mgを加え、一酸化炭素雰囲気下110℃に加熱して2時間撹拌した。冷却後、メタノール4.5mlと5N水酸化ナトリウム水溶液0.45mlを加え、室温で30分撹拌した。その後2NHClでpHを5.3に調整し、生じた固体を濾取した。粗体をシリカゲルカラムで精製し(クロロホルムーメタノール)表題化合物を257mg白色固体として得た。物性値:m/z[M+H]+ 479.3
工程1で得た(R)-tert-ブチル-3-(4-アミノ-3-((ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート5gをアセトニトリル50mlに懸濁させ、ヨウ化ナトリウム7.85gを加えた。室温で撹拌下、トリメチルシリルクロライド6.65mlを滴下し1時間撹拌した。水87.5mlと5N水酸化ナトリウム水溶液12.5mlを加えた後、氷冷した。塩化アクリル0.895mlを滴下し氷冷下1時間撹拌した。水を加え生じた固体を濾取して水洗し乾燥して表題化合物4.13gを白色固体として得た。
実施例13に準じ、塩化アクリルの代わりにクロトン酸クロリドを用いて表題化合物を白色固体として得た。
実施例1の工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート5mgに4N-塩酸/1,4-ジオキサン1mlを加え、10分撹拌した。その後エバポレーターで除媒し、トルエンで共沸した。残渣にDMF1mlに溶解させ、ジイソプロピルエチルアミン8.5μlと(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩2.4mg及びHATU5.5mgを加えた。室温で1時間撹拌後、溶液を減圧濃縮した。残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を3.96mg白色固体として得た。
実施例15に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(エチル(メチル)アミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例15に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ジエチルアミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例15に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(イソプロピル(メチル)アミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例15に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ピロリジン-1-イル)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例15に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ピペリジン-1-イル)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例15に準じ、実施例3(工程2)で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートを用いることで表題化合物を白色固体として得た。
実施例15に準じ、実施例13(工程1)で得られた(R)-tert-ブチル-3-(4-アミノ-3-((ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートと、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりにブタ-2-イノイル酸を用いることで表題化合物を淡黄色固体として得た。
(工程1)(R)-1-(1-アシロキシピペリジン-3-イル)-4-アミノ-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸の合成
合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸1gに4N-塩酸/1,4-ジオキサン15mlを加え、室温で1時間撹拌した。その後除媒し、さらにトルエンを加え共沸した。残渣にクロロホルム50ml、トリエチルアミン3.8mlを加えた。撹拌しながら、塩化アクリル780μlを徐々に加えた。反応終了を確認後、2-プロパノールを加え反応を停止した。除媒し、残渣にギ酸水溶液を加え、pH3に調節すると固体が析出した。生じた固体を濾取して乾燥して、黄色固体として表題化合物を840mg得た。物性値:m/z[M+H]+ 318.1
上記工程1で得られた(R)-1-(1-アシロキシピペリジン-3-イル)-4-アミノ-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸5mgをDMF150μlに溶解させた。その溶液にジイソプロピルエチルアミン8.26μl、5、6-ジメチルベンゾ[d]オキサゾール-2-アミン3.85mg、HATU9mgを加えた。終夜撹拌後、DMSO850μlを加え、逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として1.2mg得た。
(工程1)(R)-tert-ブチル-3-(4-アミノ-3-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピリジン-1-カルボキシレートの合成
合成例3で得られた(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸 100mgのDMF5mlの溶液にCDI56mgを加え室温で1時間撹拌した。氷冷下5-クロロベンゾ[d]オキサゾール-2-アミン73mgを加え、60%水素化ナトリウム17mgを加えた。氷冷下30分撹拌後、水を1ml加え反応を停止した。反応溶液を濃縮し、シリカゲルカラムクロマトグラフィー(展開溶媒:クロロホルム-メタノール)で精製することにより、表題化合物を114mg白色固体として得た。物性値:m/z[M+H]+ 499.1
工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート15mgを4N-塩酸/1,4-ジオキサン1.5mlを加え、1時間撹拌後、エバポレーターで除媒した。残渣にクロロホルム2ml、トリエチルアミン21μlを加え氷冷後、塩化アクリル2.4μlを加えた。3h撹拌後、飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣をシリカゲルカラムで精製し(展開溶媒:酢酸エチル:メタノール)表題化合物を6.8mg白色固体として得た。
実施例24に準じ、塩化アクリルの代わりにクロトン酸クロリドを用いて表題化合物を白色固体として得た。
実施例24に準じ、塩化アクリルの代わりに3-メチルブタ-2-エノイルクロリドを用いて表題化合物を白色固体として得た。
実施例24に準じ、合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸とベンゾ[d]オキサゾール-2-アミンから表題化合物を白色固体として得た。
実施例24に準じ、合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-アミンから表題化合物を白色固体として得た。
実施例24に準じ、合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-メチルベンゾ[d]オキサゾール-2-アミンから表題化合物を淡黄色固体として得た。
実施例24に準じ、合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-フルオロベンゾ[d]オキサゾール-2-アミンから表題化合物を淡黄色固体として得た。
(工程1)5-(4-クロロフェニル)ベンゾ[d]オキサゾール-2-アミンの合成
実施例3の工程1に準じ、チオフェン-2-イルボロン酸の代わりに4-クロロフェニルボロン酸を用いることで表題化合物を白色固体として得た。物性値:m/z[M+H]+ 245.1
実施例24に準じ、合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と上記工程1で得られた5-(4-クロロフェニル)ベンゾ[d]オキサゾール-2-アミンから表題化合物を白色固体として得た。
実施例24の工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート15mgに4N-塩酸/1,4-ジオキサン1.5mlを加え、10分撹拌した。その後エバポレーターで除媒し、トルエンで共沸した。残渣にDMF1mlに溶解させ、ジイソプロピルエチルアミン13μlと(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩3.7mg及びHATU8.4mgを加えた。室温で1時間撹拌後、溶液を減圧濃縮した。残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として4.2mg得た。
実施例32に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(エチル(メチル)アミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例32に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ジエチルアミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例32に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(イソプロピル(メチル)アミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例32に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ピロリジン-1-イル)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例32に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ピペリジン-1-イル)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例6に準じ、合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-メトキシベンゾ[d]オキサゾール-2-アミンから表題化合物を白色固体として得た。
実施例6に準じ、合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-シアノベンゾ[d]オキサゾール-2-アミンから表題化合物を白色固体として得た。
実施例6に準じ、合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸と5-(2-メトキシエチル)ベンゾ[d]オキサゾール-2-アミンから淡黄色固体として得た。
(工程1)(R)-tert-ブチル-3-(4-アミノ-3-((5-フェニルベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの合成
合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸20mgをTHF1mlに懸濁させ、撹拌下室温でCDI12mgを加えた。室温下終夜撹拌し、5-フェニルベンゾ[d]オキサゾール-2-アミン24mgを加えた後氷冷し、リチウムヘキサメチルジシラザン-THF1.0M溶液172μlを滴下した。1時間撹拌後、酢酸30μlを加え反応を停止した。除媒後残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として12.8mg得た。物性値:m/z[M+H]+ 541.1
上記工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-フェニルベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート12.8mgに4N-塩酸/1,4-ジオキサンを1.5ml加え1時間撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣にクロロホルム1ml、トリエチルアミン16μlを加え氷冷下撹拌した。溶液に塩化アクリルを1.9μl加え1時間撹拌後、飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣を残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として3.46mg得た。
実施例41の工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-フェニルベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート5mgにN-塩酸/1,4-ジオキサン1mlを加え30分撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣をDMF1mlに溶解し、ジイソプロピルエチルアミン7.9μlと(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩2.2mg及びHATU5.18mgを加えた。室温で1時間撹拌後、溶液を減圧濃縮した。残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として3.04mg得た。
(工程1)(R)-tert-ブチル-3-(4-アミノ-3-((5-(トリフルオロメチル)ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの合成
合成例3の(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸32mgをTHF2mlに懸濁させ、撹拌下室温でCDI55mgを加えた。室温下終夜撹拌し、5-(トリフルオロメチル)ベンゾ[d]オキサゾール-2-アミン28mgを加えた後氷冷し、リチウムヘキサメチルジシラザン-THF1.0M溶液183μlを滴下した。1時間撹拌後、水を加え生じた固体を濾取した。固体をヘキサン/酢酸エチルの混合溶媒で洗浄し、表題化合物を35mg淡黄色固体として得た。物性値:m/z[M+H]+ 533.3
上記工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-(トリフルオロメチル)ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート8mgにジクロロメタン500μlを加え、さらにトリフルオロ酢酸200μl加え30分撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣にクロロホルム2ml、トリエチルアミン11μlを加え氷冷下撹拌した。溶液に塩化アクリルを1.2μl加え1時間撹拌後、飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣を残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として1.58mg得た。
実施例43の工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((5-(トリフルオロメチル)ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート5mgにジクロロメタン500μlを加え、さらにトリフルオロ酢酸200μl加え30分撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣をDMF1mlに溶解し、ジイソプロピルエチルアミン6.5μlと(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩1.9mg及びHATU4.3mgを加えた。室温で1時間撹拌後、溶液を減圧濃縮した。残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として2.88mg得た。
(工程1)tert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートの合成
tert-ブチル 3-ヒドロキシアゼチジン-1-カルボキシレート240mgをクロロホルム2mlに溶解し、0℃にてトリエチルアミン290μl、メタンスルホニルクロライド130μlを加えた。氷冷下にて1時間撹拌したのち、クロロホルムと水を加え、有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液、水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。その残渣に国際公開WO2007/126841号パンフレットに記載されている方法にて合成した3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン300mg、炭酸カリウム570mg、DMA3mlを加え100℃に加熱し、11時間撹拌した。室温に冷却後、酢酸エチルで抽出し、有機層を水で洗い、無水硫酸マグネシウムで乾燥した。残渣をアミンゲルクロマトグラフィーで精製し(ヘキサン/酢酸エチル=1:1→0:1)表題化合物を淡黄色固体として232mg得た。物性値:m/z[M+H]+ 417.1
工程1で得られたtert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート262mgをメタノール10ml、トリエチルアミン1mlに溶解させた。一酸化炭素雰囲気に変換後、1,1′-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタンを51mg加え、80℃で14時間加熱した。冷却後、溶液を除媒し残渣に1,4-ジオキサン1mlを加え、さらに5N NaOH水溶液500μlを加えた。室温で3時間撹拌後、2N塩酸でpHを4に調整して氷冷し、水を加えて析出した固体を濾取し、乾燥することで表題化合物を淡茶色固体として42mg得た。物性値:m/z[M+H]+ 335.2
上記工程2で得られた4-アミノ-1-(1-(tert-ブチルオキシカルボニル)アゼチジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸42mgをDMF3mlに溶解し、CDI24mgを加え室温で終夜撹拌した。さらにCDI4mgを加え30分撹拌した。溶液に5-クロロベンゾ[d]オキサゾール-2-アミン42mgを加え氷冷し、水素化ナトリウム(60%)10mgを加えた。1時間撹拌後、水で反応を停止し、除媒した。残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として34mg得た。物性値:m/z[M+H]+ 485.2
上記工程3で得られたtert-ブチル-3-(4-アミノ-3-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-カルボキシレート10mgに4N-塩酸/1,4-ジオキサンを1ml加え1時間撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣にクロロホルム1ml、トリエチルアミン14μlを加え氷冷下撹拌した。溶液に塩化アクリルを1.7μl加え1時間撹拌後、飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣を残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として0.69mg得た。
(工程1)tert-ブチル 3-(4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-カルボキシレートの合成
上記工程2で得られた、tert-ブチル 3-(4-アミノ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-カルボキシレート32mg、5-クロロベンゾ[d]オキサゾール-2-アミン20mg、ジアザビシクロウンデセン28μlをDMF1mlに溶解させ、さらに1,1′-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン9mgを加え、一酸化炭素雰囲気下80℃で1.5時間撹拌した。クロロホルムと水で分配し、有機層を硫酸ナトリウムで乾燥後、除媒した残渣をシリカゲルクロマトグラフィーで精製し(ヘキサン/酢酸エチル=1/1→酢酸エチル/メタノール=10/1)淡茶色固体として表題化合物を20mg得た。物性値:m/z[M+H]+ 484.2
上記工程3で得られたtert-ブチル 3-(4-アミノ-5-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-カルボキシレート5mgに4N-塩酸/1,4-ジオキサンを1ml加え1時間撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣にクロロホルム1ml、トリエチルアミン14μlを加え氷冷下撹拌した。溶液に塩化アクリルを1.7μl加え1時間撹拌後、飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣を残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として2.21mg得た。
実施例46の工程3で得られたtert-ブチル 3-(4-アミノ-5-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-カルボキシレート5mgに4N-塩酸/1,4-ジオキサンを1ml加え1時間撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣をDMF1mlに溶解し、ジイソプロピルエチルアミン14.4μlと(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩4.1mg及びHATU9.4mgを加えた。室温で1時間撹拌後、溶液を減圧濃縮した。残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を4.67mg得た。
(工程1)(R)-tert-ブチル 3-(4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレートの合成
国際公開WO2005/042556号パンフレットに記載されている方法にて合成した、4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン5.00g、(S)-tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレート19.1g、炭酸セシウム23.5gをアセトニトリル25mlに懸濁させ、60℃で3時間加熱した。冷却後、水とメタノールを加え生じた固体を濾取、乾燥して表題化合物を淡茶色固体として5.65g得た。
上記工程1で得られた(R)-tert-ブチル 3-(4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート5gに28%アンモニア水40mlを加え、反応液をマイクロウェーブ反応装置で、100℃で1.5時間撹拌した。氷冷下1時間撹拌して析出した固体を濾取し、冷メタノールで洗浄し、表題化合物を白色固体として3.91g得た。
上記工程2で得られた、tert-ブチル 3-(4-アミノ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート93mg、5-クロロベンゾ[d]オキサゾール-2-アミン110mg、ジアザビシクロウンデセン100μlをDMF2mlに溶解させ、さらに1,1’-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン35mgを加え、一酸化炭素雰囲気下80℃で2.5時間撹拌した。クロロホルムと水で分配し、有機層を硫酸ナトリウムで乾燥後、除媒した残渣をシリカゲルクロマトグラフィーで精製し(ヘキサン/酢酸エチル=1/1→酢酸エチル/メタノール=10/1)淡茶色固体として表題化合物を106mg得た。物性値:m/z[M+H]+ 498.1
上記工程3で得られた(R)-tert-ブチル 3-(4-アミノ-5-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート20mgに4N-塩酸/1,4-ジオキサンを1ml加え1時間撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣にクロロホルム2ml、トリエチルアミン28μlを加え氷冷下撹拌した。溶液に塩化アクリルを3.2μl加え1時間撹拌後、飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣を残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として3.52mg得た。
実施例48の工程3で得られた(R)-tert-ブチル 3-(4-アミノ-5-((5-クロロベンゾ[d]オキサゾール-2-イル)カルバモイル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート13mgに4N-塩酸/1,4-ジオキサンを1ml加え1時間撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣をDMF1mlに溶解し、ジイソプロピルエチルアミン14.4μlと(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩4.1mg及びHATU9.6mgを加えた。室温で1時間撹拌後、溶液を減圧濃縮した。残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を6.66mg得た。
実施例49に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(エチル(メチル)アミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例49に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ジエチルアミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例49に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(イソプロピル(メチル)アミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例49に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ピロリジン-1-イル)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例49に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ピぺリジン-1-イル)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
(工程1)(R)-tert-ブチル 3-(4-アミノ-5-((5-フェニルベンゾ[d]オキサゾール-2-イル)カルバモイル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレートの合成
実施例48の工程3に準じ、5-クロロベンゾ[d]オキサゾール-2-アミンの代わりに5-フェニルベンゾ[d]オキサゾール-2-アミンを用いることで表題化合物を褐色固体として得た。物性値:m/z[M+H]+ 540.3
実施例48の工程4に準じ、上記工程1で得られた(R)-tert-ブチル 3-(4-アミノ-5-((5-フェニルベンゾ[d]オキサゾール-2-イル)カルバモイル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレートを用いて表題化合物を白色固体として得た。
実施例55の工程1で得られた(R)-tert-ブチル 3-(4-アミノ-5-((5-フェニルベンゾ[d]オキサゾール-2-イル)カルバモイル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート13mgに4N-塩酸/1,4-ジオキサンを1ml加え1時間撹拌した。その後除媒し、さらにトルエン1mlで共沸した。残渣をDMF1mlに溶解し、ジイソプロピルエチルアミン14.4μlと(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩4.1mg及びHATU9.6mgを加えた。室温で1時間撹拌後、溶液を減圧濃縮した。残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を6.66mg得た。
実施例56に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(エチル(メチル)アミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例56に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ジエチルアミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例56に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(イソプロピル(メチル)アミノ)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例56に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ピロリジン-1-イル)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
実施例56に準じ、(E)-4-(ジメチルアミノ)ブタ-2-エン酸塩酸塩の代わりに(E)-4-(ピぺリジン-1-イル)ブタ-2-エン酸塩酸塩を用いることで表題化合物を白色固体として得た。
(工程1)(E)-4-(4-(2((tert-ブトキシカルボニル)アミノ)エチル)ピペラジン-1-イル)ブタ-2-エノン酸の合成
tert-ブチル-(2-(ピペラジン)-1-イル)エチル)カルバメート2gをDMSO20mlに溶解させ、トリエチルアミン1.35mlを加えた。その溶液に(E)-メチル 4-ブロモブタ-2-エノエートを合計1.14ml室温で加えた。1時間半撹拌後、溶液を飽和重曹水中に加え、酢酸エチルで抽出した。硫酸ナトリウムで乾燥後、除媒して残渣をシリカゲルクロマトグラフィーで精製(展開溶媒:クロロホルム:メタノール)した。取得物にトリエチルアミン10ml、水10mlを加え、100℃で終夜撹拌した。反応溶液を除媒して表題化合物を橙色アモルファスとして2.05g得た。
実施例13の工程1で得られた(R)-tert-ブチル-3-(4-アミノ-3-((ベンゾ[d]オキサゾール-2-イル)カルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレート200mgをクロロホルム3mlに溶解させ、室温でトリフルオロ酢酸1mlを加えた。1時間後除媒しアセトニトリルに溶解させ、トリエチルアミンを加えた。その後除媒し再びクロロホルム/メタノールに溶解させ除媒した。その残渣にDMF5mlに溶解し、上記工程1で得られた(E)-4-(4-(2((tert-ブトキシカルボニル)アミノ)エチル)ピペラジン-1-イル)ブタ-2-エノン酸176mgを加え、WSC104mgを加え撹拌した。2時間後、酢酸エチルを加え、飽和塩化アンモニウム水溶液で有機層を洗浄した。有機層を硫酸ナトリウムで乾燥後、除媒し、シリカゲルクロマトグラフィーで精製し(展開溶媒:クロロホルム:メタノール)表題化合物を128.4mg得た。
上記工程2で得られた(R,E)-tert-ブチル(2-(4-(4-(3-(4-アミノ-3-(ベンゾ[d]オキサゾール-2-イルカルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-イル)-4-オキソブタ-2-エン-1-イル)ピペラジン-1-イル)エチル)カルバメート128mgをクロロホルム2mlに溶解させ、トリフルオロ酢酸1mlを加えた。10分後反応溶液を濃縮し、アセトニトリルに溶解させた。トリエチルアミンを加え、再度濃縮した。残渣をアミンゲルクロマトグラフィー(展開溶媒:クロロホルム:メタノール)で精製し表題化合物98.1mgを得た。
上記工程3で得られた(R,E)-4-アミノ-1-(1-(4-(4-(2-アミノエチル)ピペラジン-1-イル)ブタ-2-エノイル)ピペリジン-3-イル)-N-(ベンゾ[d]オキサゾール-2-イルカルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド93mgをクロロホルム10mlに溶解し、7-(2-カルボキシエチル)-5,5-ジフルオロ-1,3-ジメチル-5H-ジピロロ[1,2-c:2’,1’-f][1,3,2]ジアザボリンイン-4-イウム-5-ウイド73mg、HOBt22mg、WSC48mgを加えた。2時間撹拌後、反応溶液をクロロホルムと飽和重曹水に分配した。有機層を硫酸ナトリウムで乾燥後、濃縮して残渣をアミンゲルクロマトグラフィー(展開溶媒:クロロホルム:メタノール)で精製し、表題化合物を98.1mg得た。
実施例62の工程3で得られた(R,E)-4-アミノ-1-(1-(4-(4-(2-アミノエチル)ピペラジン-1-イル)ブタ-2-エノイル)ピペリジン-3-イル)-N-(ベンゾ[d]オキサゾール-2-イルカルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド3mgのDMF0.5ml溶液にビオチン-NHS(登録商標)1.5mg、トリエチルアミン4μlを加え、終夜で撹拌した。溶液にDMSO0.5mlを加え、逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として1.0mg得た。
(工程1)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸の合成
合成例2で得られた(R)-4-アミノ-1-(1-(tert-ブチルオキシカルボニル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸 10gに4N-塩酸/1,4-ジオキサン50mLを加え、1時間撹拌後、エバポレーターで除媒した。残渣にクロロホルム140mL、トリエチルアミン25mLを加え氷冷後、塩化アクリル2.23mLを加えた。1.5時間撹拌後、エバポレーターで除媒した。残渣にpH3.0のギ酸水溶液を加え、2時間撹拌後、析出物を濾取し、減圧乾燥することで表題化合物の白褐色固体8.93gを得た。
工程1で得られた(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボン酸 5mgをDMF150μLに溶解させた後に、ジイソプロピルエチルアミン8.2μLと7-クロロベンゾ[d]オキサゾール-2-アミン4.0mg、HATU9.0mgを加え、1時間撹拌した。反応溶液にDMSO850μLを加え逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として0.36mg得た。
(工程1)(R)-tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレートの合成
合成例3に準じ(R)-N-Boc-3-ピロリジノールから表題の油状化合物を得た。
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンと(R)-tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレートから表題化合物の淡黄色固体を得た。
工程2で得られた(S)-tert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート500mgにクロロホルム5mLとトリフルオロ酢酸1.7mlを加え、1時間撹拌後、エバポレーターで除媒した。残渣にクロロホルム12mL、トリエチルアミン810μLを加え氷冷後、塩化アクリル89μLを加えた。30分撹拌後飽和重曹水で反応を停止し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、除媒後の残渣をシリカゲルカラムで精製し(展開溶媒:酢酸エチル:メタノール)表題化合物350mgを白色固体として得た。
工程3で得られた(S)-1-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロロピロリジン-1-イル)プロパ-2-エン-1-オン20mgをDMF520mLに溶解させ、ベンゾ[d]オキサゾール-2-アミン13mg、PdCl2(PPh3)2 3.65mg、DBU23μLを加え、一酸化炭素雰囲気下120度で2h撹拌した後に、エバポレーターで除媒した。残渣にDMSOを加え逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))で精製し、表題化合物を白色固体として1.9mg得た。
(工程1)tert-ブチル 3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピロリジン-1-カルボキシレートの合成
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン300mgとtert-ブチル 3-(ブロモメチル)ピロリジン-1-カルボキシレート396mgから表題化合物の淡黄色固体を464mg得た。
実施例65の工程3に準じ、工程1で得られたtert-ブチル 3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピロリジン-1-カルボキシレート464mgから表題化合物の淡黄色固体を274mg得た。
実施例65の工程4に準じ、工程2で得られた1-(3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピロリジン-1-イル)プロパ-2-エン-1-オン10mgから表題化合物の白色固体を3.2mg得た。
(工程1)tert-ブチル 3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-カルボキシレートの合成
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン300mgとtert-ブチル 3-(ブロモメチル)ピロリジン-1-カルボキシレート416mgから表題化合物の淡黄色固体を375mg得た。
実施例65の工程3に準じ、工程1で得られたtert-ブチル-3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-カルボキシレート375mgから表題化合物の淡黄色固体を228mg得た。
実施例65の工程4に準じ、工程2で得られた1-(3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-イル)プロパ-2-エン-1-オン10mgから表題化合物の白色固体を1.4mg得た。
(工程1)tert-ブチル 4-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-カルボキシレートの合成
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン100mgとtert-ブチル 4-(ブロモメチル)ピペリジン-1-カルボキシレート130mgから表題化合物の淡黄色固体を120mg得た。
実施例65の工程3に準じ、工程1で得られたtert-ブチル 4-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-カルボキシレート120mgから表題化合物の淡黄色固体を85mg得た。
実施例65の工程4に準じ、工程2で得られた1-(4-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-イル)プロパ-2-エン-1-オン10mgから表題化合物の白色固体を3.12mg得た。
(工程1)tert-ブチル 4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートの合成
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンとtert-ブチル 4-ブロモピペリジン-1-カルボキシレートから表題化合物の淡黄色固体を得た。
実施例65の工程3に準じ、工程1で得られたtert-ブチル 4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-カルボキシレートから表題化合物の淡黄色固体を得た。
実施例65の工程4に準じ、工程3で得られた1-(4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-イル)プロパ-2-エン-1-オン10mgから表題化合物の白色固体を2.4mg得た。
(工程1)tert-ブチル 3-((メチルスルホニルオキシ)メチル)アゼチジン-1-カルボキシレートの合成
合成例3に準じ、tert-ブチル 3-(ヒドロキシメチル)アゼチジン-1-カルボキシレートから表題の油状化合物を得た。
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン200mgと工程1で得られたtert-ブチル 3-((メチルスルホニルオキシ)メチル)アゼチジン-1-カルボキシレートから表題化合物の淡黄色固体を得た。
実施例65の工程3に準じ、工程2で得られたtert-ブチル 3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)アゼチジン-1-カルボキシレートから表題化合物の淡黄色固体を得た。
実施例65の工程4に準じ、工程3で得られた1-(3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)アゼチジン-1-イル)プロピル-2-エン-1-オン10mgから表題化合物の白色固体を2.44mg得た。
(工程1)(1R,4R)-4-((tert-ブトキシカルボニル)アミノ)シクロヘキシルメタンスルホネートの合成
合成例3に準じ、tert-ブチル(1R,4R)-4-シクロヘキシルカルバメート500mgから表題の油状化合物を780mg得た。
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン630mgと工程1で得られた(1R,4R)-4-((tert-ブトキシカルボニル)アミノ)シクロヘキシルメタンスルホネート780mgから表題化合物の淡黄色固体を614mg得た。
実施例65の工程3に準じ、工程2で得られたtert-ブチル((1S,4S)-4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)シクロヘキシルカルバマメート200mgから表題化合物の淡黄色固体を137mg得た。
実施例65の工程4に準じ、工程3で得られたN-((1S,4S)-4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)シクロヘキシル)アクリルアミド10mgから表題化合物の白色固体を2.08mg得た。
(工程1)(1S,4S)-4-((tert-ブトキシカルボニル)アミノ)シクロヘキシルメタンスルホネートの合成
合成例3に準じ、tert-ブチル(1S,4S)-4-シクロヘキシルカルバメート500mgから表題の油状化合物を704mg得た。
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン570mgと工程1で得られた(1S,4S)-4-((tert-ブトキシカルボニル)アミノ)シクロヘキシルメタンスルホネート704mgから表題化合物の淡黄色固体を375mg得た。
実施例65の工程3に準じ、工程2で得られたtert-ブチル((1R,4R)-4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)シクロヘキシルカルバマメート200mgから表題化合物の淡黄色固体を90mg得た。
実施例65の工程4に準じ、工程3で得られたN-((1S,4S)-4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)シクロヘキシル)アクリルアミド10mgから表題化合物の白色固体を3.43mg得た。
(工程1)(S)-tert-ブチル 3-(4-アミノ-3-(ベンゾ[d]オキサゾール-2-イルカルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート
実施例65の工程4に準じ、実施例65の工程2で得られた(S)-tert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートから表題化合物を得た。
実施例32に準じ、工程1で得られた(S)-tert-ブチル 3-(4-アミノ-3-(ベンゾ[d]オキサゾール-2-イルカルバモイル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート20mgから表題化合物の白色固体を13.8mg得た。
(工程1)tert-ブチル 3-(メチルスルホニルオキシ)アゼチジン-1-カルボキシレートの合成
合成例3に準じ、tert-ブチル 3-ヒドロキシアゼチジン-1-カルボキシレート500mgから表題の油状化合物を774mg得た。
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン670mgと工程1で得られたtert-ブチル 3-(メチルスルホニルオキシ)アゼチジン-1-カルボキシレート774mgから表題化合物の淡黄色固体を690mg得た。
実施例65の工程3に準じ、工程2で得られたtert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-カルボキシレート200mgから表題化合物の淡黄色固体を129mg得た。
実施例65の工程4に準じ、工程3で得られた1-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)プロピル-2-エン-1-オンから表題化合物の白色固体を得た。
(工程1)実施例65の工程4に準じ、実施例70の工程3で得られた1-(3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)アゼチジン-1-イル)プロピル-2-エン-1-オン10mgと5-フルオロベンゾ[d]オキサゾール-2-アミン5.2mgから表題化合物の白色固体を3.36mg得た。
(工程1)実施例65の工程4に準じ、実施例70の工程3で得られた1-(3-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)アゼチジン-1-イル)プロピル-2-エン-1-オン10mgと5-クロロベンゾ[d]オキサゾール-2-アミン5.2mgから表題化合物の白色固体を3.76mg得た。
(工程1)実施例65の工程4に準じ、実施例68の工程2で得られた1-(4-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-イル)プロパ-2-エン-1-オン10mgと5-フルオロベンゾ[d]オキサゾール-2-アミン4.8mgから表題化合物の白色固体を6.37mg得た。
(工程1)実施例65の工程4に準じ、実施例72の工程3で得られたN-((1S,4S)-4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)シクロヘキシル)アクリルアミド10mgと5-クロロベンゾ[d]オキサゾール-2-アミン5.2mgから表題化合物の白色固体を1.93mg得た。
(工程1)実施例65の工程4に準じ、実施例74の工程3で得られた1-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)プロピル-2-エン-1-オン10mgと5-フルオロベンゾ[d]オキサゾール-2-アミン4.8mgから表題化合物の白色固体を2.21mg得た。
(工程1)実施例65の工程4に準じ、実施例68の工程2で得られた1-(4-((4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-イル)プロパ-2-エン-1-オン10mgと5-クロロベンゾ[d]オキサゾール-2-アミン5.2mgから表題化合物の白色固体を4.30mg得た。
(工程1)実施例65の工程4に準じ、実施例72の工程3で得られたN-((1S,4S)-4-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)シクロヘキシル)アクリルアミド10mgと5-フルオロベンゾ[d]オキサゾール-2-アミン4.8mgから表題化合物の白色固体を2.91mg得た。
(工程1)tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレートの合成
合成例3に準じ、N-Boc-3-ピロリジノールから表題の油状化合物を得た。
実施例65(工程2)に準じ、3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレートから表題化合物の淡黄色固体を得た。
実施例65の工程3に準じ、工程2で得られたtert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートから表題化合物を白色固体として得た。
実施例65の工程4に準じ、工程3で得られた1-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロロピロリジン-1-イル)プロパ-2-エン-1-オン10mgから表題化合物を白色固体として3.9mg得た。
(工程1)実施例65の工程4に準じ、実施例82の工程3で得られた1-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロロピロリジン-1-イル)プロパ-2-エン-1-オン10mgと5-フルオロベンゾ[d]オキサゾール-2-アミン4.8mgから表題化合物を白色固体として4.09mg得た。
(工程1)実施例65の工程4に準じ、実施例82の工程3で得られた1-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロロピロリジン-1-イル)プロパ-2-エン-1-オン10mgと5-クロロベンゾ[d]オキサゾール-2-アミン5.2mgから表題化合物を白色固体として3.47mg得た。
(工程1)tert-ブチル (3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)プロピル)カルボキシレートの合成
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン200mgとtert-ブチル (3-ブロモプロピル)カルボキシレート273mgから表題化合物の淡黄色固体を223mg得た。
実施例65の工程3に準じ、工程1で得られたtert-ブチル (3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)プロピル)カルボキシレート240mgから表題化合物の淡黄色固体125mgを得た。
実施例65の工程4に準じ、工程3で得られたN-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)プロピル)アクリルアミド10mgから表題化合物の白色固体を3.2mg得た。
(工程1)tert-ブチル (2-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)エチル)カルボキシレートの合成
合成例3(工程2)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン200mgとtert-ブチル (2-ブロモエチル)カルボキシレート257mgから表題化合物の淡黄色固体を239mg得た。
実施例65の工程3に準じ、工程1で得られたtert-ブチル(2-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)エチル)カルボキシレート239mgから表題化合物の淡黄色固体140mgを得た。
実施例65の工程4に準じ、工程2で得られたN-(2-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)エチル)アクリルアミド10mgから表題化合物の白色固体を1.8mg得た。
国際公開WO2008/121742号パンフレットの方法に準じて合成し、表題化合物を白色固体として得た。
BTKキナーゼ活性に対する化合物のインビトロでの阻害活性測定法の条件設定において、パーキンエルマー社のLabChip(登録商標)シリーズ試薬消耗品価格表にFL-Peptide 2がBTKキナーゼ活性測定において基質ペプチドとして対応していることが記載されていたので、FL-Peptide 2を基質に用いた。試験に用いた精製リコンビナントヒトBTK蛋白質はカルナバイオサイエンス社から購入した。
化合物の阻害活性測定においては、まず、本発明化合物をジメチルスルホキシド(DMSO)で段階希釈した。次に、キナーゼ反応用緩衝液(20mM HEPES(pH 7.5)、2mM dithiotheitol、0.01% Triton X-100)中にBTK蛋白質、基質ペプチド(終濃度は1uM)、塩化マグネシウム(終濃度は10mM)、ATP(終濃度は45uM)と本発明化合物DMSO溶液(DMSOの終濃度は5%)を加えて25℃で40分間インキュベーションしキナーゼ反応を行った。そこへ終濃度30mMになるようEDTAを加えることで反応を停止させた。最後に、LabChip EZ Reader II(パーキンエルマー社)でリン酸化されなかった基質ペプチド(S)とリン酸化されたペプチド(P)をマイクロ流路キャピラリー電気泳動によって分離・検出した。SとPそれぞれのピークの高さからリン酸化反応量を求め、リン酸化反応を50%抑制することのできる化合物濃度をIC50値(nM)と定義し以下の表に示した。
1)BTK阻害活性測定
試験例1と同様にして、BTK阻害活性測定を測定した。
2)EGFR阻害活性測定
EGFRキナーゼ活性に対する化合物のインビトロでの阻害活性測定法の条件設定において、パーキンエルマー社のLabChip(登録商標)シリーズ試薬消耗品価格表にFL-Peptide 22がEGFRキナーゼ活性測定において基質ペプチドとして対応していることが記載されていたので、そのアミノ酸配列を参考にしてビオチン化ペプチド(biotin-EEPLYWSFPAKKK)を作製した。試験に用いた精製リコンビナントヒトEGFR蛋白質はカルナバイオサイエンス社から購入した。
化合物の阻害活性測定においては、まず、本発明化合物をジメチルスルホキシド(DMSO)で段階希釈した。次に、キナーゼ反応用緩衝液(20mM HEPES(pH 7.5)、2mM dithiotheitol、0.01% Triton X-100)中にEGFR蛋白質、基質ペプチド(終濃度は250nM)、塩化マグネシウム(終濃度は10mM)、塩化マンガン(終濃度は10mM)、ATP(終濃度は1.5uM)と本発明化合物DMSO溶液(DMSOの終濃度は2.5%)を加えて25℃で120分間インキュベーションしキナーゼ反応を行った。そこへ終濃度24mMになるようEDTAを加えることで反応を停止させた後、Euラベル化抗リン酸化チロシン抗体PT66(パーキンエルマー社)とSureLight APC-SA(パーキンエルマー社)を含む検出液を添加し室温で2時間以上静置した。最後に、PHERAstar FS(BMG LABTECH社)で波長337nmの励起光照射時における蛍光量を620nmと665nmの二波長で測定した。二波長の蛍光量比からリン酸化反応量を求め、リン酸化反応を50%抑制することのできる化合物濃度をIC50値(nM)と定義した。
3)BTK阻害選択性
上記1)及び2)で得られた結果をもとに、「EGFR阻害活性 IC50値(nM)/BTK阻害活性 IC50値(nM)」を算出することにより、被検化合物のBTK阻害選択性を確認した。
BTKを発現しているびまん性大細胞型B細胞性リンパ腫株であるTMD8細胞は、10%ウシ胎児血清を含むRPMI1640培地(ライフテクノロジーズ社製)中に懸濁させた。EGFR過剰発現・高活性化ヒト類上皮癌細胞株であるA431細胞は、10%ウシ胎児血清を含むDMEM、high glucose培地(ライフテクノロジーズ社製)中に懸濁させた。細胞懸濁液を、384ウェル平底マイクロプレートの各ウェルに播種し、5%炭酸ガス含有の培養器中37℃で1日培養した。本発明化合物、および比較例化合物1をDMSOに溶解し、DMSOを用いて被検化合物を終濃度の500倍の濃度になるように希釈した。被検化合物のDMSO溶液を各細胞の懸濁に用いた培地で希釈し、これを細胞の培養プレートの各ウェルにDMSOの最終濃度が0.2%になるように加え、5%炭酸ガス含有の培養器中37℃でさらに3日培養した。化合物添加前および化合物存在下での3日間培養後の細胞数計測はセルタイターグロ(プロメガ社製)を用いて、プロメガ社の推奨するプロトコールに基づき行った。以下の式より増殖阻害率を算出し、50%阻害する被検化合物の濃度(GI50(nM))を求めた。
増殖阻害率(%)=(C-T)/(C-C0)×100
T:被検化合物を添加したウェルの発光強度
C:被検化合物を添加しなかったウェルの発光強度
C0:被検化合物添加前に測定したウェルの発光強度
EGFR増殖シグナルに依存したA431細胞に対する細胞増殖抑制活性とBTKシグナルに増殖が依存したTMD8細胞に対する細胞増殖抑制活性を比較すれば、細胞レベルでのそれぞれのキナーゼの影響を評価することができる。すなわち「A431細胞増殖阻害率/TMD8細胞増殖阻害率」を算出しその値が大きいほど、細胞においてEGFRに対するBTKの選択性が高いと考えられる。表49及び表50に「A431細胞増殖阻害率/TMD8細胞増殖阻害率」の値を示した。
ヒトB細胞リンパ腫由来細胞株TMD8をSCIDマウスの皮下に移植し、生着した腫瘍の体積が100~200mm3になった時点で、各群の腫瘍体積が均一になるように、無作為層別化法により1群5匹に群分けし(1日目)、経口投薬を開始した。グループ1:比較例化合物1(100mg/kg)を1日1回経口投与、グループ2:本発明化合物(実施例化合物13)(50mg/kg)を1日1回経口投与、グループ3:本発明化合物(実施例化合物12)(50mg/kg)を1日1回経口投与、グループ4:本発明化合物(実施例化合物6)(50mg/kg)を1日1回経口投与した。薬剤投与における抗腫瘍効果を比較するため、腫瘍の増殖割合として群分け時の腫瘍体積を1とした相対腫瘍体積(RTV;Relative Tumor Volume)を以下の式に従って求めた。
BWC(%)=([(体重計測日のマウス体重)-(群分け時のマウス体重)]/(群分け時のマウス体重))×100
したがって、本発明化合物は比較例化合物1に比べて低用量で優れた抗腫瘍効果を示し、かつ、安全性が高い化合物であることが明らかとなった。
比較例化合物1及び本発明化合物を用いて二週間反復投与によるSDラットの体重増加への影響を溶媒投与群と比較した。各群の平均体重がほぼ均一になるように、無作為層別化法により各群4匹として以下のように群分けした(一日目)。
グループ1:比較例化合物1(280mg/kg)を1日1回経口投与、グループ2:本発明化合物(実施例化合物12)(750mg/kg)を1日1回経口投与、グループ3:本発明化合物(実施例化合物13)(750mg/kg)を1日1回経口投与した。
薬剤投与による全身毒性を表す指標として、体重変化率(BWC;Body Weight Change)を使用した。BWCは、以下の式に従って算出した。
相対体重変化率(%)=(化合物投与群のBWC)/(溶媒投与群のBWC)×100
ヒトB細胞リンパ腫由来細胞株Ramosを10%ウシ血清含有RPMI1640培地で懸濁後、2.0×106(cells/well)濃度で培養プレートに播種し、24時間37℃のCO2インキュベーター(SANYO)内で培養した。実施例化合物P-1または比較例化合物1の蛍光ラベル化合物(PCI-33380、非特許文献2)(10mMストック)をDMSOでそれぞれ希釈し、細胞を播種したプレートに添加し、1時間CO2インキュベーター内で培養した。その後、蛍光ラベル化合物(10mMストック)をDMSOにて2mMに希釈し、各ウェルに添加し、さらに1時間CO2インキュベーター内で培養した。その後、細胞を回収し、細胞ペレットに50μl(1×プロテアーゼ阻害剤(Roche)、1×フォスフォターゼカクテル阻害剤(Sigma)を含む細胞抽出液(NP-40;Invitrogen))を添加し、10分氷上で静置した。回収した細胞抽出液中のタンパク量をDC protein assay(Biorad)にて定量し、レーンあたり20ugのタンパクをSDS-濃度勾配ゲル(4-20%)(和光純薬)にアプライし、泳動後、Molecular Dynamics Typhoon Scanner(GEヘルスケア)を使用して泳動ゲルの画像を取り込んだ。その後、i-Blot(Invitrogen)を用いてウエスタンブロットを実施し、BTK抗体(Abcam)を用いてLAS4000(GEヘルスケア)にてBTKタンパクを検出した(図1)。
Claims (16)
- 下記一般式(I)
nは、0から2の整数を示し;
mは、1から4の整数を示し;
Xは、置換基を有しても良い含窒素C3-C10ヘテロシクロアルキレンを示し;
Yは、-C(R4)=C(R5)(R6)、又は-C≡C-R7を示し;
W及びZは、各々独立してN又はCHを示し;
R1は、置換基を有しても良いアミノ基を示し;
R2及びR3は、同一又は相異なって、水素原子、ハロゲン原子、置換基を有しても良いC1-C6アルキル基、置換基を有しても良いC1-C6アルコキシ基、置換基を有しても良いC3-C7シクロアルキル基、置換基を有しても良いC6-C14芳香族炭化水素基、置換基を有しても良く、窒素原子、酸素原子及び硫黄原子から選択される同種若しくは異種のヘテロ原子を1~3個含む4~10員の単環式若しくは多環式の不飽和複素環式基、又はシアノ基を示し;
R4、R5、R6及びR7は、同一又は相異なって、水素原子、又は置換基を有しても良いC1-C6アルキル基を示す。)で表される化合物又はその塩。 - 一般式(I)中、
Aが-(CH2)n-X-であり;
nが0であり;
Xが含窒素C3-C10ヘテロシクロアルキレンであり;
R1がアミノ基である、請求項1記載の化合物又はその塩。 - 一般式(I)中、
Aが-(CH2)n-X-であり;
nが0であり;
Xがアゼチジニレン、ピロリジニレン、又はピペリジニレンであり;
R1がアミノ基である、請求項1又は2記載の化合物又はその塩。 - 一般式(I)中、
Aが-(CH2)n-X-であり;
nが0であり;
Xが、アゼチジニレン、ピロリジニレン、又はピペリジニレンであり;
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はC1-C6アルキル基であり、他方が水素原子、ハロゲン原子、C1-C6アルキル基、ハロゲノC1-C6アルキル基、C1-C4アルコキシ置換C1-C6アルキル基、C1-C6アルコキシ基、ハロゲン原子で置換されていても良いフェニル基、硫黄原子を1個含む4~6員の単環式の不飽和複素環式基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5、及びR6が、同一又は相異なって、水素原子、C1-C6アルキル基、2個のC1-C6アルキル基で置換されたアミノ基で置換されているC1-C6アルキル基(C1-C6アルキル基はこれらが結合する窒素原子と共に4~8員環のヘテロシクロアルキル基を形成しても良い。)であり;
Yが-C≡C-R7である場合、
R7が、水素原子又はC1-C6アルキル基である、請求項1~3のいずれか記載の化合物又はその塩。 - 一般式(I)中、
Aが-(CH2)n-X-であり;
nが0であり;
Xが、1,3-アゼチジニレン、1,3-ピロリジニレン、又は1,3-ピペリジニレンであり;
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
ZがNのとき、WがNであり、ZがCHのとき、WがN又はCHであり;
R1がアミノ基であり;
R2及びR3の一方が、水素原子又はC1-C4アルキル基であり、他方が水素原子、ハロゲン原子、C1-C4アルキル基、ハロゲノC1-C4アルキル基、C1-C4アルコキシ置換C1-C4アルキル基、C1-C4アルコキシ基、ハロゲン原子で置換されていても良いフェニル基、硫黄原子を1個含む4~6員の単環式の不飽和複素環式基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5、及びR6が、同一又は相異なって、水素原子、C1-C6アルキル基、2個のC1-C6アルキル基で置換されたアミノ基で置換されているC1-C6アルキル基(C1-C6アルキル基はこれらが結合する窒素原子と共に4~8員環のヘテロシクロアルキル基を形成しても良い。)であり;
Yが-C≡C-R7である場合、
R7が、水素原子又はC1-C4アルキル基である、請求項1~4のいずれか記載の化合物又はその塩。 - 一般式(I)中、
Aが-(CH2)n-X-であり;
nが0であり;
Xが、1,3-アゼチジニレン、1,3-ピロリジニレン、又は1,3-ピペリジニレンであり;
Yが、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
ZがNのとき、WがNであり、ZがCHのとき、WがN又はCHであり;
R1がアミノ基であり;
R2及びR3の一方が、水素原子又はメチル基であり、他方が水素原子、ハロゲン原子、メチル基、トリフルオロメチル基、メトキシエチル基、メトキシ基、フェニル基、4-クロロフェニル基、2-チエニル基、又はシアノ基であり;
Yが-C(R4)=C(R5)(R6)である場合、
R4、R5及びR6が、同一又は相異なって、水素原子、メチル基、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基、又は1-ピロリジニルメチル基であり;
Yが-C≡C-R7である場合、
R7がメチル基である、請求項1~5のいずれか記載の化合物又はその塩。 - 一般式(I)中、
Aが-(CH2)n-X-であり;
nが0であり;
R1がアミノ基であり;
R2及びR3の一方が水素原子又はメチル基であり、他方が水素原子、ハロゲン原子、トリフルオロメチル基、メトキシエチル基、フェニル基、2-チエニル基、又はシアノ基であり、
(1)ZがNで、WがNの場合、
Xが1,3-ピペリジニレンで、
Yがビニル基であり、
(2)ZがCHで、WがNの場合、
Xが1,3-ピロリジニレン、又は1,3-ピペリジニレンで、
Yが-C(R4)=C(R5)(R6)、又は-C≡C-(R7)で、
Yが-C(R4)=C(R5)(R6)の場合、
R4、R5及びR6が、同一又は相異なって、水素原子、メチル基、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基、又は1-ピロリジニルメチル基であり、
Yが-C≡C-(R7)の場合、
R7がメチル基であり、
(3)ZがCHで、WがCHの場合、
Xが1,3-アゼチジニレン、又は1,3-ピロリジニレンで、
Yが-C((R4)=C(R5)(R6)で、
R4、R5及びR6が、同一又は相異なって、水素原子、ジメチルアミノメチル基、メチルエチルアミノメチル基、ジエチルアミノメチル基、メチルイソプロピルアミノメチル基、1-ピペリジニルメチル基又は1-ピロリジニルメチル基である、請求項1~6のいずれか記載の化合物又はその塩。 - 一般式(I)中、
Aが-(CH2)n-X-であり;
nが0であり;
Xが1,3-ピペリジニレンであり;
Yがビニル基であり;
ZがCHであり;
WがNであり;
R1がアミノ基であり;
R2及びR3の一方が水素原子であり、他方が水素原子、ハロゲン原子、又はシアノ基である、請求項1~7のいずれか記載の化合物又はその塩。 - 次の(1)~(86)のいずれかに記載の化合物又はその塩。
(1)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(2)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-ブロモベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(3)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(4)(R)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-メタクリロイルピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(5)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(6)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-シアノベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(7)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-メトキシベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(8)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-(2-メトキシエチル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(9)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(オキサゾロ[4,5-b]ピリジン-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、)
(10)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(4-メチルベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(11)(R)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1-(1-メタクリロイルピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(12)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(13)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(14)(R,E)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1-(1-(ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(15)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(16)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-エチル(メチル)アミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(17)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-ジエチルアミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(18)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-イソプロピル(メチル)アミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(19)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ピロリジン-1-イル)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(20)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ピペリジン-1-イル)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(21)(R,E)-4-アミノ-N-(5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(22)(R)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1-(1-ブタ-2-イノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(23)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(5,6-ジメチルベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(24)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(25)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(26)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(3-メチルブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(27)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(28)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-(チオフェン-2-イル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(29)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-メチルベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(30)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(31)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-(4-クロロフェニル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(32)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(33)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-エチル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(34)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-ジエチルアミノ)ブタ-2-エノイル)ピペリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(35)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-イソプロピル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(36)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ピロリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(37)(R,E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ピペリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(38)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-メトキシベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(39)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-シアノベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(40)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-(2-メトキシエチル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(41)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(42)(R,E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(43)(R)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-(トリフルオロメチル)ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(44)(R,E)-4-アミノ-N-(5-(トリフルオロメチル)ベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(45)1-(1-アクリロイルアゼチジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド、
(46)7-(1-アクリロイルアゼチジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(47)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)アゼチジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(48)(R)-7-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(49)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(50)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(エチル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(51)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジエチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(52)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(イソプロピル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(53)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ピロリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(54)(E)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ピぺリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(55)(R)-7-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(56)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(57)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(エチル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(58)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ジエチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(59)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(イソプロピル(メチル)アミノ)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(60)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ピロリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド、
(61)(E)-4-アミノ-N-(5-フェニルベンゾ[d]オキサゾール-2-イル)-7-(1-(4-(ピぺリジン-1-イル)ブタ-2-エノイル)ピロリジン-3-イル)7H-ピロロ[2,3-d]ピリミジン-5-カルボキサミド
(64)(R)-1-(1-アクリロイルピペリジン-3-イル)-4-アミノ-N-(7-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(65)(S)-1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(66)1-((1-アクリロイルピロリジン-3-イル)メチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(67)1-((1-アクリロイルピペリジン-3-イル)メチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(68)1-((1-アクリロイルピペリジン-4-イル)メチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(69)1-(1-アクリロイルピペリジン-4-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(70)1-((1-アクリロイルアゼチジン-3-イル)メチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(71)1-((1S,4S)-4-アクリルアミドシクロヘキシル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(72)1-((1R,4R)-4-アクリルアミドシクロヘキシル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(73)(S、E)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(74)1-(1-アクリロイルアゼチジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(75)1-((1-アクリロイルアゼチジン-3-イル)メチル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(76)1-((1-アクリロイルアゼチジン-3-イル)メチル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(77)1-((1-アクリロイルピペリジン-4-イル)メチル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(78)1-((1S,4S)-4-アクリルアミドシクロヘキシル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(79)1-(1-アクリロイルアゼチジン-3-イル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(80)1-((1-アクリロイルピペリジン-4-イル)メチル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(81)1-((1S,4S)-4-アクリルアミドシクロヘキシル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(82)1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(83)1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-フルオロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(84)1-(1-アクリロイルピロリジン-3-イル)-4-アミノ-N-(5-クロロベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(85)1-(3-アクリルアミドプロピル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド
(86)1-(2-アクリルアミドエチル)-4-アミノ-N-(ベンゾ[d]オキサゾール-2-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-カルボキサミド - 請求項1~9のいずれか1項記載の化合物又はその塩、検出可能なラベルまたは親和性タグ、及びリンカーを備えるプローブであって、前記リンカーは前記化合物と前記ラベル又はタグをつないでいるプローブ。
- 請求項1~9のいずれか1項記載の化合物又はその塩を有効成分とするBTK阻害剤。
- 請求項1~9のいずれか1項記載の化合物又はその塩を含有する医薬組成物。
- 請求項1~9のいずれか1項記載の化合物又はその塩を有効成分とする抗腫瘍剤。
- 腫瘍治療のための請求項1~9のいずれか1項記載の化合物又はその塩。
- 抗腫瘍剤製造のための、請求項1~9のいずれか1項記載の化合物又はその塩。
- 請求項1~9のいずれか1項記載の化合物又はその塩を投与することを特徴とする腫瘍の治療方法。
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EP14836782.4A EP2947086B1 (en) | 2013-08-12 | 2014-08-11 | Novel fused pyrimidine compound or salt thereof |
RU2015156524A RU2666349C2 (ru) | 2013-08-12 | 2014-08-11 | Новое конденсированное пиримидиновое соединение или его соль |
KR1020167003396A KR101828187B1 (ko) | 2013-08-12 | 2014-08-11 | 신규 축합 피리미딘 화합물 또는 그 염 |
ES14836782.4T ES2661733T3 (es) | 2013-08-12 | 2014-08-11 | Compuesto de pirimidina condensado novedoso o sal del mismo |
CN201480043405.1A CN105452257B (zh) | 2013-08-12 | 2014-08-11 | 新型稠合嘧啶化合物或其盐 |
PL14836782T PL2947086T3 (pl) | 2013-08-12 | 2014-08-11 | Nowy skondensowany związek pirymidynowy lub jego sól |
CA2921208A CA2921208C (en) | 2013-08-12 | 2014-08-11 | Fused pyrimidine compound or salt thereof |
AU2014307437A AU2014307437B2 (en) | 2013-08-12 | 2014-08-11 | Novel fused pyrimidine compound or salt thereof |
JP2015531804A JP6035423B2 (ja) | 2013-08-12 | 2014-08-11 | 新規な縮合ピリミジン化合物又はその塩 |
DK14836782.4T DK2947086T3 (en) | 2013-08-12 | 2014-08-11 | UNKNOWN CONDENSED PYRIMIDINE COMPOUND OR SALT THEREOF |
NO14836782A NO2947086T3 (ja) | 2013-08-12 | 2014-08-11 | |
MX2016001845A MX360498B (es) | 2013-08-12 | 2014-08-11 | Compuesto novedoso de pirimidina fusionada o sal del mismo. |
US14/784,239 US9580432B2 (en) | 2013-08-12 | 2014-08-11 | Fused pyrimidine compound or salt thereof |
BR112016002069-3A BR112016002069B1 (pt) | 2013-08-12 | 2014-08-11 | Composto de pirimidina fusionada ou sal deste, sonda, inibidor de btk, agente antitumor e composição farmacêutica compreendendo dito composto e usos terapêuticos do mesmo |
SG11201600048VA SG11201600048VA (en) | 2013-08-12 | 2014-08-11 | Novel fused pyrimidine compound or salt thereof |
PH12015502737A PH12015502737A1 (en) | 2013-08-12 | 2015-12-07 | Novel fused pyrimidine compound or salt thereof |
HK16105780.5A HK1217703A1 (zh) | 2013-08-12 | 2016-05-20 | 新型稠合嘧啶化合物或其鹽 |
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EP (1) | EP2947086B1 (ja) |
JP (1) | JP6035423B2 (ja) |
KR (1) | KR101828187B1 (ja) |
CN (1) | CN105452257B (ja) |
AU (1) | AU2014307437B2 (ja) |
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WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
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